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Epithelial fibroblast triggering and interactions in pulmonary fibrosis

CORRESPONDENCE: P. W. Noble, Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, MSRBII, 106 Research Drive, DUMC Box 103000, Durham, NC 27710, USA. Fax: 1 9196845389. E-mail: paul.noble{at}duke.edu

Idiopathic pulmonary fibrosis (IPF) is characterised by repeated injury to the alveolar epithelium with loss of lung epithelial cells and abnormal tissue repair, resulting in excessive accumulation of fibroblasts and myofibroblasts, deposition of extracellular matrix components and distortion of lung architecture, eventually leading to respiratory failure.

There is growing circumstantial evidence to suggest that in IPF the alveolar epithelium is prone to undergoing programmed cell death following repeated injury, although the mechanism for inducing epithelial apoptosis is, as yet, unknown. Potentially, one explanation may be the formation of misfolded proteins and an unfolded protein response-mediated apoptosis in alveolar epithelial cells (AECs), in response to abnormal protein production and aggregation.

Epithelial apoptosis is accompanied by damage to the basement membrane leading to the release of growth factors and chemokines, which recruit fibroblasts to the site of injury (fibroblastic foci). Instead of AECs healing by repair, myofibroblast proliferation and extracellular matrix deposition continues unabated in IPF.

The transformation of epithelial cells into mesenchymal cells, a process known as epithelial-mesenchymal transition, which allows direct communication between cells, is a possible explanation for the activation of alveolar epithelial cells in idiopathic pulmonary fibrosis. The present article discusses this process and other potential mechanisms by which epithelial cell injury can lead to fibroblast recruitment and accumulation in idiopathic pulmonary fibrosis.

KEYWORDS: Alveolar epithelial cells, apoptosis, epithelial–mesenchymal transition, misfolded proteins, unfolded protein response