While an exact cause of IPF may not be well established, a growing body of evidence suggests that fibrosis arises from repeated epithelial injury.1
Endogenous or environmental stimuli repeatedly damage alveolar epithelial cells. Stimulated alveolar epithelial cells release cytokines and other mediators, which leads to a fibrotic response.2,3
It is thought that the activity of lung epithelial cells is mediated through the activation of downstream signaling pathways, triggered in response to growth factor binding to receptors (including the TGF-beta, FGF, and PDGF receptors*).4–6
The fibrotic response is mediated through fibroblast proliferation and differentiation into myofibroblasts.5 TGF-beta is thought to promote the transformation of fibroblasts into myofibroblasts, as well as collagen secretion and deposition. Signaling through PDGF and FGF receptors may promote the recruitment, migration, and proliferation of fibroblasts and myofibroblasts at sites of injury.5–10
Fibroblasts and myofibroblasts deposit collagen in the extracellular matrix, while evading apoptosis.2,3 As fibrosis continues, the tissue thickens and lung architecture becomes distorted.
There is still a lot to be understood about the cause of IPF. A greater understanding of the pathways implicated in its pathogenesis could help fuel development of novel therapies that could help control disease progression.3,4
*PDGF, platelet-derived growth factor; TGF-beta, transforming growth factor beta; FGF, fibroblast growth factor
- Borensztajn K., et al. Idiopathic pulmonary fibrosis: from epithelial injury to biomarkers--insights from the bench side. Respir Int Rev Thorac Dis 2013;86:441–452.
- Selman M., et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136–151.
- Fernandez IE., et al. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 2012;380:680–688.
- Strieter RM., et al. New mechanisms of pulmonary fibrosis. Chest 2009;136:1364–1370.
- Richeldi L., et al. Mapping the future for pulmonary fibrosis: report from the 17th International Colloquium on Lung and Airway Fibrosis. Eur Respir J 2013;42:230–238.
- Chaudhary NI., et al. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 2007;29:976–985.
- Todd NW., et al. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair 2012;5:11.
- Wollin L., et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 2014;349:209–220.
- Leask A. Towards an anti-fibrotic therapy for scleroderma: targeting myofibroblast differentiation and recruitment. Fibrogenesis Tissue Repair 2010;3:8.
- Inoue Y., et al. Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. Am J Respir Crit Care Med 2002;166:765–773.