Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. Interstitial lung disease in itself is an umbrella term for various diseases that cause inflammation, cellular proliferation, and fibrosis of lung tissue. The fibrosis of the lung replaces healthy tissue with a modified extracellular matrix that deeply damages it.
There is much we still do not know about IPF, particularly its pathogenesis, but we are getting closer to unlocking key mysteries surrounding it with each new piece of research. Researchers conducted a review of currently available scientific literature around IPF and published their findings recently in Experimental Gerontology. They looked into the clinical features, molecular mechanisms, and therapies of IPF, which will be summarized in this article.
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Prognosis Remains Poor
IPF has a histological presentation of usual interstitial pneumonia (UIP) that is also commonly found in other lung diseases such as asbestosis. Among the common clinical presentations of IPF are dyspnea, bibasilar end-inspiratory crackles, oxygen desaturation, and cough.
Although IPF accounts for roughly 20% to 50% of ILD cases, it is considered a rare disease because it has a prevalence of less than 5 per 10,000 population. Predicting the disease progression of IPF has proven to be difficult because it varies greatly among patients. In some patients, lung fibrosis progresses slowly; in others, it occurs rapidly, resulting ultimately in lung destruction. Regardless of the speed of disease progression, the prognosis remains poor; studies show a median survival time of between 3 to 5 years after diagnosis.
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Age, Environment May Play a Role
Although the exact causes of IPF are not yet established, there are a few things we do know about the disease. For example, we know that age plays a factor; the disease is almost nonexistent in patients under the age of 50, while morbidity is known to significantly increase in those over the age of 75. This suggests that the mechanisms of aging — such as the shortening of telomeres, cellular senescence, and oxidative stress — have something to do with the disease.
Researchers have also looked into the role of environmental factors in causing IPF. Air pollution, for example, has significantly worsened over the years, and the lungs are the human organs most susceptible to its effects. Air pollution is known to cause and worsen fibrosis in susceptible lungs. In addition, researchers have also looked into the possible link between smoking and IPF. A meta-analysis found that smoking significantly increases the risk of developing IPF, although its exact mechanisms for doing so remain unknown.
Additionally, the authors of this study looked into possible genetic factors that may be linked to IPF. Familial interstitial pneumonia (FIP) is an inherited form of IPF that is characterized by 2 or more members of a family developing IPF. Researchers have identified 4 genes that cause FIP, and recent whole exome sequencing has uncovered additional genes in the telomerase complex that are associated with FIP. This suggests IPF may have an underlying genetic cause.
Researchers have also examined the role of fibroblast cells in IPF disease progression. IPF is known to develop from the chronic activation of fibroblasts, which causes the remodeling of the fibroblast matrix. This impairs the ability of the lung to heal itself when an injury occurs. In addition, studies have shown that IPF fibroblasts overexpress certain genes that are fundamental to IPF progression.
IPF progression is also known to be caused by the enhanced apoptosis of alveolar epithelial cells and the greater differentiation of epithelial cells to myofibroblasts. The excessive production of oxidants is known to mediate this process. Both primarily reactive oxygen species (ROS) and reactive nitrogen species (RNS) cause the direct deterioration of the intracellular component. Free radicals can also activate many pro-fibrogenic factors that carry out apoptotic signaling.
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A Lack of Consensus on Treatment
To this day, there is no consensus on the standard therapy needed to effectively treat IPF. Therapies in countering IPF progression are predominantly based on the perception that inflammation causes lung injury and fibrosis, thus explaining the widespread use of agents that suppress or eliminate the inflammatory response. The current goals in IPF management are to interfere with the disease progression and to prevent acute exacerbations.
The most common therapies used in IPF patients are immunomodulatory agents, such as prednisolone and azathioprine. However, the poor median survival time indicates that their efficacy is low. A recent study looking into the combined therapy of prednisolone, N-acetylcysteine, and azathioprine was stopped due to safety concerns.
Pirfenidone, an antifibrotic agent, has been approved for oral usage and a study conducted in 2020 shows that its usage can significantly reduce IPF disease progression after 1 year of therapy. Another study confirms its efficacy in slowing disease progression, as well as improving progression-free survival rate.
A significant factor hindering advancements in IPF therapies is our lack of knowledge regarding the mechanisms behind tissue remodeling and the fate of altered somatic cells. The complexity and heterogeneity of lung tissue change present a challenge to interpreting data collected from prior research. Thus, the individual cell types involved in IPF pathogenesis remain elusive, although researchers have attempted to use single-cell RNA sequencing to solve this problem.
“As far as upcoming therapeutic regimens are concerned, the development of effective and efficient therapies for the treatment of acute exacerbation of IPF should be a deciding factor in the next decade,” the authors of this study opine.
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Improving Clinical Practice
Our understanding of IPF is improving on almost all fronts that matter most. We now have a better grasp of the risk factors that causes IPF, the pathogenesis of the disease, as well as possible new therapies that can prolong the survival rates of IPF patients. It often takes some time for research conducted to make an impact on real-world clinical practice; however, with such promising new information as detailed in this article, we can expect our understanding of IPF to solidify significantly in the years ahead, leading to better therapies and better patient outcomes.
Signh Suri G, Kaur G, Kumar Jha C, Tiwari M. Understanding idiopathic pulmonary fibrosis – clinical features, molecular mechanism and therapies. Experimental Gerontology. 2021;153:111473. doi:10.1016/j.exger.2021.111473
Lawson WE, Loyd JE, Degryse AL. Genetics in pulmonary fibrosis–familial cases provide clues to the pathogenesis of idiopathic pulmonary fibrosis. Am J Med Sci. 2011;341(6):439-443. doi:10.1097/MAJ.0b013e31821a9d7a