Evolving concepts of apoptosis in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive fibrosing disease of the lung of unknown etiology. Significant progress has been made in recent years in elucidating key aspects of the pathobiology of IPF. Insights into disease pathogenesis have come from studies of cell biology, growth factor/cytokine signaling, animal models of pulmonary fibrosis, and human IPF cells and tissue. A consistent finding in the ultrastructural pathology of IPF is alveolar epithelial cell injury and apoptosis. Another consistent finding in the histopathology of human IPF, described as usual interstitial pneumonia, is the accumulation of aggregates of myofibroblasts in fibroblastic foci. The extent or profusion of fibroblastic foci in lung biopsies is strongly correlated with increased mortality in patients with IPF. There is emerging evidence that myofibroblasts in IPF/usual interstitial pneumonia, both in the in vivo microenvironment and during the process of differentiation in vitro, acquire resistance to apoptosis. Here, we review the current evidence and mechanisms for this apparent "apoptosis paradox" in the pathogenesis of IPF.

Figure 1.

Proposed proapoptotic mediators and pathways activated in alveolar epithelial cells of idiopathic pulmonary fibrosis (IPF). Additional proapoptotic mechanisms in epithelial cells that may need to be considered include latent viral infections and acquired defects in protein processing and trafficking (not depicted—see text for details). AR = angiotensin receptor (subtype I); ATII = angiotensin II; BAX = BCL-2–associated protein; BCL-2 = B-cell lymphoma 2; EGR-1 = early growth response protein-1; FADD = Fas-associated death domain; Fas = apoptosis-mediating surface antigen (aka Apo-1 and CD95); FasL = Fas ligand; p38 MAPK = p38 mitogen-activated protein kinase; ROS = reactive oxygen species; Smads = mothers against decapentaplegia in Drosophila (Mad) gene and the related Sma gene in Caenorlabditis elegans.

Figure 2.

Proposed antiapoptotic (survival) mediators and pathways activated in fibroblasts/myofibroblasts of IPF. Akt = protein kinase B; FAK = focal adhesion kinase; FLIP(L) = Fas-like interleukin-1β–converting enzyme-inhibitory protein; IGF-1 = insulin growth factor-1; ILK = integrin-linked kinase; XIAP = X-linked inhibitor of apoptosis.