Idiopathic Pulmonary Fibrosis
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 (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, 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 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 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).
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)
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