When germ theory was first proposed in the 19th century, its proponents were widely ridiculed and shunned. At that time, it was difficult to imagine that something invisibly small, like germs, could be responsible for causing illnesses. The far more popular theory at that time was “miasma theory”—the idea that diseases are caused by “bad air.”
Today, the medical community is in full agreement on the validity of the germ theory. When it was accepted, it was a true paradigm shift in every sense.
Paradigm shifts still occur in medicine from time to time, but smaller shifts in the way we think about the etiology and treatment of certain diseases occur far more frequently. This is certainly true in diseases such as idiopathic pulmonary fibrosis (IPF), which we still know little about.
Oldham and Vancheri wrote an article published in Clinics in Chest Medicine entitled “Rethinking Idiopathic Pulmonary Fibrosis.” In their paper, they discussed past thinking on various aspects of the disease and how some of it has changed over the years.
Because inflammatory processes can be observed in IPF, the medical community initially accepted an inflammatory framework in thinking about this disease. When scientists first described IPF in 1964, they thought it represented an inflammatory parenchymal process with the alveoli being primarily involved. The idea was that alveolar inflammation caused the fibrosis typically observed in IPF, as was the case in other lung diseases.
However, studies indicated that the alveolar inflammation in IPF was minimal. This led to the medical community embracing a new way of thinking about the etiology of IPF: that it was caused by repeated alveolar injury followed by abnormal wound healing. Hadjicharalambous and Lindsay concurred, stating, “As is the case with most inflammatory lung diseases, inflammation was initially thought to be the major player in IPF until unresponsiveness to anti-inflammatory medications prompted the re-evaluation of this idiom.”
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Hadjicharalambous and Lindsay continued to describe this theory in more detail. They wrote, “Under physiological conditions, fibrogenesis is initiated in response to tissue injury and forms part of the wound repair process involved in the restoration of homeostasis.” In IPF, this is not the case, leading to the irreversible accumulation of scar tissue. This results in pathological remodeling of the lung architecture. What drives the abnormal wound repair process in IPF is still under investigation.
Scientists are also trying to uncover any genetic causes underpinning IPF. For example, Oldham and Vancheri discussed a theory linking IPF susceptibility to telomere length. Telomeres serve as “protective caps” at the end of each chromosome. They wrote, “Although gene variants are static, telomere maintenance is a dynamic process that can result in critically short telomere length in the setting of deleterious telomerase gene mutations, increasing age, and repetitive toxic exposures.” Scientists thus believe that telomere shortening may create conditions that allow individuals to become susceptible to developing IPF.
Due to the initial inflammatory theory on the pathophysiology of IPF, the standard treatment protocol consisted of corticosteroids and immunosuppressant therapies, such as azathioprine and cyclophosphamide, for decades. In 2011, a landmark clinical trial demonstrated that a greater proportion of deaths and hospitalizations occurred in patients treated with a combination of prednisolone, azathioprine, and N-acetylcysteine. This trial and others suggest that inflammation plays a supporting role in profibrotic signaling, rather than driving it. This brought the era of treating IPF purely through immunosuppression to a close.
At the same time, clinical trials involving drugs with antifibrotic properties, such as pirfenidone and nintedanib, were gaining traction. Oldham and Vancheri wrote, “After promising phase II results, these therapies were studied in large phase III clinical trials and showed each therapy to effectively slow lung function decline in patients with IPF, resulting in their approval for the treatment of IPF in many countries around the world.”
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A number of studies since then have confirmed the clinical benefits of antifibrotic agents; they were discovered to reduce the risks of acute exacerbations, hospitalizations, and mortality. In fact, evidence shows that they result in better clinical outcomes for patients with IPF regardless of age, the onset of the disease, and lung function.
Hadjicharalambous and Lindsay wrote about the investigations into the role of long, noncoding RNAs in causing IPF. Long, noncoding RNAs regulate gene expression, and there are several noncoding RNAs that are thought to be possible drivers of the disease. This is significant because further research into the genetics of IPF may lead to the development of future gene therapies.
The authors concluded, “As a consequence of their cell and tissue-specific expression, the identification of long, non-coding RNAs that drive cellular activities within the IPF lungs could present a great opportunity for the development of novel treatment strategies.”
In light of what we currently understand about IPF, what can we expect to change in the years ahead? We can anticipate deepening our understanding of the pathophysiology of the disease, especially in terms of the link between lung injury and fibrosis. In addition, our diagnostic tools might be refined as a result of these changes. We can also expect treatment guidelines to evolve according to the development of new, effective, and safe therapies.
Oldham JM, Vancheri C. Rethinking idiopathic pulmonary fibrosis. Clin Chest Med. 2021;42(2):263-273. doi:10.1016/j.ccm.2021.03.005.
Hadjicharalambous MR, Lindsay MA. Idiopathic pulmonary fibrosis: pathogenesis and the emerging role of long non-coding RNAs. Int J Mol Sci. 2020;21(2):524. doi:10.3390/ijms21020524