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Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of idiopathic interstitial pneumonia. The disease is thought to arise following an aberrant reparative response to recurrent alveolar epithelial cell injury leading to progressive loss of function. The median survival time is 3–5 years from diagnosis. Cigarette smoking, exposure to organic and inorganic dust and genetic factors have been shown to increase the risk of disease, although the cause of IPF remains elusive and its pathogenesis incompletely understood. In the last decade, several clinical trials evaluating novel therapies for IPF have been conducted but the results have been mostly disappointing. Conversely, compounds that target anti-fibrotic and growth factor pathways have been proven effective in slowing functional decline and disease progression. These promising results notwithstanding, truly effective therapeutic strategies will likely require combinations of drugs in order to target the multitude of pathways involved in disease pathogenesis.
Financial & competing interests disclosure
P Spagnolo is a consultant for InterMune. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic interstitial pneumonias, is a chronic, progressive and usually lethal disease for which few therapeutic options exist.
While the cause of IPF remains unknown, the disease appears to develop in genetically predisposed individuals following exposure to a variety of fibrogenic triggers.
Epithelial cell injury is currently proposed as the initial event that triggers a series of aberrant reparative pathways leading to fibrosis. Abnormally activated alveolar epithelial cells induce the activation and proliferation of mesenchymal cells (fibroblasts and myofibroblasts) that produce an excessive amount of extracellular matrix in the lung interstitium.
A multitude of different mechanisms may potentially lead to the expansion of the fibroblastic pool, but it is unclear to what extent each of these pathways actually contributes to the fibrogenic process of IPF.
Several large, high-quality clinical trials evaluating novel therapies for IPF have recently been concluded and many more are currently ongoing.
Pirfenidone – a compound that inhibits TGF-β in vitro – has been shown to slow the rate of functional decline and prolong the progression-free survival time and is the only drug approved for the treatment of patients with mild-to-moderate IPF.
IPF is a disease characterized by abnormalities in multiple pathways – many of which are pleiotropic and redundant. Therefore, in future more effective therapies will likely consist of combinations of drugs, each targeting diverse yet specific fibrogenic pathways.
A better understanding of disease pathogenesis will not only provide new targets to therapy but also allow translation of these insights into clinical practice with the possibility to identify predictors of disease behavior.