Molecular and cellular mechanisms of pulmonary fibrosis

Pulmonary fibrosis is a chronic lung disease characterized pathologically by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture, and additionally characterized by recognizable clinical, physiologic, and radiographic findings. Though some descriptions of fibrous diseases of the lungs can be found as early as the 5th century BC by Hippocrates [1,2], more modern descriptions of pulmonary fibrosis occurred in the early part of the 20th century with reports by Hamman and Rich of four patients with rapidly progressive diffuse interstitial fibrosis of the lungs [3,4]. Although the prognosis of patients with diffuse pulmonary fibrosis is poor, it was subsequently realized that many patients did not have the extremely rapid deteriorating course that was described by Hamman and Rich. With further pathologic analysis, several distinct types of pulmonary fibrosis were described, and the terms diffuse fibrosing alveolitis, diffuse interstitial fibrosis, and idiopathic pulmonary fibrosis (IPF) were introduced to describe a more insidious, yet still debilitating form of chronic pulmonary fibrosis [5,6]. Currently, IPF is considered the most common and severe form of pulmonary fibrosis, with a disheartening median survival of approximately three years, with no proven effective therapy, and with lung transplantation remaining the only viable intervention in end-stage disease [7].The pathologic findings in pulmonary fibrosis (excessive accumulation of ECM and remodeling of the lung architecture) are a consequence of disturbances in two physiologically balanced processes: proliferation and apoptosis of fibroblasts, and accumulation and breakdown of ECM. When the normal balance between ECM deposition and turnover is shifted toward deposition or away from breakdown, excessive ECM accumulates. When the balance between fibroblast proliferation and apoptosis is shifted toward accelerated proliferation or slowed apoptosis, fibroblasts - the primary