Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis

1 Overview

Summary and Quick Facts

  • Idiopathic pulmonary fibrosis (IPF) is a chronic and progressively worsening lung disease in which the lungs become damaged and scarred. Although there is no known cure for IPF, treatments and therapies exist to slow the progression of the disease.
  • This protocol reviews how IPF is diagnosed and effective techniques for managing symptoms. Some intriguing emerging therapies are summarized, as well.
  • Combined with symptom management, the novel therapies and supplements described in this protocol may help slow the progression of IPF and improve overall quality of life.
  • Supplements such as N-acetylcysteine (NAC) and omega-3 fatty acids from fish oil may benefit people with IPF.

What is Idiopathic Pulmonary Fibrosis (IPF)?

Idiopathic pulmonary fibrosis (IPF) is the chronic and progressively worsening scarring (fibrosis) of lung tissue. The cause of this fibrosis is not known (idiopathic). The lung tissue stiffens, making it increasingly difficult for those with IPF to breathe. IPF is generally irreversible and eventually leads to fatal respiratory failure.

Unfortunately, there are currently no cure for IPF. Treatments are available that can slow the progression of the disease, and lung transplants may extend life expectancy. There are, however, many recent advances in our understanding of the disease and exploration of treatment options that give cause for optimism.

There are also emerging and natural integrative interventions like N-acetylcysteine, omega-3 fatty acids and senolytics such as quercetin, which are being explored for their anti-fibrotic and anti-inflammatory effects.

What Increases IPF Risk?

  • Genetic predisposition
  • Environmental exposure to factors such as cigarette smoke, metal or wood dust, and sand
  • Gastroesophageal reflux
  • Certain viral infections such as hepatitis C and human herpes virus-8
  • Age

What are the Signs and Symptoms of IPF?

  • Shortness of breath that worsens over time
  • Dry cough
  • Difficult or painful breathing
  • Fatigue
  • Weight loss
  • Anxiety and depression
  • “Crackling” sound in the lungs that can be heard with a stethoscope

What Treatments are Available for IPF?

  • Pulmonary rehabilitation, including exercise and education
  • Oral corticosteroids to inhibit cough
  • Psychological counseling after diagnosis
  • Antifibrotic agents such as pirfenidone and nintedanib
  • Lung transplant (uncommon for patients with IPF)

Note: Conventional treatments for IPF are generally palliative and aim to alleviate symptoms and possibly slow disease progression. Only lung transplants have been shown to increase survival time.

What Novel and Emerging IPF Therapies Appear Promising?

  • Mesenchymal stem cells to aid in repairing damaged lung tissue
  • Senolytics such as quercetin to help clear inflammatory senescent cells
  • Pentoxifylline, a drug generally used to improve vascular health, which has antifibrotic and anti-inflammatory activity
  • Antibodies against connective tissue growth factor to prevent fibrosis
  • Leukotriene antagonists to decrease inflammation
  • Lysophosphatidic acid (LPA) pathway inhibitors to prevent recruitment of fibroblasts
  • mTOR inhibitors such as rapamycin to decrease signaling in fibroblasts, as increased mTOR signaling may accelerate fibrosis
  • Proton pump inhibitors (PPIs) to treat accompanying gastroesophageal reflux. PPIs have also been associated with slower IPF progression
  • Metformin, an anti-diabetes drug, to decrease inflammation
  • Glucagon-like peptide-1, a signaling protein that can inhibit inflammation in pulmonary fibrosis

What Natural Interventions May Be Beneficial for IPF?

  • N-acetylcysteine (NAC). NAC has reduced oxidative stress and inflammation and prevented fibrosis in animal models of IFP. Genetic variations may play a part in the varying effectiveness of NAC to treat IPF in humans.
  • Niacin and taurine. The combination of niacin (vitamin B3) and taurine has been shown in preclinical research to inhibit the activities of pro-fibrotic inflammatory molecules.
  • Omega-3 fatty acids. Several animal studies have shown that omega-3 fatty acids could protect against experimentally induced IPF-like conditions.
  • Dehydroepiandrosterone (DHEA). DHEA, an endogenous androgen hormone, decreases with age and appears to be significantly lower in those with IPF. DHEA inhibited lung fibroblast proliferation in a laboratory setting as well.
  • Vitamin D. Chronic vitamin D deficiency in laboratory animals has been shown to promote fibrosis in lung tissue. Supplementation with vitamin D also decreased toxin-induced pulmonary fibrosis in mice.
  • Polyphenols. Certain plant compounds including curcumin,quercetin, resveratrol,epigallocatechin gallate (EGCG), and citrus flavonoids have demonstrated the ability to reduce fibrosis in animal models of IPF.
  • Phytochemicals. Other plant compounds including glycyrrhizic acid and ginsenoside Rg1 have shown promise in preventing or reversing pulmonary fibrosis in animal models of IPF.

Note: Most of the current research on natural interventions for IPF are animal or in vitro studies. However, based on the current understanding of IPF’s underlying mechanisms, these integrative therapies are of interest and may prove to be beneficial to those with IPF, although randomized controlled trials involving human subjects are urgently needed.

2 Introduction

Idiopathic pulmonary fibrosis (IPF) is a lung disease marked by chronic and progressively worsening scarring (fibrosis) for which a cause is not known (idiopathic). Lung tissue surrounding the lungs' air sacs becomes fibrous and stiff, interfering with their normal movement and gas exchange and making it increasingly difficult for patients with IPF to breathe (Plantier 2018).

IPF is considered irreversible and eventually leads to fatal respiratory failure, typically within three to five years of diagnosis (Tzilas 2017), but some patients experience more rapid disease progression (Lindell 2017). There are approximately 128,000 new cases of IPF and more than 16,000 IPF-related deaths in the United States each year (Murtha 2017; Lindell 2017).

Although the cause of IPF is not precisely understood, it is currently thought to stem from the inability of cells that line lung alveoli to regenerate after repeated injury. In addition to environmental factors that cause repeated micro-injury to the alveolar lining, a genetic predisposition is thought to be involved (Frangogiannis 2016; Sgalla 2018). Aging plays a fundamental role in increasing susceptibility to both alveolar injury and dysfunctional pro-fibrotic signaling and is a major risk factor for IPF (Zank 2018).

The main symptoms of IPF are shortness of breath and cough, which gradually worsen over several years (Ferrara 2018). Computed tomography (CT) scan and lung biopsy show a pattern of fibrosis that indicates likely IPF, but a diagnosis is only secured after a rigorous search for other causes has yielded no results (Sgalla 2018).

IPF treatment is evolving along with understanding of its underlying mechanisms. New anti-fibrotic drugs—pirfenidone (Esbriet) and nintedanib (Ofev)—recently received approval for use in patients with IPF (Sharif 2017; Sathiyamoorthy 2017). Along with medications that reduce inflammation and oxidative stress, they represent the current best options in conventional treatment; unfortunately, medical approaches pose significant adverse side effects, and none have yet been shown to prolong life (Sgalla 2018). Lung transplant is the only treatment that increases the odds of survival, but is nonetheless associated with a high mortality rate and is only appropriate in select cases (Kistler 2014).

Although IPF is always progressive, new understandings about mechanisms and recent advances in diagnosis and treatment are reasons for optimism (Sgalla 2018). Emerging technologies may lead to earlier diagnosis and more rapid initiation of appropriate therapy (Tzilas 2017; Drakopanagiotakis 2018; Fois 2018). Novel treatment approaches such as mesenchymal stem cell therapy (Glassberg 2017) and the use of senolytics (ie, agents that trigger degradation of aged, dysfunctional cells) are topics of current research (Kirkland 2017). Also, the drug pentoxifylline has demonstrated some anti-fibrotic properties in animal models of pulmonary fibrosis and represents an interesting area of ongoing research (Entzian, Schlaak 1997; Kaya 2014; Naranjo 2011; Lee 2017). Proton-pump inhibitors (PPIs), usually used to treat gastroesophageal reflux, are of interest in IPF research as well. Some studies have found that they have anti-fibrotic properties, and that IPF patients even without GERD symptoms often have elevated esophageal acid levels (Lee 2011; Raghu 2006).

Nutritional and herbal supplements that reduce inflammation, inhibit oxidative lung damage, and ameliorate age-related cellular dysfunction have shown promising anti-fibrotic effects in preclinical research related to IPF. These include N-acetylcysteine (Myllarniemi 2015); omega-3 fatty acids (Zhao 2014); niacin (Nagai 1994); sulfur compounds from cruciferous and onion-family vegetables (Mojiri-Forushani 2017; Yan 2017); and polyphenols such as quercetin, resveratrol, and curcumin (Impellizzeri 2015; Mojiri-Forushani 2017). Furthermore, evidence showing that some IPF patients have lower levels of the hormone dehydroepiandrosterone (DHEA) and demonstrating its anti-fibrotic potential in isolated lung cells suggests DHEA may be helpful in cases of IPF (Mendoza-Milla 2013).

3 Background

Fibrosis is a common feature in many chronic diseases and does not affect only the lungs—fibrosis can occur in every organ system. Such common conditions as atherosclerosis, chronic kidney disease, and fatty liver disease are fibrotic in nature. Because fibrosis interferes with normal tissue and organ function, it is an important contributor to organ failure (Kendall 2014; Vassiliadis 2013). It is estimated that fibrotic diseases account for 45% of deaths worldwide each year (Murtha 2017).

In IPF, the fibrotic process takes place in the interstitial tissues and spaces that surround and support the lungs' capillaries and air sacs (alveoli) (Murtha 2017). A similar pattern of interstitial lung scarring may be caused by radiation exposure, connective tissue diseases, certain medications, and inhaled irritants like asbestos, silica, and mold (Salvatore 2018); however, in IPF, the exact cause is not known (Plantier 2018).

The hallmark of fibrotic disease is overactive fibroblasts (ie, specialized cells found in connective tissue and interstitial spaces that form part of what is known as extracellular matrix). The extracellular matrix is made of collagen and other fibrous proteins, and provides structural support and cohesiveness to an organ's functioning cellular network. It also participates in intercellular communication. Fibroblasts play a critical role in wound healing and tissue repair, but in fibrotic diseases, an increase in their number and activity results in excessive production of extracellular matrix, leading to tissue stiffness and dysfunction (Murtha 2017; Kendall 2014; Frangogiannis 2016).

4 Causes and Risk Factors

It is currently widely accepted that IPF is the result of a combination of environmental and genetic predisposition to increased fibrotic activity, setting the stage for repeated micro-injuries to an aging alveolar lining and triggering dysfunctional signaling between the alveolar cells and fibroblasts (Fois 2018; Sgalla 2018). Certain environmental factors and exposures that can cause airway micro-injury have been associated with increased risk of IPF. These include (Desai 2018; Sgalla 2018; Sharif 2017):

  • Cigarette/tobacco smoke
  • Certain chronic viral infections
  • Gastroesophageal reflux
  • Metal dust
  • Wood dust
  • Agricultural dust (from animals and plants)
  • Sand
  • Wood smoke

Oxidative Stress

Increased oxidative stress is a major cause of micro-injuries triggering the fibrotic process in IPF (Day 2008; Fois 2018). The lungs are especially prone to oxidative stress, which is defined as an imbalance between free radical (oxidant) production and reducing (antioxidant) capacity. Inhaled pollutants increase the oxidant load in the lungs, and inflammatory activity initiated by cell injury can further add to the burden (Fois 2018). Although high levels of certain antioxidants, such as vitamins A, C, and E, were found to be present in fluid samples from the lungs of IPF patients, there appears to be an inability to restore oxidant/antioxidant balance and prevent oxidative injury in this condition (Markart 2009).

Aging

Aging is an important risk factor for IPF: most diagnoses are made in people aged 50 years and older, and the incidence increases with age (Sharif 2017). Age-related changes in the cells that line the airways appear to render them more vulnerable to injury and dysfunctional signaling. In addition, aging may alter fibroblast responsiveness, increasing the likelihood of excessive activation (Sgalla 2018; Kendall 2014).

Mitochondrial dysfunction, marked by decreased energy production in cells (Nicolson 2014), is seen in normal aging and may be an important contributor to IPF. Features of mitochondrial dysfunction, such as increased oxygen free radical production, reduced activation of the enzyme adenosine monophosphate-activated protein kinase (AMPK), and altered signaling via receptors known as mammalian target of rapamycin (mTOR), have been noted in fibroblasts and airway-lining cells from IPF-affected lungs and in animal models of IPF (Zank 2018). In fact, some compounds that inhibit mTOR have been shown to have a normalizing effect on fibroblast growth and activity in some preclinical studies of IPF (Lawrence 2018).

The Role of the Lung Microbiome

Until recently, the presence of microbes in the lungs was believed to be a sign of present or impending infection; however, it is now known that even healthy lungs harbor a distinct microbial community. This microbial community, or microbiome, plays a critical role in regulating immune cell signaling and function in the lungs. A shift in the lung microbiome composition toward a greater number of bacteria overall or the presence of more potentially harmful bacteria has been noted in IPF and has been associated with progression, acute flare-ups, and poor outcomes (Fastres 2017; Hewitt 2017). The mouth and gastrointestinal tract have been proposed as possible sources of bacteria that may contribute to IPF, a notion supported by the correlation between gastroesophageal reflux and increased risk of IPF (Desai 2018). In addition, certain viruses have also been frequently found in the lungs of IPF patients. These include Epstein-Bar virus, cytomegalovirus, hepatitis C virus, and human herpes virus-8 (Sgalla 2018). The effects of the presence of specific bacteria and viruses in the lung microbiome on IPF occurrence and progression remains an important topic of current investigation.

5 Diagnosis

Early diagnosis and initiation of treatment to slow the loss of lung function offers the best prognosis in IPF (Scelfo 2017). Most IPF patients are older men and their histories often include risk factors such as cigarette smoking, certain occupational exposures, or gastroesophageal reflux disease (Salvatore 2018). They typically describe experiencing shortness of breath that has gradually worsened over years, sometimes with periods of acute exacerbation. Other common symptoms include (Tzilas 2017; Scelfo 2017; Cottin 2015; Atkins 2016; Vainshelboim 2016):

  • Dry cough
  • Difficult breathing
  • Painful breathing
  • Fatigue
  • Weight loss
  • Weakness of respiratory and other muscles
  • Anxiety and depression

Physical exam will reveal crackles, a type of popping or "crackling" sound emanating from the lungs that can be heard with a stethoscope (Vyshedskiy 2012; Sarkar 2015). Clubbing, a deformity of the fingers and toes frequently associated with lung diseases, may be seen in as many as 50% of IPF cases (Tzilas 2017; Sarkar 2012; Magazine 2012). Pulmonary function tests usually, but not invariably, demonstrate restricted lung expansion (Salvatore 2018; Tzilas 2017). If the history and exam findings suggest fibrotic lung disease, other possible causes, such as medication toxicity, sclerotic diseases, sarcoidosis, and exposure to radiation, asbestos, silica, mold, or other known fibrosis triggers, need to be explored as part of achieving an accurate diagnosis and identifying an appropriate course of treatment (Tzilas 2017; Sharif 2017).

High-resolution computed tomography (CT) scan is the next diagnostic step in patients with suspected IPF. A fibrotic pattern known as usual interstitial pneumonia, with a characteristic honeycomb appearance, is an indication of interstitial scarring and, in the absence of another known cause, confirms the diagnosis of IPF without the need for a surgical lung biopsy (Salvatore 2018). If findings from high-resolution CT scan are inconclusive, a lung biopsy can be performed to make a certain diagnosis; however, because of its highly invasive nature, lung biopsy is generally reserved for those in whom a clear diagnosis is likely to affect treatment decisions and those deemed resilient enough to endure such a procedure (Tzilas 2017; Sharif 2017).

6 Conventional Treatment

Lung transplantation is the only option known to increase survival time in those with IPF, but is only performed in a minority of cases (Caminati 2017). Other treatment approaches are palliative and aim to alleviate symptoms, improve quality of life, manage acute exacerbations, and possibly slow disease progression. The best supportive care for an individual with IPF may include not only medication and disease monitoring but also physical therapies, occupational therapy, and counseling (Ferrara 2018; Scelfo 2017).

Symptom Management

Shortness of breath and cough are the main symptoms of IPF and contribute substantially to declining quality of life (Scelfo 2017; Ferrara 2018).

Comprehensive pulmonary rehabilitation, with exercise and educational components, is helpful in managing shortness of breath, increasing ability to exercise, and improving quality of life (Ferrara 2018; Shaw 2017; Caminati 2017). Oxygen administration during exertion may also be a consideration for those who only experience breathing difficulties with physical activity, but its optimal timing and dosage are still unclear (Ferrara 2018). Furthermore, oxygen therapy can interfere with mobility and psychosocial interactions, and may have an overall negative impact on quality of life (Shaw 2017).

Typical cough-suppressing medications are generally not effective for IPF-associated cough, but oral corticosteroids such as prednisone may be beneficial in some cases (Ferrara 2018; Shaw 2017). Gabapentin (Neurontin), an anti-seizure medication, has been shown to be beneficial in cases of neurologically induced cough and has been proposed as a possible option for treating IPF-related cough (Atreya 2016; Ferrara 2018; Goa 1993). Sedatives like opioid and benzodiazepine drugs may be helpful as palliative therapies in alleviating both cough and shortness of breath in the end stages of IPF (Ferrara 2018; Shaw 2017).

Weight loss may be due to decreased appetite, increased energy demands of labored breathing, or gastrointestinal side effects of medications. The possibility of extra nutritional demands and the use of supplemental nutrition should be explored in cases involving substantial weight loss (Ferrara 2018).

Patients with IPF frequently suffer from anxiety and depression, which can contribute independently to a reduced quality of life. Anxiety and depression are closely correlated with breathlessness and disease severity, and the progressive nature of the disease can affect emotional well-being of the patients; treatment of anxiety and depression have to be addressed as soon as problems appear. In addition, antidepressant medications may be helpful in some cases (Ferrara 2018; Shaw 2017). Perhaps most importantly, psychological counseling should be offered soon after diagnosis (Shaw 2017; Lindell 2017). The importance of supporting patients' emotional well-being is often overlooked. IPF patients and their caregivers need guidance in understanding the condition's prognosis (Scelfo 2017; Lindell 2017; Caminati 2017).

Vaccination against influenza and pneumonia is important for IPF patients as well (National Heart, Lung, and Blood Institute 2018).

Antifibrotic Therapies

Effective treatments for IPF have historically been elusive. Despite the role of inflammation in triggering fibrotic activity, anti-inflammatory approaches have been consistently ineffective (Sgalla 2018). Two anti-fibrotic agents—pirfenidone (Esbriet) and nintedanib (Ofev)—were approved in 2014 based on evidence of benefits in treating IPF (Sharif 2017; Scelfo 2017; Bando 2016; McCormack 2015). Both drugs may slow disease progression, but do not completely stop or reverse the underlying disease processes.

  • Pirfenidone. Although the exact mechanism of action is still uncertain, pirfenidone inhibits fibroblast and collagen synthesis. It also has anti-inflammatory and oxidative stress-reducing activities that may contribute to its benefits (Sgalla 2018). Findings from several randomized placebo-controlled trials suggest pirfenidone may slow disease progression (Azuma 2005; Taniguchi 2010; Noble 2011). In an uncontrolled trial, subjects from a previous trial who had received placebo were subsequently treated with pirfenidone and reported positive findings (Costabel 2014).
  • Nintedanib. Nintedanib inhibits enzymes in the tyrosine kinase family that are involved in the formation of fibrotic tissue in the lungs (Sgalla 2018). In a clinical study in which 62 IPF patients used nintedanib in a compassionate use program, the drug stabilized IPF progression in 63% of patients after six months (Bonella 2016).

The most frequent and important adverse side effects of these medications are gastrointestinal in nature, including indigestion, nausea, and diarrhea; in addition, pirfenidone use can cause light sensitivity (Jiang 2012; Margaritopoulos 2016; Hughes 2016). The available data so far does not favor one over the other in terms of efficacy or safety, but does suggest that treatment with either agent may be more helpful if started early (Scelfo 2017). The potential advantage of using pirfenidone and nintedanib together is currently under investigation (Sgalla 2018).

Lung Transplant

A lung transplant may increase survival time and is an important option in appropriate patients with moderate-to-advanced IPF (Sharif 2017; Kistler 2014). Nonetheless, post-transplant survival in IPF is lower than in other pulmonary diseases, at approximately 75% at one year, 59% at two years, 47% at five years, and 24% at 10 years (Kistler 2014). In addition, despite being the most common condition represented on waiting lists for lung transplant, fewer than 20% of patients with IPF receive a lung transplant, reflecting the long waiting lists and high rate of death among IPF patients on them (Caminati 2017; Lindell 2017).

Treatment of Related Conditions

IPF patients frequently suffer from other chronic conditions. Emphysema, lung cancer, pulmonary hypertension, sleep apnea, gastroesophageal reflux, and coronary artery disease are among the most common co-occurring conditions (Scelfo 2017). Medical management of these co-occurring conditions may have a positive impact on the course of IPF. For example, in IPF patients with sleep apnea, treatment with continuous positive airway pressure (CPAP) appears to improve sleep and quality of life (Mermigkis 2015). Observational evidence suggests proton pump inhibitor treatment for those with gastroesophageal reflux may slow IPF progression and increase survival time, and some research findings suggest they may even be helpful in IPF patients without evidence of gastroesophageal reflux (Ghebre 2016). The use of bronchodilators may be helpful in those with combined IPF and emphysema, but their impact on symptoms and prognosis have not yet been established (Sgalla 2018; Zhang 2016).

Pulmonary hypertension is a frequent finding and contributor to symptoms and mortality in patients with IPF. It may occur as a result of fibrosis in pulmonary vessels or blood vessel constriction in response to low oxygen levels. Sildenafil (Viagra) is a blood vessel dilator with an effect on pulmonary vessels. Findings from some, but not all, studies suggest sildenafil has a positive impact on breathlessness, ability to exercise, and quality of life in IPF patients with pulmonary hypertension (Han 2013; Zisman 2010; Jackson 2010; Collard 2007).

Management of Acute Exacerbation

Sudden worsening of symptoms, or acute exacerbation, is a significant problem in IPF. It can be difficult to distinguish from infectious pneumonia and other respiratory problems and is a frequent cause of fatal respiratory failure. An accurate assessment will guide therapy. Management of acute exacerbation typically involves mechanical ventilation, intravenous fluids, high-dose steroids, morphine, and antibiotics as appropriate (Scelfo 2017).

7 Novel and Emerging Interventions

While the availability of high-resolution CT scans and addition of anti-fibrotic drugs to the medication arsenal have changed the landscape of IPF diagnosis and management, they have had little impact on survival (Tzilas 2017). Therefore, the search for more effective treatments is ongoing.

Diagnostic Techniques

Bronchoscopic lung cryobiopsy is emerging as a possible alternative to surgical lung biopsy for diagnosis of interstitial fibrosis. In this technique, a tissue sample is retrieved during an incision-free procedure called bronchoscopy. The tissue sample is generally larger than in a conventional surgical lung biopsy, which increases the likelihood of finding the tissue features indicative of IPF (Scelfo 2017). Bronchoscopic lung cryobiopsy was found to be as useful as surgical biopsy for reaching a confident diagnosis of IPF in uncertain cases (Tomassetti 2016).

The identification of reliable biomarkers could prove valuable in making an early diagnosis, assessing severity, predicting prognosis, and monitoring progression and response to therapy in those with IPF (Drakopanagiotakis 2018). Matrix metalloproteinase-7 is the most widely studied IPF biomarker to date. Elevated blood levels of this enzyme have been helpful in distinguishing patients with IPF from some, but not all, other lung diseases that cause fibrosis (Tzilas 2017).

Mitochondrial DNA and the composition of the respiratory microbiome could provide clues regarding diagnosis and prognosis (Drakopanagiotakis 2018). It has further been proposed that genetic biomarkers as well as markers of oxidative stress have potential value in guiding therapeutic choices (Fois 2018). These and other types of biomarkers are current topics of research.

Therapeutic Advances

Mesenchymal stem cells. Mesenchymal stem cells are a type of stem cell with the capacity to produce a variety of cell types. They occur in many body tissues, such as bone marrow, adipose tissue, umbilical cord blood, or placental tissues. They have been shown to induce anti-inflammatory signaling, promote tissue regeneration and repair, and rescue dysfunctional cells by transferring functional mitochondria (Wecht 2016; Li, Yue 2017).

Mesenchymal stem cells are attracted to the sites of tissue injury; in IPF, mesenchymal stem cells travel to the injured airway lining where they may participate in repair activities (Wecht 2016; Li, Yue 2017). Studies in mice suggest the potential usefulness of mesenchymal stem cell therapy in IPF treatment (Li, Han 2017). In a rat model, injection of adipose-derived mesenchymal stem cells led to remission of silica-induced pulmonary fibrosis (Chen 2018). In a case report, intravenous infusions of mesenchymal stem cells led, a year later, to reduced need for oxygen therapy in an individual with emphysema and IPF (Zhang, Yin 2017). The safety of intravenous mesenchymal stem cells in IPF patients has been shown in phase I trials, paving the way for future clinical research (Chambers 2014; Glassberg 2017).

Senolytics. Senolytic compounds trigger the breakdown of senescent cells—aged and dysfunctional cells that have lost their sensitivity to cell-death signals. In this way, they have the potential to reverse one of the root causes of age-related tissue change and restore healthy tissue function (Kirkland 2017). Senolytics are of special interest in IPF because of the condition's close relationship with aging and cell senescence.

Both fibroblasts and cells from the alveolar lining from subjects with IPF show high levels of markers of senescence. Senescence in these two cell types and impaired signaling are important parts of the fibrotic process (Schafer 2017; Kuwano 2016; Yanai 2015). In addition, molecules secreted by senescent cells up-regulate inflammation, cause direct cellular damage, disrupt repair mechanisms involving stem cells, and even induce senescence in other cells, leading to widespread pulmonary dysfunction (Kirkland 2017).

Dasatinib (Sprycel), a chemotherapy drug and inhibitor of enzymes in the tyrosine kinase family, and quercetin, a flavonoid that is widely distributed in the plant world, were among the first agents to be identified as having senolytic potential (Zhu 2015). Treatment with the combination of dasatinib plus quercetin reduced markers of senescence and improved pulmonary function and physical health in an animal model of IPF (Lehmann 2017; Schafer 2017). The first clinical trial using dasatinib plus quercetin to target senescent cells in people with IPF was published in early 2019 (Justice 2019). In this open-label pilot trial, 14 participants over age 50 who had stable IPF were given dasatinib and quercetin intermittently for three weeks. They received oral dosages of 100 mg of dasatinib plus 1,250 mg of quercetin daily for three consecutive days per week for three consecutive weeks (for a total of nine days of treatment and 12 days of non-treatment in the 21-day period). Functional measures including distance walked in six minutes, gait speed during a four-minute walk, and the time it took participants to stand from sitting in a chair significantly improved. Changes in some markers of cellular senescence correlated with the improvements in physical function. Adverse events were primarily mild to moderate. This trial provides a basis for larger randomized controlled trials of senolytics in IPF and other senescence-related diseases.

Pentoxifylline. Pentoxifylline is a xanthine derivative and a drug that has been used for decades to improve vascular health. It has immunomodulatory and anti-fibrotic properties (Lopera 2015; McCarty 2016). It is also a suppressor of inflammation by several mechanisms, including the inhibition of TNF-alpha and IL-6, and one study reported that it resembles anti-inflammatory corticosteroids (Li, Tan 2016; Whitehouse 2004; Garcia 2015). Numerous preclinical studies, several of which are summarized here, have shown that pentoxifylline ameliorates fibrosis due to various diseases (Wen 2017). Nevertheless, pentoxifylline has not been studied extensively in people with IPF, so it is not clear whether the anti-fibrotic benefits of pentoxifylline observed in preclinical models and studies of fibrosis in patients due to other diseases will translate to meaningful benefits for IPF patients. Clinical trials of pentoxifylline on people with IPF are needed.

In a study on 43 patients with radiation-induced fibrosis of the skin and underlying tissues who had radiation therapy for head, neck, or breast cancers, oral pentoxifylline (800 mg/day) and vitamin E (1,000 IU/day) led to regression in the surface area of the lesions and a decrease in a score used to measure the extent of injuries (Delanian 1999). A phase II clinical trial, which enrolled 29 patients with radiation-induced fibrosis in the skin and underlying tissues, showed that pentoxifylline and vitamin E treatment for 3 months led to a 43% average decrease in the surface area of the lesions. A subgroup of patients treated for 6 months exhibited a 72% average lesion surface area regression. In this study, the response at 3 months was better in older patients (Haddad 2005).

Pentoxifylline and vitamin E were found to reduce fibrosis associated with breast cancer (which usually develops in the skin and underlying tissues) in patients undergoing radiotherapy (Kaidar-Person 2018). In a study on fluid that accumulated outside the lungs collected from patients with various non-cancerous diseases (such as congestive heart failure or tuberculosis), pentoxifylline inhibited the proliferation of fibroblasts and synthesis of collagen, and the authors concluded that it may offer a new approach to treat pulmonary fibrosis (Entzian, Schlaak 1997). A meta-analysis examined three randomized controlled trials that used pentoxifylline for oral submucous fibrosis, a condition characterized by fibrosis in the lining of the oral cavity. Both short- and long-term administration of pentoxifylline improved signs and symptoms, including maximal mouth opening, and the efficacy increased with time (Liu, Chen 2017).

Various animal and laboratory studies have observed anti-fibrotic effects of pentoxifylline:

  • In a laboratory model of schistosoma infection, a disease that causes liver fibrosis, pentoxifylline inhibited activation of cells involved in liver fibrosis (Li, Hua 2016).
  • In a laboratory model of radiation-induced fibrosis, pentoxifylline decreased collagen deposition in irradiated fibroblasts (Kumar 2018).
  • In a mouse model of a fungal disease that affects the lungs, early administration of pentoxifylline helped control disease progression by decreasing lung inflammation and collagen deposition in the lung (Lopera 2015).
  • The combination of pentoxifylline and alpha-tocopherol significantly reduced collagen deposition in rats with radiation-induced heart muscle fibrosis (Boerma 2008).
  • In a rat model of pulmonary fibrosis, oral pentoxifylline (at a dose equivalent to about 1,200 mg/day for an adult human) and intraperitoneal dl-alpha-tocopheryl acetate reduced fibrosis scores after 12 weeks, and the combination was better than either administered alone (Bese 2007).
  • In a rat model of radiation-induced lung fibrosis, pentoxifylline showed anti-fibrotic effects, possibly by modulating the expression of proteins involved in signaling pathways (Lee 2017).
  • In another study that examined a rat model of radiation-induced lung injury, the combination of vitamin E and pentoxifylline administered orally (into the animal feed) prevented lung fibrosis (Kaya 2014).
  • In a rat model of bleomycin-induced fibrosing alveolitis, pentoxifylline reduced the amount of proliferating cells in the lungs and the formation of reactive oxygen species (Entzian, Gerlach 1997).

Antibodies against connective tissue growth factor. Connective tissue growth factor promotes fibrosis in several situations, including radiation injury to the lung. A laboratory study on irradiated mice showed that pamrevlumab, an antibody against connective tissue growth factor, ameliorated radiation-induced lung injury and prolonged survival when compared with non-irradiated animals (Sternlicht 2018). In a study on a mouse model of radiation-induced lung fibrosis, this antibody prevented or reversed lung remodeling, improved lung function, and led to beneficial molecular changes (Bickelhaupt 2017). In a randomized, double-blind, placebo-controlled phase II clinical trial, IPF patients receiving pamrevlumab showed significantly less decline in lung function at 48 weeks compared to a control group (Eduard Gorina 2017).

Leukotriene antagonists. Leukotrienes, a group of inflammatory mediators, are increased locally in IPF, and are one of the more recent targets considered for anti-fibrotic therapies. (Castelino 2012; Gharaee-Kermani 2007; Failla 2006). In a mouse model of lung fibrotic injury, the inhibition of leukotrienes reduced fluid collection in the lungs and decreased inflammation and collagen deposition (Failla 2006). In another study on mice, a molecule that blocks the leukotriene B4 receptor prevented lung fibrosis induced by a toxic compound by decreasing inflammation and changing signaling through several signaling molecules (Izumo 2009). A randomized, placebo-controlled, phase II clinical trial is currently examining the use of a molecule that blocks a leukotriene receptor for its safety and efficacy in IPF patients (Aryal 2018).

Lysophosphatidic acid (LPA) pathway inhibitors. Lysophosphatidic acid (LPA) is small lipid molecule involved in various cellular functions, including the recruitment of fibroblasts. Increased levels of LPA and autotaxin, the enzyme that makes this molecule, were found in the lungs of patients with IPF. Therefore, inhibiting the autotaxin-LPA axis emerges as an attractive therapeutic strategy (Chu 2015; Aryal 2018). Several phase II clinical trials have generated positive results and showed that inhibitors of this pathway could help lung function in patients with IPF (Aryal 2018).

mTOR inhibitors/Rapamycin. Mammalian target of rapamycin, or mTOR, is an enzyme with an important and complex role in regulating key cellular activities affecting cellular metabolism, function, growth, proliferation, survival, and senescence. Excessive mTOR signaling has been linked to age-related immune dysfunction and cancer development, and has recently been implicated in fibrotic diseases, including IPF (Lawrence 2018). Fibroblasts from IPF-affected lungs demonstrate increased mTOR signaling, which may accelerate fibrosis in part by increasing proliferation and activity of fibroblasts, decreasing their sensitivity to normal down-regulating signals, and inactivating cell-death pathways (Lawrence 2018; Nho 2014; Patel 2012).

In early research using animal and laboratory models of pulmonary fibrosis, mTOR-inhibiting agents such as rapamycin have demonstrated anti-fibrotic effects (Shao 2015; Chang 2014; Patel 2012; Jin 2014). A single case report describes marked improvement in an individual with IPF treated with rapamycin (Buschhausen 2005). A clinical trial of the mTOR inhibitor GSK2126458 (Omipalisib) in IPF patients is currently underway. GSK2126458 is an anti-cancer drug that disables both mTOR and another related enzyme (Mercer 2016). However, in a randomized controlled trial in 89 subjects with IPF, treatment with the mTOR inhibitor everolimus (Afinitor) led to more rapid disease progression and a lower chance of survival after three years (Malouf 2011). In an ongoing double-blind, placebo-controlled, phase II clinical trial, rapamycin is being evaluated for its ability to decrease the number of circulating fibrocytes (Aryal 2018). Further research on outcomes associated with mTOR inhibition in IPF is urgently needed.

Proton pump inhibitors, or PPIs, block acid production in the stomach and are used to treat gastroesophageal reflux, a condition that may be more prevalent than it appears in those with IPF. In a study that looked at esophageal acidity in subjects with IPF, high acid levels were detected in 87% of cases, but fewer than half reported experiencing reflux symptoms (Raghu 2006). In an observational study, IPF patients using antacids for gastroesophageal reflux (mainly PPIs) had slower disease progression, fewer episodes of acute worsening, and longer survival time (Lee 2011). Other observational studies examining the relationship between PPI use and IPF survival time have had mixed findings (Lee 2016; Kreuter 2016).

Antacid use has been recommended in patients with IPF and co-existing gastroesophageal reflux, and in 2015, a conditional recommendation was expanded to include patients without gastroesophageal reflux based on a growing body of supportive research (Raghu 2015). Emerging evidence indicates that PPIs in particular may have positive effects beyond the stomach, such as free radical scavenging, improving the oxidant/antioxidant balance, reducing inflammation, and regulating immune function (Ghebre 2016). The PPI esomeprazole (Nexium) has been reported to improve alveolar cell function and inhibit proliferation and collagen production in lung fibroblasts from individuals with IPF; in addition, esomeprazole reduced lung inflammation and fibrosis in an animal model of IPF (Ghebremariam 2015). These findings highlight the need for future research to identify those most likely to benefit from PPI therapy.

Metformin. Metformin (Glucophage) is a commonly prescribed anti-diabetes medication that has also been shown to reduce oxidative stress, inflammation, and fibrosis (Nesti 2017; Ladeiras-Lopes 2015). Metformin has been found to reduce levels of inflammatory markers in both lung tissue and blood samples, lower oxidative stress, and inhibit lung fibrosis in animal models of IPF (Gamad 2018; Choi 2016; Sato 2016). In one study, metformin reversed established lung fibrosis in mice with an IPF-like condition apparently by activating the enzyme AMPK (Rangarajan 2018). AMPK regulates a number of cellular metabolic pathways, and decreased AMPK activity is associated with a wide range of age-related and fibrosis-linked health problems (Jiang, Li 2017).

Glucagon-like peptide-1. Glucagon-like peptide-1 is a signaling molecule involved in glucose regulation that has also been found to inhibit a key inflammatory protein involved in pulmonary fibrosis. In mice with experimentally induced pulmonary fibrosis, the administration of glucagon-like peptide-1 reduced pulmonary inflammation and fibrosis (Gou 2014; Liu, Gou 2017). In other animal research, the anti-diabetes drug vildagliptin (Galvus), which acts in part by inhibiting the breakdown of glucagon-like peptide-1, prevented fibrotic transformation in pulmonary blood vessel cells (Suzuki 2017). Clinical trials are needed to determine whether these benefits extend to humans with IPF.

Participating in a Clinical Trial

Clinical trials can give patients access to emerging and experimental treatments that are not yet approved or widely available, such as those described in the "Novel and Emerging Interventions" section of this protocol. For patients with IPF, participation in a clinical trial may be the only way to access such treatments. Your medical team can help you evaluate whether available clinical trials may be right for you and your situation.

Clinical trials meant to eventually lead to FDA-approved treatments are conducted in five phases (Institute of Medicine 2012; FDA 2018):

  • Phase 0 clinical trials are brief, small, preliminary trials intended to determine whether further clinical development should proceed.
  • Phase I clinical trials involve under 100 study subjects, last months to years, and test the safety of a drug.
  • About 70% of drugs then proceed to a phase II clinical trial. In this phase, researchers study a drug's effectiveness and continue to examine its safety and side effects, over months to up to two years, in up to a few hundred subjects.
  • Roughly one-third of drugs then enter phase III clinical trials which are conducted in hundreds to thousands of participants, and last from one to four years. Phase III trials more fully explore the risks, benefits, and efficacy of new treatments, and provide the most robust safety data of the four phases.
  • Phase IV trials are conducted on already-approved treatments and are thus sometimes known as "post-market" studies. This phase continues to collect and refine data on risks, benefits, safety, and efficacy.

Participation in a trial does have risks, including unexpected side effects, and undergoing an experimental treatment may not be effective. Benefits to participants include being among the first to have access to cutting-edge treatments and receiving excellent patient care (NIH 2017). Regardless of the trial outcome, every participant helps researchers improve treatment options for future patients.

Information about clinical trials for pulmonary fibrosis is available through the following resources:

Pulmonary Fibrosis Foundation
https://pulmonaryfibrosis-org.clinicaltrialconnect.com/trials

CenterWatch Clinical Trial Resource
https://www.centerwatch.com/clinical-trials/listings/condition/511/idiopathic-pulmonary-fibrosis

8 Integrative Interventions

Integrative therapies hold some promise in benefiting individuals with IPF. Although most of the evidence at this time comes from laboratory and animal studies, based on current understandings of the underlying mechanism(s) in IPF, integrative therapies that target restoring the oxidant/antioxidant balance and preventing cellular micro-injury, as well as those with anti-fibrotic and anti-senescence properties, are of interest.

N-acetylcysteine

N-acetylcysteine (NAC) is a form of the sulfur-containing amino acid cysteine. NAC reduces oxidative stress and has been used as a powerful anti-toxin. It has been shown to break down mucous secretions, making them easier to clear, and is used for this reason to treat pulmonary fibrosis associated with the genetic disease cystic fibrosis (Rushworth 2014). NAC has been shown to reduce oxidative stress and inflammation and inhibit fibrosis in laboratory and animal models of IPF (Myllarniemi 2015).

Studies in IPF patients have yielded conflicting results (Sun 2016). In one randomized controlled trial in IPF patients taking prednisone and azathioprine (Imuran, an immunosuppressant anti-inflammatory), the addition of 600 mg of NAC three times daily for one year led to slower disease progression and better preservation of lung function, but did not significantly affect mortality (Demedts 2005). In another clinical trial that included 155 subjects with IPF, about half of them being treated with prednisone, azathioprine, and NAC, the combination was associated with increased rates of adverse events and mortality as compared with placebo (Raghu 2012). The same researchers found that treatment with NAC alone had no impact on disease progression relative to placebo, and, although NAC was associated with better walking capacity and quality of life, these differences were not statistically significant (Martinez 2014).

Genetic variation may help explain these inconsistent findings. Researchers have discovered that variants within a specific gene (TOLLIP, on human chromosome 11) may predict the response to NAC therapy: when participants from clinical trials were grouped according to this gene variant, those with one variant fared worse than placebo when treated with NAC, those with another variant had no response to NAC therapy, and those with a third variant showed significant improvement when treated with NAC (Oldham 2016). It is hoped that a better understanding of gene variation-drug therapy interactions will help physicians individualize treatment selection in the future.

Niacin and Taurine

Niacin (vitamin B3) is the main precursor for nicotinamide adenine dinucleotide (NAD+), an essential cofactor for cellular activities related to metabolism and energy production. Levels of NAD+ decrease with age and are associated with metabolic dysfunction, while raising cellular NAD+ levels has been shown to increase activation of certain anti-aging proteins (Srivastava 2016). Because of IPF's close relationship with aging (Sgalla 2018), it is thought that raising NAD+ levels may be beneficial.

Findings from several studies using animal models of IPF indicate that niacin administration may prevent depletion of NAD+ in the lungs and reduce lung fibrosis (Wang 1990; Nagai 1994; O'Neill 1994). Other research in animals and lung cells demonstrate that the combination of niacin plus taurine may have a unique benefit. Taurine is a conditionally essential amino acid known to neutralize certain toxins and protect against oxidative tissue damage (AMR 2001). Evidence from preclinical research suggests taurine plus niacin may inhibit the activities of pro-fibrotic inflammatory molecules (Gurujeyalakshmi 2000b; Gurujeyalakshmi 1998), suppress free radical production in the lungs (Gurujeyalakshmi 2000a), and ultimately reduce collagen deposition in the lungs (Blaisdell 1994; Giri 1994).

Other NAD+ precursors, such as nicotinamide riboside, have yet to be studied in the context of pulmonary fibrosis. However, some preliminary evidence suggested nicotinamide riboside ameliorated liver fibrosis in a mouse model of non-alcoholic fatty liver disease (Zhou 2016).

Omega-3 Fatty Acids

Alpha-linolenic acid is an essential omega-3 fatty acid found in flaxseed and some other plant oils. It is the precursor to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which can also be obtained from fish oil and have been reported to have numerous health benefits related mainly to their anti-inflammatory effects (Baker 2016). (Note, however, that the conversion of alpha-linolenic acid to EPA and DHA is inefficient in humans.) In one study, replacing all dietary fat with fish oil protected rats against an agent used to induce an experimental IPF-like condition (Kennedy 1989). A similar protective effect was seen in a study in which mice were fed standard laboratory food plus flaxseed oil (Lawrenz 2012). In another study, mice treated with DHA prior to exposure to the same fibrotic agent had lower levels of inflammatory molecules in the lungs and alveolar fluid, less lung fibrosis, less weight loss, and lower mortality (Zhao 2014). In two other studies, treatment of mice already exhibiting IPF-like illness with resolvin D1 or protectin DX, lipid molecules derived from the metabolism of DHA, reduced inflammation and fibrosis and improved pulmonary function (Yatomi 2015; Li, Hao 2017).

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone, or DHEA, is an androgen hormone produced mainly by the adrenal glands. Levels of DHEA and its sulfated form (DHEA-sulfate) decrease with age. Low levels are associated with chronic disease and frailty, and higher levels have been correlated with health and well-being (Lois 2000; Samaras 2014).

Blood levels of DHEA-sulfate have been noted to be significantly lower in some individuals with IPF compared with healthy controls. In addition, DHEA inhibited lung fibroblast proliferation and migration in laboratory research (Mendoza-Milla 2013), indicating its potential usefulness in IPF treatment. Clinical trials have not yet investigated whether DHEA replacement therapy benefits IPF patients.

Vitamin D

Vitamin D has many beneficial immune-supportive and anti-inflammatory effects (Yin 2014; Hoe 2016). Chronic vitamin D deficiency has been noted in laboratory animals to increase the production of extracellular matrix components like collagen and to promote fibrosis in lung tissue (Shi 2017). One interesting study examined the influence of season on mortality related to pulmonary fibrosis, including IPF. The study found that, compared with the summer months, deaths due to pulmonary fibrosis were 5.2% higher in the fall, 17.1% higher in the winter, and 12.7% higher in the spring months (Olson 2009). Although the reasons underlying this relationship between season and mortality are unknown, lower vitamin D levels may be a contributing factor (Grant 2017). In a study that examined patients with systemic sclerosis, an autoimmune condition characterized by extracellular matrix deposition and connective tissue fibrosis, their serum vitamin D level was lower than that in healthy controls (Zhang, Duan 2017).

In a laboratory study, 1,25-dihydroxyvitamin D3, the metabolically active form of vitamin D, reduced the fibrotic transformation of human lung epithelial cells in response to stimulation by transforming growth factor-beta (Jiang, Yang 2017). In a mouse model, vitamin D supplementation decreased pulmonary fibrosis induced by bleomycin, a toxic anti-cancer drug (Zhang, Yu 2015).

Polyphenols

Polyphenols are a large group of plant compounds with powerful free radical-scavenging and anti-inflammatory actions. Polyphenols, including flavonoids and phenolic acids, are an important component of the diet and have been studied for their many health-promoting and anti-aging properties (Impellizzeri 2015; Queen 2010).

Numerous animal and laboratory studies have examined the potential role of polyphenols in preventing and treating fibrotic lung diseases. Many polyphenols have shown promise in reducing fibrosis in animal models of IPF, increasing antioxidant enzyme activity, and/or inhibiting specific inflammatory signaling molecules involved in the progression of IPF (though clinical trials are needed). These include:

  • Curcumin from turmeric (Gouda 2018; Liu 2016)
  • Quercetin, found in onion, apples, and many other plants (Verma 2013; Impellizzeri 2015)
  • Resveratrol, found in red wine, grapes, and berries (Akgedik 2012; Impellizzeri 2015)
  • Caffeic acid phenethyl ester from bee propolis (Larki-Harchegani 2013; Larki 2013)
  • Apigenin, found in parsley, celery, and many other herbs and vegetables (Chen 2016)
  • Gallic acid, found in tea and many other plants (Nikbakht 2015)
  • Epigallocatechin gallate (EGCG) from green tea (Sriram 2009)
  • Citrus flavonoids from citrus fruit (Zhou 2009)
  • Magnolol from magnolia bark (Zhang, Huang 2015)
  • Polyphenol-rich extract from pomegranate (Hemmati 2013)
  • Mangiferin from mango leaf (Impellizzeri 2015)
  • Dihydroquercetin from grape leaf (Impellizzeri 2015)
  • Salidroside from rhodiola (Rhodiola rosea) (Tang 2016)
  • Proanthocyanidin from grape seed (Agackiran 2012)
  • Emodin from rhubarb (Rheum rhabarbarum) (Chen 2009)
  • Salvianolic acid from red sage (Salvia miltiorrhiza) (Pan 2014)

Curcumin is a yellow flavonoid compound found in turmeric. Curcumin's anti-inflammatory and free radical-scavenging properties are well known and contribute to its potential benefits in pulmonary diseases, including IPF (Lelli 2017). A number of preclinical studies have found that curcumin can reduce lung inflammation and oxidative stress and prevent experimentally induced pulmonary fibrosis in animal models of IPF (Punithavathi 2000; Xu 2007; Zhang 2007; Zhao 2008; Smith 2010). Animal research also suggests curcumin can prevent fibrotic changes in lung fibroblasts (Liu 2016), and, in laboratory studies, it reduced inflammatory signaling in cells that line the lung alveoli (Gouda 2018).

Quercetin is a flavonoid commonly found in fruits and vegetables. It has anti-inflammatory, free radical-scavenging, and possibly senolytic properties (Anand David 2016; Zhu 2015). In laboratory research, it was shown to suppress the production of collagen in fibroblasts by acting on a molecule known to be involved in several lung diseases (Nakamura 2011). Orally administered quercetin has also been found to raise antioxidant enzyme levels, decrease levels of markers of inflammation, prevent oxidative lung damage, and reduce fibrosis in rats and mice with an experimentally induced condition similar to IPF (Verma 2013; Impellizzeri 2015). In a preliminary study, quercetin reduced the production of inflammatory cytokines when incubated with blood from IPF patients, and, interestingly, the anti-inflammatory effect was less evident in blood from healthy control subjects than in blood from IPF patients (Veith 2017).

Resveratrol, a polyphenol best known for its presence in red wine, is also found in grapes, berries, Japanese knotweed, and peanuts. Like quercetin, it has anti-inflammatory and free radical-scavenging capacities and has demonstrated anti-cancer and cardio-protective potential. Resveratrol has been shown to inhibit proliferation and collagen production by fibroblasts from IPF-affected lungs (Fagone 2011). Resveratrol has been found to protect against lung injury and fibrosis in animal models of IPF (Impellizzeri 2015; Akgedik 2012). In one study, resveratrol lowered lung tissue injury, fibrosis, and the death rate in mice exposed to a fibrotic agent, and also increased the activation of sirtuin-1, a protein that may have an important anti-fibrotic function (Rong 2016; Zeng 2017).

Caffeic acid phenethyl ester, a flavonoid extracted from bee propolis, has numerous biological activities including regulating immune function and reducing inflammation. Caffeic acid phenethyl ester was found to prevent collagen deposition in the lungs of animals with an experimentally induced IPF-like condition. It was also found to decrease lung and plasma levels of key pro-fibrotic and inflammatory molecules (Larki-Harchegani 2013; Larki 2013) and reduce lung tissue free radicals (Ozyurt 2004) in this animal model of IPF. Treatment with propolis also inhibited pro-fibrotic signaling in human alveolar cells triggered by an inflammatory molecule implicated in IPF (Kao 2013).

Other Phytochemicals

Several other types of plant chemicals, or phytochemicals, have been found to alter inflammatory and oxidative pathways to fibrosis and normalize alveolar cell signaling and fibroblast activity in laboratory experiments, and have shown promise in preventing or reversing pulmonary fibrosis in animal models of IPF. Some examples are:

  • Ginsenoside Rg1, a triterpene saponin from Asian ginseng (Panax ginseng) (Zhan 2016)
  • Notoginsenosides, triterpene saponins from Chinese ginseng (Panax notoginseng) (Ren 2015; Wu 2013)
  • Glycyrrhizic acid, a triterpenoid saponin from licorice (Glycyrrhiza glabra) (Gao 2015; Zhang, Liu 2017)
  • Schisandrin B, a lignin from schisandra (Schisandra chinensis) (Zhang, Liu 2017)
  • Diallyl sulfide and related sulfur compounds from garlic (Kalayarasan 2008; Kalayarasan 2013; Wang 2014; Tsukioka 2017)
  • Sulforaphane, a sulfur compound from cruciferous vegetables like broccoli and cabbage (Yan 2017; Kyung 2018)

Agackiran Y, Gul H, Gunay E, Akyurek N, Memis L, Gunay S, . . . Ide T. The efficiency of proanthocyanidin in an experimental pulmonary fibrosis model: comparison with taurine. Inflammation. Aug 2012;35(4):1402-1410.

Akgedik R, Akgedik S, Karamanli H, Uysal S, Bozkurt B, Ozol D, . . . Yildirim Z. Effect of resveratrol on treatment of bleomycin-induced pulmonary fibrosis in rats. Inflammation. Oct 2012;35(5):1732-1741.

AMR. Taurine - monograph. Alternative medicine review: a journal of clinical therapeutic. Feb 2001;6(1):78-82.

Anand David AV, Arulmoli R, Parasuraman S. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacognosy reviews. Jul-Dec 2016;10(20):84-89.

Aryal S, Nathan SD. An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis. Expert opinion on emerging drugs. May 2 2018.

Atkins CP, Gilbert D, Brockwell C, Robinson S, Wilson AM. Fatigue in sarcoidosis and idiopathic pulmonary fibrosis: differences in character and severity between diseases. Sarcoidosis, vasculitis, and diffuse lung diseases: official journal of WASOG. Aug 1 2016;33(2):130-138.

Atreya S, Kumar G, Datta SS. Gabapentin for Chronic Refractory Cancer Cough. Indian journal of palliative care. Jan-Mar 2016;22(1):94-96.

Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, . . . Kudoh S. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine. May 1 2005;171(9):1040-1047.

Baker EJ, Miles EA, Burdge GC, Yaqoob P, Calder PC. Metabolism and functional effects of plant-derived omega-3 fatty acids in humans. Progress in lipid research. Oct 2016;64:30-56.

Bando M. Pirfenidone: Clinical trials and clinical practice in patients with idiopathic pulmonary fibrosis. Respiratory investigation. Sep 2016;54(5):298-304.

Bese NS, Munzuroglu F, Uslu B, Arbak S, Yesiladali G, Sut N, . . . Ober A. Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats. Clinical oncology (Royal College of Radiologists (Great Britain)). May 2007;19(4):260-264.

Bickelhaupt S, Erbel C, Timke C, Wirkner U, Dadrich M, Flechsig P, . . . Huber PE. Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis. J Natl Cancer Inst. Aug 1 2017;109(8).

Blaisdell RJ, Schiedt MJ, Giri SN. Dietary supplementation with taurine and niacin prevents the increase in lung collagen cross-links in the multidose bleomycin hamster model of pulmonary fibrosis. Journal of biochemical toxicology. Apr 1994;9(2):79-86.

Boerma M, Roberto KA, Hauer-Jensen M. Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. International journal of radiation oncology, biology, physics. Sep 1 2008;72(1):170-177.

Bonella F, Kreuter M, Hagmeyer L, Neurohr C, Keller C, Kohlhaeufl MJ, . . . Prasse A. Insights from the German Compassionate Use Program of Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis. Respiration. 2016;92(2):98-106.

Buschhausen L, Kamm M, Arns W, Schulze-Lohoff E, Weber M. [Successful treatment of a severe case of idiopathic pulmonary fibrosis with rapamycin]. Med Klin (Munich). Mar 15 2005;100(3):161-164.

Caminati A, Cassandro R, Torre O, Harari S. Severe idiopathic pulmonary fibrosis: what can be done? European respiratory review: an official journal of the European Respiratory Society. Sep 30 2017;26(145).

Castelino FV. Lipids and eicosanoids in fibrosis: emerging targets for therapy. Curr Opin Rheumatol. Nov 2012;24(6):649-655.

Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J, . . . Hopkins PM. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology (Carlton, Vic.). Oct 2014;19(7):1013-1018.

Chang W, Wei K, Ho L, Berry GJ, Jacobs SS, Chang CH, Rosen GD. A critical role for the mTORC2 pathway in lung fibrosis. PloS one. 2014;9(8):e106155.

Chen L, Zhao W. Apigenin protects against bleomycin-induced lung fibrosis in rats. Experimental and therapeutic medicine. Jan 2016;11(1):230-234.

Chen S, Cui G, Peng C, Lavin MF, Sun X, Zhang E, . . . Shao H. Transplantation of adipose-derived mesenchymal stem cells attenuates pulmonary fibrosis of silicosis via anti-inflammatory and anti-apoptosis effects in rats. Stem Cell Research & Therapy. April 19 2018;9(1):110.

Chen XH, Sun RS, Hu JM, Mo ZY, Yang ZF, Jin GY, . . . Zhong NS. Inhibitory effect of emodin on bleomycin-induced pulmonary fibrosis in mice. Clin Exp Pharmacol Physiol. Feb 2009;36(2):146-153.

Choi SM, Jang AH, Kim H, Lee KH, Kim YW. Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice. Journal of Korean medical science. Sep 2016;31(9):1419-1425.

Chu X, Wei X, Lu S, He P. Autotaxin-LPA receptor axis in the pathogenesis of lung diseases. Int J Clin Exp Med. 2015;8(10):17117-17122.

Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest. Mar 2007;131(3):897-899.

Costabel U, Albera C, Bradford WZ, Hormel P, King TE, Jr., Noble PW, . . . du Bois RM. Analysis of lung function and survival in RECAP: An open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis. Sarcoidosis, vasculitis, and diffuse lung diseases: official journal of WASOG. Oct 20 2014;31(3):198-205.

Cottin V, Bergot E, Bourdin A, Cadranel J, Camus P, Crestani B, . . . Cordier JF. Adherence to guidelines in idiopathic pulmonary fibrosis: a follow-up national survey. ERJ open research. Oct 2015;1(2).

Day BJ. Antioxidants as potential therapeutics for lung fibrosis. Antioxid Redox Signal. Feb 2008;10(2):355-370.

Delanian S, Balla-Mekias S, Lefaix JL. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. Oct 1999;17(10):3283-3290.

Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, . . . Montanari M. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. Nov 24 2005;353(21):2229-2242.

Desai O, Winkler J, Minasyan M, Herzog EL. The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2018;5:43.

Drakopanagiotakis F, Wujak L, Wygrecka M, Markart P. Biomarkers in idiopathic pulmonary fibrosis. Matrix biology: journal of the International Society for Matrix Biology. Jan 31 2018.

Eduard Gorina LR, Ganesh Raghu, et al. . PRAISE, a randomized, placebo-controlled, double-blind Phase 2 clinical trial of pamrevlumab (FG-3019) in IPF patients . . European Respiratory Journal 2017 50: OA3400; DOI: 10.1183/1393003.congress-2017.OA3400 *Phase 2 result of Pamrevlumab. 2017.

Entzian P, Gerlach C, Gerdes J, Schlaak M, Zabel P. [Pentoxifylline inhibits experimental bleomycin-induced fibrosing alveolitis]. Pneumologie (Stuttgart, Germany). Apr 1997;51(4):375-380.

Entzian P, Schlaak M, Seitzer U, Acil Y, Ernst M, Zabel P. Pentoxifylline inhibits the fibrogenic activity of pleural effusions and transforming growth factor-beta. Mediators of inflammation. 1997;6(2):119-126.

Fagone E, Conte E, Gili E, Fruciano M, Pistorio MP, Lo Furno D, . . . Vancheri C. Resveratrol inhibits transforming growth factor-beta-induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration. Experimental lung research. Apr 2011;37(3):162-174.

Failla M, Genovese T, Mazzon E, Gili E, Muia C, Sortino M, . . . Vancheri C. Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury. Respiratory research. Nov 21 2006;7:137.

Fastres A, Felice F, Roels E, Moermans C, Corhay JL, Bureau F, . . . Guiot J. The Lung Microbiome in Idiopathic Pulmonary Fibrosis: A Promising Approach for Targeted Therapies. International journal of molecular sciences. Dec 16 2017;18(12).

FDA. U.S. Food and Drug Administration. The Drug Development Process: Step 3: Clinical Research. https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm. Last updated 1/4/2018. Accessed 5/3/2018.

Ferrara G, Luppi F, Birring SS, Cerri S, Caminati A, Skold M, Kreuter M. Best supportive care for idiopathic pulmonary fibrosis: current gaps and future directions. European respiratory review: an official journal of the European Respiratory Society. Mar 31 2018;27(147).

Fois AG, Paliogiannis P, Sotgia S, Mangoni AA, Zinellu E, Pirina P, . . . Zinellu A. Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review. Respiratory research. Mar 27 2018;19(1):51.

Frangogiannis NG. Fibroblast—Extracellular Matrix Interactions in Tissue Fibrosis. Current pathobiology reports. Mar 2016;4(1):11-18.

Gao L, Tang H, He H, Liu J, Mao J, Ji H, . . . Wu T. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats. Frontiers in pharmacology. 2015;6:215.

Gamad N, Malik S, Suchal K, Vasisht S, Tomar A, Arava S, . . . Bhatia J. Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: Pharmacological effects and molecular mechanisms. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Jan 2018;97:1544-1553.

Garcia FA, Reboucas JF, Balbino TQ, da Silva TG, de Carvalho-Junior CH, Cerqueira GS, . . . Viana GS. Pentoxifylline reduces the inflammatory process in diabetic rats: relationship with decreases of pro-inflammatory cytokines and inducible nitric oxide synthase. Journal of inflammation (London, England). 2015;12:33.

Gharaee-Kermani M, Hu B, Thannickal VJ, Phan SH, Gyetko MR. Current and emerging drugs for idiopathic pulmonary fibrosis. Expert opinion on emerging drugs. Nov 2007;12(4):627-646.

Ghebre YT, Raghu G. Idiopathic Pulmonary Fibrosis: Novel Concepts of Proton Pump Inhibitors as Antifibrotic Drugs. American journal of respiratory and critical care medicine. Jun 15 2016;193(12):1345-1352.

Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, . . . Rosen GD. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. Journal of translational medicine. Aug 1 2015;13:249.

Giri SN, Blaisdell R, Rucker RB, Wang Q, Hyde DM. Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms. Environ Health Perspect. Dec 1994;102 Suppl 10:137-147.

Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio GA, DiFede D, . . . Hare JM. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest. May 2017;151(5):971-981.

Goa KL, Sorkin EM. Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. Drugs. Sep 1993;46(3):409-427.

Gou S, Zhu T, Wang W, Xiao M, Wang XC, Chen ZH. Glucagon like peptide-1 attenuates bleomycin-induced pulmonary fibrosis, involving the inactivation of NF-kappaB in mice. International immunopharmacology. Oct 2014;22(2):498-504.

Gouda MM, Prabhu A, Bhandary YP. Curcumin alleviates IL-17A-mediated p53-PAI-1 expression in bleomycin-induced alveolar basal epithelial cells. Journal of cellular biochemistry. Feb 2018;119(2):2222-2230.

Grant WB, Bhattoa HP, Boucher BJ. Seasonal variations of U.S. mortality rates: Roles of solar ultraviolet-B doses, vitamin D, gene exp ression, and infections. The Journal of steroid biochemistry and molecular biology. Oct 2017;173:5-12.

Gurujeyalakshmi G, Hollinger MA, Giri SN. Regulation of transforming growth factor-beta1 mRNA expression by taurine and niacin in the bleomycin hamster model of lung fibrosis. American journal of respiratory cell and molecular biology. Mar 1998;18(3):334-342.

Gurujeyalakshmi G, Wang Y, Giri SN. Suppression of bleomycin-induced nitric oxide production in mice by taurine and niacin. Nitric Oxide. Aug 2000a;4(4):399-411.

Gurujeyalakshmi G, Wang Y, Giri SN. Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kappaB in mice. The Journal of pharmacology and experimental therapeutics. Apr 2000b;293(1):82-90.

Haddad P, Kalaghchi B, Amouzegar-Hashemi F. Pentoxifylline and vitamin E combination for superficial radiation-induced fibrosis: a phase II clinical trial. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. Dec 2005;77(3):324-326.

Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, . . . Martinez FJ. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest. Jun 2013;143(6):1699-1708.

Hemmati AA, Rezaie A, Darabpour P. Preventive effects of pomegranate seed extract on bleomycin-induced pulmonary fibrosis in rat. Jundishapur journal of natural pharmaceutical products. Spring 2013;8(2):76-80.

Hewitt RJ, Molyneaux PL. The respiratory microbiome in idiopathic pulmonary fibrosis. Annals of translational medicine. Jun 2017;5(12):250.

Hoe E, Nathanielsz J, Toh ZQ, Spry L, Marimla R, Balloch A, . . . Licciardi PV. Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection. Nutrients. Dec 12 2016;8(12).

Hughes G, Toellner H, Morris H, Leonard C, Chaudhuri N. Real World Experiences: Pirfenidone and Nintedanib are Effective and Well Tolerated Treatments for Idiopathic Pulmonary Fibrosis. Journal of clinical medicine. Sep 2 2016;5(9).

Impellizzeri D, Talero E, Siracusa R, Alcaide A, Cordaro M, Maria Zubelia J, . . . Motilva V. Protective effect of polyphenols in an inflammatory process associated with experimental pulmonary fibrosis in mice. The British journal of nutrition. Sep 28 2015;114(6):853-865.

Institute of Medicine. Public Engagement and Clinical Trials: New Models and Disruptive Technologies: Workshop Summary. Washington (DC): National Academies Press (US); 2012. Appendix B, The Clinical Trials Process. 2012.

Izumo T, Kondo M, Nagai A. Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis. The European respiratory journal. Dec 2009;34(6):1444-1451.

Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, Gomez-Marin O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung. Apr 2010;188(2):115-123.

Jiang C, Huang H, Liu J, Wang Y, Lu Z, Xu Z. Adverse events of pirfenidone for the treatment of pulmonary fibrosis: a meta-analysis of randomized controlled trials. PloS one. 2012;7(10):e47024.

Jiang F, Yang Y, Xue L, Li B, Zhang Z. 1α,25-dihydroxyvitamin D3 Attenuates TGF-β-Induced Pro-Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial–Mesenchymal Transition. Nutrients. 2017;9(9):980.

Jiang S, Li T, Yang Z, Yi W, Di S, Sun Y, . . . Yang Y. AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging. Ageing research reviews. Sep 2017;38:18-27.

Jin X, Dai H, Ding K, Xu X, Pang B, Wang C. Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue. Chin Med J (Engl). 2014;127(7):1304-1309.

Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, . . . Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. Jan 4 2019.

Kaidar-Person O, Marks LB, Jones EL. Pentoxifylline and vitamin E for treatment or prevention of radiation-induced fibrosis in patients with breast cancer. The breast journal. Apr 23 2018.

Kalayarasan S, Sriram N, Soumyakrishnan S, Sudhandiran G. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2. Toxicology and applied pharmacology. Sep 1 2013;271(2):184-195.

Kalayarasan S, Sriram N, Sudhandiran G. Diallyl sulfide attenuates bleomycin-induced pulmonary fibrosis: critical role of iNOS, NF-kappaB, TNF-alpha and IL-1beta. Life sciences. Jun 6 2008;82(23-24):1142-1153.

Kao HF, Chang-Chien PW, Chang WT, Yeh TM, Wang JY. Propolis inhibits TGF-beta1-induced epithelial-mesenchymal transition in human alveolar epithelial cells via PPARgamma activation. International immunopharmacology. Mar 2013;15(3):565-574.

Kaya V, Yazkan R, Yildirim M, Doguc DK, Suren D, Bozkurt KK, . . . Yalcin AY. The relation of radiation-induced pulmonary fibrosis with stress and the efficiency of antioxidant treatment: an experimental study. Med Sci Monit. Feb 21 2014;20:290-296.

Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Frontiers in pharmacology. 2014;5.

Kennedy JI, Jr., Chandler DB, Fulmer JD, Wert MB, Grizzle WE. Dietary fish oil inhibits bleomycin-induced pulmonary fibrosis in the rat. Experimental lung research. Mar 1989;15(2):315-329.

Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. Oct 2017;65(10):2297-2301.

Kistler KD, Nalysnyk L, Rotella P, Esser D. Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature. BMC pulmonary medicine. Aug 16 2014;14:139.

Kreuter M, Ehlers-Tenenbaum S, Palmowski K, Bruhwyler J, Oltmanns U, Muley T, . . . Herth FJ. Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis. PloS one. 2016;11(3):e0151425.

Kumar D, Yalamanchali S, New J, Parsel S, New N, Holcomb A, . . . Thomas SM. Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis. Radiation research. Mar 2018;189(3):326-336.

Kuwano K, Araya J, Hara H, Minagawa S, Takasaka N, Ito S, . . . Nakayama K. Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Respiratory investigation. Nov 2016;54(6):397-406.

Kyung SY, Kim DY, Yoon JY, Son ES, Kim YJ, Park JW, Jeong SH. Sulforaphane attenuates pulmonary fibrosis by inhibiting the epithelial-mesenchymal transition. BMC pharmacology & toxicology. Apr 2 2018;19(1):13.

Ladeiras-Lopes R, Fontes-Carvalho R, Bettencourt N, Sampaio F, Gama V, Leite-Moreira A. Novel therapeutic targets of metformin: metabolic syndrome and cardiovascular disease. Expert opinion on therapeutic targets. Jul 2015;19(7):869-877.

Larki-Harchegani A, Hemmati AA, Arzi A, Ghafurian-Boroojerdnia M, Shabib S, Zadkarami MR, Esmaeilzadeh S. Evaluation of the Effects of Caffeic Acid Phenethyl Ester on Prostaglandin E2 and Two Key Cytokines Involved in Bleomycin-induced Pulmonary Fibrosis. Iranian journal of basic medical sciences. Jul 2013;16(7):850-857.

Larki A, Hemmati AA, Arzi A, Borujerdnia MG, Esmaeilzadeh S, Zad Karami MR. Regulatory effect of caffeic acid phenethyl ester on type I collagen and interferon-gamma in bleomycin-induced pulmonary fibrosis in rat. Res Pharm Sci. Oct 2013;8(4):243-252.

Lawrence J, Nho R. The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis. International journal of molecular sciences. Mar 8 2018;19(3).

Lawrenz J, Herndon B, Kamal A, Mehrer A, Dim DC, Baidoo C, . . . Baybutt RC. Dietary Flaxseed Oil Protects against Bleomycin-Induced Pulmonary Fibrosis in Rats. Pulmonary medicine. 2012;2012:457031.

Lee CM, Lee DH, Ahn BK, Hwang JJ, Yoon H, Shin CM, . . . Kim N. Protective Effect of Proton Pump Inhibitor for Survival in Patients with Gastroesophageal Reflux Disease and Idiopathic Pulmonary Fibrosis. J Neurogastroenterol Motil. Jul 30 2016;22(3):444-451.

Lee JG, Shim S, Kim MJ, Myung JK, Jang WS, Bae CH, . . . Park S. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis. BioMed research international. 2017;2017:1279280.

Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, . . . Collard HR. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine. Dec 15 2011;184(12):1390-1394.

Lehmann M, Korfei M, Mutze K, Klee S, Skronska-Wasek W, Alsafadi HN, . . . Konigshoff M. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. The European respiratory journal. Aug 2017;50(2).

Lelli D, Sahebkar A, Johnston TP, Pedone C. Curcumin use in pulmonary diseases: State of the art and future perspectives. Pharmacological research: the official journal of the Italian Pharmacological Society. Jan 2017;115:133-148.

Li F, Han F, Li H, Zhang J, Qiao X, Shi J, . . . Liu X. Human placental mesenchymal stem cells of fetal origins-alleviated inflammation and fibrosis by attenuating MyD88 signaling in bleomycin-induced pulmonary fibrosis mice. Mol Immunol. Oct 2017;90:11-21.

Li H, Hao Y, Zhang H, Ying W, Li D, Ge Y, . . . Jin S. Posttreatment with Protectin DX ameliorates bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. Sci Rep. May 3 2017;7:46754.

Li H, Hua J, Guo CX, Wang WX, Wang BJ, Yang DL, . . . Lu YP. Pentoxifylline inhibits liver fibrosis via hedgehog signaling pathway. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. Jun 2016;36(3):372-376.

Li H, Tan G, Tong L, Han P, Zhang F, Liu B, Sun X. Pentoxifylline inhibits pulmonary inflammation induced by infrarenal aorticcross-clamping dependent of adenosine receptor A2A. American journal of translational research. 2016;8(5):2210-2221.

Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget. Nov 24 2017;8(60):102600-102616.

Lindell KO, Kavalieratos D, Gibson KF, Tycon L, Rosenzweig M. The palliative care needs of patients with idiopathic pulmonary fibrosis: A qualitative study of patients and family caregivers. Heart & lung : the journal of critical care. Jan - Feb 2017;46(1):24-29.

Liu D, Gong L, Zhu H, Pu S, Wu Y, Zhang W, Huang G. Curcumin Inhibits Transforming Growth Factor beta Induced Differentiation of Mouse Lung Fibroblasts to Myofibroblasts. Frontiers in pharmacology. 2016;7:419.

Liu J, Chen F, Wei Z, Qiu M, Li Z, Dan H, . . . Jiang L. Evaluating the efficacy of pentoxifylline in the treatment of oral submucous fibrosis: A meta-analysis. Oral diseases. Jul 24 2017.

Liu M, Gou S, Chen HT, Chen ZH. [The Study of the Effect and Mechanism of Glucagon Like Peptide-1 in Bleomycin-induced Pulmonary Fibrosis in Mice]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition. Jul 2017;48(4):509-514.

Lois K, Kassi E, Prokopiou M, Chrousos GP. Adrenal Androgens and Aging. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.

Lopera DE, Naranjo TW, Hidalgo JM, Echeverri L, Patino JH, Moreno AR, . . . Cano LE. Pentoxifylline immunomodulation in the treatment of experimental chronic pulmonary paracoccidioidomycosis. Fibrogenesis & tissue repair. 2015;8:10.

Magazine R, Shetty R, Goneppanavar U, Mohapatra AK. Idiopathic clubbing confined to lower limb digits and idiopathic pulmonary fibrosis: an unusual association. Case reports in pulmonology. 2012;2012:684285.

Malouf MA, Hopkins P, Snell G, Glanville AR. An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis. Respirology (Carlton, Vic.). Jul 2011;16(5):776-783.

Margaritopoulos GA, Vasarmidi E, Antoniou KM. Pirfenidone in the treatment of idiopathic pulmonary fibrosis: an evidence-based review of its place in therapy. Core evidence. 2016;11:11-22.

Markart P, Luboeinski T, Korfei M, Schmidt R, Wygrecka M, Mahavadi P, . . . Ruppert C. Alveolar oxidative stress is associated with elevated levels of nonenzymatic low-molecular-weight antioxidants in patients with different forms of chronic fibrosing interstitial lung diseases. Antioxid Redox Signal. Feb 2009;11(2):227-240.

Martinez FJ, de Andrade JA, Anstrom KJ, King TE, Jr., Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. May 29 2014;370(22):2093-2101.

McCarty MF, O'Keefe JH, DiNicolantonio JJ. Pentoxifylline for vascular health: a brief review of the literature. Open heart. 2016;3(1):e000365. McCormack PL. Nintedanib: first global approval. Drugs. Jan 2015;75(1):129-139.

Mendoza-Milla C, Valero Jimenez A, Rangel C, Lozano A, Morales V, Becerril C, . . . Selman M. Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis. The European respiratory journal. Nov 2013;42(5):1309-1321.

Mercer PF, Woodcock HV, Eley JD, Plate M, Sulikowski MG, Durrenberger PF, . . . Chambers RC. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax. Aug 2016;71(8):701-711.

Mermigkis C, Bouloukaki I, Antoniou K, Papadogiannis G, Giannarakis I, Varouchakis G, . . . Schiza SE. Obstructive sleep apnea should be treated in patients with idiopathic pulmonary fibrosis. Sleep & breathing = Schlaf & Atmung. Mar 2015;19(1):385-391.

Mojiri-Forushani H, Hemmati AA, Dehghani MA, Malayeri AR, Pour HH. Effects of herbal extracts and compounds and pharmacological agents on pulmonary fibrosis in animal models: a review. Journal of integrative medicine. Nov 2017;15(6):433-441.

Murtha LA, Schuliga MJ, Mabotuwana NS, Hardy SA, Waters DW, Burgess JK, . . . Boyle AJ. The Processes and Mechanisms of Cardiac and Pulmonary Fibrosis. Front Physiol. 2017;8.

Myllarniemi M, Kaarteenaho R. Pharmacological treatment of idiopathic pulmonary fibrosis - preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine. European clinical respiratory journal. 2015;2.

Nagai A, Matsumiya H, Hayashi M, Yasui S, Okamoto H, Konno K. Effects of nicotinamide and niacin on bleomycin-induced acute injury and subsequent fibrosis in hamster lungs. Experimental lung research. Jul-Aug 1994;20(4):263-281.

Nakamura T, Matsushima M, Hayashi Y, Shibasaki M, Imaizumi K, Hashimoto N, . . . Kawabe T. Attenuation of transforming growth factor-beta-stimulated collagen production in fibroblasts by quercetin-induced heme oxygenase-1. American journal of respiratory cell and molecular biology. May 2011;44(5):614-620.

Naranjo TW, Lopera DE, Diaz-Granados LR, Duque JJ, Restrepo AM, Cano LE. Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic pulmonary paracoccidioidomycosis in mice. Pulmonary pharmacology & therapeutics. Feb 2011;24(1):81-91.

National Heart, Lung, and Blood Institute. Idiopathic Pulmonary Fibrosis. Treatment. https://www.nhlbi.nih.gov/health-topics/idiopathic-pulmonary-fibrosis. Accessed 5/3/2018.

Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutrition, metabolism, and cardiovascular diseases : NMCD. Aug 2017;27(8):657-669.

Nho RS, Hergert P. IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases. PloS one. 2014;9(4):e94616.

Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements. Integrative medicine (Encinitas, Calif.). Aug 2014;13(4):35-43.

NIH. National Institute on Aging. Clinical Trials: Benefits, Risks, and Safety. https://www.nia.nih.gov/health/clinical-trials-benefits-risks-and-safety. 5/17/2017. Accessed 5/3/2018.

Nikbakht J, Hemmati AA, Arzi A, Mansouri MT, Rezaie A, Ghafourian M. Protective effect of gallic acid against bleomycin-induced pulmonary fibrosis in rats. Pharmacological reports: PR. Dec 2015;67(6):1061-1067.

Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, . . . du Bois RM. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. May 21 2011;377(9779):1760-1769.

O'Neill CA, Giri SN. Biochemical mechanisms for the attenuation of bleomycin-induced lung fibrosis by treatment with niacin in hamsters: the role of NAD and ATP. Experimental lung research. Jan-Feb 1994;20(1):41-56.

Oldham JM, Noth I, Martinez FJ. Pharmacogenetics and interstitial lung disease. Current opinion in pulmonary medicine. Sep 2016;22(5):456-465.

Olson AL, Swigris JJ, Raghu G, Brown KK. Seasonal Variation: Mortality From Pulmonary Fibrosis Is Greatest in the Winter. Chest. Jul 2009;136(1):16-22.

Ozyurt H, Sogut S, Yildirim Z, Kart L, Iraz M, Armutcu F, . . . Akyol O. Inhibitory effect of caffeic acid phenethyl ester on bleomycine-induced lung fibrosis in rats. Clinica chimica acta; international journal of clinical chemistry. Jan 2004;339(1-2):65-75.

Pan Y, Fu H, Kong Q, Xiao Y, Shou Q, Chen H, . . . Chen M. Prevention of pulmonary fibrosis with salvianolic acid a by inducing fibroblast cell cycle arrest and promoting apoptosis. Journal of ethnopharmacology. Sep 29 2014;155(3):1589-1596.

Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, . . . Morse D. Autophagy in idiopathic pulmonary fibrosis. PloS one. 2012;7(7):e41394.

Plantier L, Cazes A, Dinh-Xuan AT, Bancal C, Marchand-Adam S, Crestani B. Physiology of the lung in idiopathic pulmonary fibrosis. European respiratory review: an official journal of the European Respiratory Society. Mar 31 2018;27(147).

Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats. British journal of pharmacology. Sep 2000;131(2):169-172.

Queen BL, Tollefsbol TO. Polyphenols and aging. Current aging science. Feb 2010;3(1):34-42.

Raghu G, Anstrom KJ, King TE, Jr., Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. May 24 2012;366(21):1968-1977.

Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, . . . Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. The European respiratory journal. Jan 2006;27(1):136-142.

Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, . . . Schunemann HJ. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. American journal of respiratory and critical care medicine. Jul 15 2015;192(2):e3-19.

Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, . . . Zmijewski JW. Metformin reverses established lung fibrosis in a bleomycin model. Nature medicine. Jul 2 2018.

Ren ZX, Yu HB, Li JS, Shen JL, Li JK, Luo S. [Inhibitory effect of Panax notoginseng saponins on alveolar epithelial to mesenchymal transition]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. Dec 2015;40(23):4667-4671.

Rong L, Wu J, Wang W, Zhao RP, Xu XW, Hu D. Sirt 1 activator attenuates the bleomycin-induced lung fibrosis in mice via inhibiting epithelial-to-mesenchymal transition (EMT). European review for medical and pharmacological sciences. May 2016;20(10):2144-2150.

Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacology & therapeutics. Feb 2014;141(2):150-159.

Salvatore M, Ishikawa G, Padilla M. Is It Idiopathic Pulmonary Fibrosis or Not? Journal of the American Board of Family Medicine: JABFM. Jan-Feb 2018;31(1):151-162.

Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J, . . . Kuwano K. Metformin attenuates lung fibrosis development via NOX4 suppression. Respiratory research. Aug 30 2016;17(1):107.

Samaras N, Papadopoulou MA, Samaras D, Ongaro F. Off-label use of hormones as an antiaging strategy: a review. Clin Interv Aging. 2014;9:1175-1186.

Sarkar M, Madabhavi I, Niranjan N, Dogra M. Auscultation of the respiratory system. Annals of thoracic medicine. Jul-Sep 2015;10(3):158-168.

Sarkar M, Mahesh DM, Madabhavi I. Digital clubbing. Lung India: official organ of Indian Chest Society. Oct 2012;29(4):354-362.

Sathiyamoorthy G, Sehgal S, Ashton RW. Pirfenidone and Nintedanib for Treatment of Idiopathic Pulmonary Fibrosis. Southern medical journal. Jun 2017;110(6):393-398.

Scelfo C, Caminati A, Harari S. Recent advances in managing idiopathic pulmonary fibrosis. F1000Research. 2017;6:2052.

Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, . . . LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nature communications. Feb 23 2017;8:14532.

Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: pathogenesis and management. Respiratory research. Feb 22 2018;19(1):32.

Shao X, Li M, Luo C, Wang YY, Lu YY, Feng S, . . . Chen JH. Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice. Journal of Zhejiang University. Science. B. Jan 2015;16(1):52-61.

Sharif R. Overview of idiopathic pulmonary fibrosis (IPF) and evidence-based guidelines. The American journal of managed care. Jul 2017;23(11 Suppl):S176-s182.

Shaw J, Marshall T, Morris H, Hayton C, Chaudhuri N. Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age. J Thorac Dis. Nov 2017;9(11):4700-4707.

Shi Y, Liu T, Yao L, Xing Y, Zhao X, Fu J, Xue X. Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system. Sci Rep. Jun 12 2017;7(1):3312.

Smith MR, Gangireddy SR, Narala VR, Hogaboam CM, Standiford TJ, Christensen PJ, . . . Reddy RC. Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury. American journal of physiology. Lung cellular and molecular physiology. May 2010;298(5):L616-625.

Sriram N, Kalayarasan S, Sudhandiran G. Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling. Pulmonary pharmacology & therapeutics. Jun 2009;22(3):221-236.

Srivastava S. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clin Transl Med. Dec 2016;5(1):25.

Sternlicht MD, Wirkner U, Bickelhaupt S, Lopez Perez R, Tietz A, Lipson KE, . . . Huber PE. Radiation-induced pulmonary gene expression changes are attenuated by the CTGF antibody Pamrevlumab. Respiratory research. Jan 18 2018;19(1):14.

Sun T, Liu J, Zhao de W. Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Medicine. May 2016;95(19):e3629.

Suzuki T, Tada Y, Gladson S, Nishimura R, Shimomura I, Karasawa S, . . . West J. Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition. Respiratory research. Oct 16 2017;18(1):177.

Tang H, Gao L, Mao J, He H, Liu J, Cai X, . . . Wu T. Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-kappaB and TGF-beta1/Smad-2/-3 pathways. Cell stress & chaperones. Mar 2016;21(2):239-249.

Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, . . . Nukiwa T. Pirfenidone in idiopathic pulmonary fibrosis. The European respiratory journal. Apr 2010;35(4):821-829.

Tomassetti S, Wells AU, Costabel U, Cavazza A, Colby TV, Rossi G, . . . Poletti V. Bronchoscopic Lung Cryobiopsy Increases Diagnostic Confidence in the Multidisciplinary Diagnosis of Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine. Apr 1 2016;193(7):745-752.

Tsukioka T, Takemura S, Minamiyama Y, Mizuguchi S, Toda M, Okada S. Attenuation of Bleomycin-Induced Pulmonary Fibrosis in Rats with S-Allyl Cysteine. Molecules. Mar 29 2017;22(4).

Tzilas V, Tzouvelekis A, Chrysikos S, Papiris S, Bouros D. Diagnosis of Idiopathic Pulmonary Fibrosis “Pragmatic Challenges in Clinical Practice”. Front Med (Lausanne). 2017;4.

Vainshelboim B. Exercise training in idiopathic pulmonary fibrosis: is it of benefit? Breathe (Sheffield, England). Jun 2016;12(2):130-138.

Vassiliadis E, Barascuk N, Karsdal MA. Atherofibrosis - a unique and common process of the disease pathogenesis of atherosclerosis and fibrosis - lessons for biomarker development. Am J Transl Res. 2013;5(1):1-14.

Veith C, Drent M, Bast A, van Schooten FJ, Boots AW. The disturbed redox-balance in pulmonary fibrosis is modulated by the plant flavonoid quercetin. Toxicology and applied pharmacology. Dec 1 2017;336:40-48.

Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats. Pulmonary medicine. 2013;2013:921724.

Vyshedskiy A, Murphy R. Crackle Pitch Rises Progressively during Inspiration in Pneumonia, CHF, and IPF Patients. Pulmonary medicine. 2012;2012:240160.

Wang QJ, Giri SN, Hyde DM, Nakashima JM, Javadi I. Niacin attenuates bleomycin-induced lung fibrosis in the hamster. Journal of biochemical toxicology. Spring 1990;5(1):13-22.

Wang Y, Cao R, Wei B, Chai X, Sun D, Guan Y, Liu XM. Diallyl disulfide inhibits proliferation and transdifferentiation of lung fibroblasts through induction of cyclooxygenase and synthesis of prostaglandin E(2). Molecular and cellular biochemistry. Aug 2014;393(1-2):77-87.

Wecht S, Rojas M. Mesenchymal stem cells in the treatment of chronic lung disease. Respirology (Carlton, Vic.). Nov 2016;21(8):1366-1375.

Wen WX, Lee SY, Siang R, Koh RY. Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview. Advances in therapy. Jun 2017;34(6):1245-1269.

Whitehouse MW. Anti-TNF-alpha therapy for chronic inflammation: reconsidering pentoxifylline as an alternative to therapeutic protein drugs. Inflammopharmacology. 2004;12(3):223-227.

Wu J, Ling C, He H, Sun G, Gu Z, Ji B. [Effect of compound panax notoginsenoside granules on TGF-beta1/Smads signaling pathway in rats with bleomycin-induced pulmonary fibrosis]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology. Sep 2013;29(9):927-930.

Xu M, Deng B, Chow YL, Zhao ZZ, Hu B. Effects of curcumin in treatment of experimental pulmonary fibrosis: a comparison with hydrocortisone. Journal of ethnopharmacology. Jun 13 2007;112(2):292-299.

Yan B, Ma Z, Shi S, Hu Y, Ma T, Rong G, Yang J. Sulforaphane prevents bleomycininduced pulmonary fibrosis in mice by inhibiting oxidative stress via nuclear factor erythroid 2related factor2 activation. Molecular medicine reports. Jun 2017;15(6):4005-4014.

Yanai H, Shteinberg A, Porat Z, Budovsky A, Braiman A, Ziesche R, Fraifeld VE. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging (Albany NY). Sep 2015;7(9):664-672.

Yatomi M, Hisada T, Ishizuka T, Koga Y, Ono A, Kamide Y, . . . Okajima F. 17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice. Physiological reports. Dec 2015;3(12).

Yin K, Agrawal DK. Vitamin D and inflammatory diseases. Journal of inflammation research. 2014;7:69-87.

Zank DC, Bueno M, Mora AL, Rojas M. Idiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics. Frontiers in medicine. 2018;5:10.

Zeng Z, Cheng S, Chen H, Li Q, Hu Y, Wang Q, . . . Wang J. Activation and overexpression of Sirt1 attenuates lung fibrosis via P300. Biochemical and biophysical research communications. May 13 2017;486(4):1021-1026.

Zhan H, Huang F, Ma W, Zhao Z, Zhang H, Zhang C. Protective Effect of Ginsenoside Rg1 on Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of Caveolin-1 and TGF-beta1 Signal Pathway. Biological & pharmaceutical bulletin. 2016;39(8):1284-1292.

Zhang C, Yin X, Zhang J, Ao Q, Gu Y, Liu Y. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: A case report. Experimental and therapeutic medicine. May 2017;13(5):1922-1926.

Zhang D, Liu B, Cao B, Wei F, Yu X, Li GF, . . . Wang PL. Synergistic protection of Schizandrin B and Glycyrrhizic acid against bleomycin-induced pulmonary fibrosis by inhibiting TGF-beta1/Smad2 pathways and overexpression of NOX4. International immunopharmacology. Jul 2017;48:67-75.

Zhang DP, Qiu H, Zhuang Y, Meng FQ. [The effect of curcumin on bleomycin-induced pulmonary fibrosis in rats]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases. Mar 2007;30(3):197-201.

Zhang L, Duan Y, Zhang TP, Huang XL, Li BZ, Ye DQ, Wang J. Association between the serum level of vitamin D and systemic sclerosis in a Chinese population: a case control study. International journal of rheumatic diseases. Aug 2017;20(8):1002-1008.

Zhang L, Zhang C, Dong F, Song Q, Chi F, Liu L, . . . Che C. Combined pulmonary fibrosis and emphysema: a retrospective analysis of clinical characteristics, treatment and prognosis. BMC pulmonary medicine. Nov 3 2016;16(1):137.

Zhang X, Huang H, Chang H, Jin X. Magnolol reduces bleomycin-induced rodent lung fibrosis. Int J Clin Exp Med. 2015;8(9):15450-15457.

Zhang Z, Yu X, Fang X, Liang A, Yu Z, Gu P, . . . Yi X. Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis. Sci Rep. Dec 2 2015;5:17638.

Zhao CJ, Niu JZ, Wang JF, Zhou G, Tang BH. [Effects of curcumin on bleomycin-induced damages in pulmonary functions in rats]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. Jun 2008;33(12):1434-1438.

Zhao H, Chan-Li Y, Collins SL, Zhang Y, Hallowell RW, Mitzner W, Horton MR. Pulmonary delivery of docosahexaenoic acid mitigates bleomycin-induced pulmonary fibrosis. BMC pulmonary medicine. Apr 18 2014;14:64.

Zhou CC, Yang X, Hua X, Liu J, Fan MB, Li GQ, . . . Miao CY. Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. British journal of pharmacology. Aug 2016;173(15):2352-2368.

Zhou XM, Huang MM, He CC, Li JX. Inhibitory effects of citrus extracts on the experimental pulmonary fibrosis. Journal of ethnopharmacology. Oct 29 2009;126(1):143-148.

Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, . . . Kirkland JL. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. Aug 2015;14(4):644-658.

Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. Aug 12 2010;363(7):620-628.