Idiopathic Pulmonary Fibrosis
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)
- Wood smoke
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 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.