Conceptual pathogenesis of idiopathic pulmonary fibrosis: Key role of the fibroblast

In a genetically predisposed host (eg, telomerase mutation/deficiency), recurrent injury disrupts the alveolar epithelium and basement membrane, and activates cells within the alveolar wall to release proinflammatory cytokines and chemokines, including TNF-alpha, IL-1, and MCP-1. These soluble mediators may activate residential and/or recruit circulating cells including fibrocytes, thus perpetuating the response to recurrent insults. Profibrogenic molecules, such as PDGF and TGF-beta, are also secreted by inflammatory, epithelial, and endothelial cells. Fibroblasts respond to these changes in one of several ways: they may increase in number, they may differentiate into myofibroblasts and actively synthesize collagen; or they may undergo further differentiation, resulting in the expression of unique cell surface receptors. Increased collagen synthesis, coupled with decreased degradation, causes excessive and abnormal collagen deposition. The resulting aggregates, composed of mesenchymal cells and newly synthesized collagen, are called "fibrotic foci". Progressive deposition of extracellular matrix leads to distorted pulmonary architecture with loss of capillary surface area and gas exchange units; the resulting honeycomb fibrotic lung has no potential for regeneration and repair.