Pharmacologic Treatment of Idiopathic Pulmonary Fibrosis
Pharmacologic Treatment of Idiopathic Pulmonary Fibrosis
The exact mechanisms underlying the development of IPF remain elusive, although greater insight into the complicated disease pathogenesis has emerged in recent years. Historically, IPF was viewed as a chronic inflammatory response resulting in progressive pulmonary fibrosis. On the basis of this hypothesis, prior therapeutic trials primarily targeted inflammatory pathways and yielded disappointing results. The current paradigm regarding the pathogenesis of IPF is one of aberrant fibrosis due to recurrent injury to alveolar epithelial cells in a susceptible host. Proposed causes of this repetitive injury include smoking, particulate inhalation, viral infections, gastroesophageal reflux, and chronic aspiration. Although these stimuli are commonly encountered, only a small percentage of exposed individuals develop IPF, suggesting affected individuals have an underlying predisposition to the disease, possibly contributed to by genetic abnormalities, telomere shortening, and aging. The complex pathogenic cascade leading to the development of fibrosis in IPF involves numerous mediators and signaling pathways with considerable redundancy. It is therefore likely that an effective IPF therapy needs to target more than one mechanism or pathway. Indeed, both pirfenidone and nintedanib have pleiotropic effects, and it is likely their clinical efficacy derives from their broad-based mechanisms of action.
Pirfenidone is an orally bioavailable synthetic compound purported to have antifibrotic, anti-inflammatory, and antioxidant effects, although the exact mechanism of action in IPF is incompletely understood. Anti-inflammatory effects are believed to occur from suppression of tumor necrosis factor [alpha] (TNF-α), interleukin (IL)-6, IL-12, and IL-8. Pirfenidone's antifibrotic properties are thought to result primarily from inhibition of expression of transforming growth factor (TGF)-β – a profibrotic cytokine – although a number of other antifibrotic pathways have also been suggested.
Nintedanib is a small molecule tyrosine kinase inhibitor originally designed as an antiangiogenic cancer drug. Nintedanib targets the receptors of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGR). Blockade of these receptors is believed to inhibit downstream signaling cascades of fibroblasts and myofibroblasts, attenuating the development of aberrant fibrosis.
Pathogenesis of Idiopathic Pulmonary Fibrosis and Mechanism of Action of Pirfenidone and Nintedanib
The exact mechanisms underlying the development of IPF remain elusive, although greater insight into the complicated disease pathogenesis has emerged in recent years. Historically, IPF was viewed as a chronic inflammatory response resulting in progressive pulmonary fibrosis. On the basis of this hypothesis, prior therapeutic trials primarily targeted inflammatory pathways and yielded disappointing results. The current paradigm regarding the pathogenesis of IPF is one of aberrant fibrosis due to recurrent injury to alveolar epithelial cells in a susceptible host. Proposed causes of this repetitive injury include smoking, particulate inhalation, viral infections, gastroesophageal reflux, and chronic aspiration. Although these stimuli are commonly encountered, only a small percentage of exposed individuals develop IPF, suggesting affected individuals have an underlying predisposition to the disease, possibly contributed to by genetic abnormalities, telomere shortening, and aging. The complex pathogenic cascade leading to the development of fibrosis in IPF involves numerous mediators and signaling pathways with considerable redundancy. It is therefore likely that an effective IPF therapy needs to target more than one mechanism or pathway. Indeed, both pirfenidone and nintedanib have pleiotropic effects, and it is likely their clinical efficacy derives from their broad-based mechanisms of action.
Pirfenidone is an orally bioavailable synthetic compound purported to have antifibrotic, anti-inflammatory, and antioxidant effects, although the exact mechanism of action in IPF is incompletely understood. Anti-inflammatory effects are believed to occur from suppression of tumor necrosis factor [alpha] (TNF-α), interleukin (IL)-6, IL-12, and IL-8. Pirfenidone's antifibrotic properties are thought to result primarily from inhibition of expression of transforming growth factor (TGF)-β – a profibrotic cytokine – although a number of other antifibrotic pathways have also been suggested.
Nintedanib is a small molecule tyrosine kinase inhibitor originally designed as an antiangiogenic cancer drug. Nintedanib targets the receptors of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGR). Blockade of these receptors is believed to inhibit downstream signaling cascades of fibroblasts and myofibroblasts, attenuating the development of aberrant fibrosis.