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.

Mechanisms of Lung Fibrosis Resolution

“…67 There is significant overlap and cross talk between different modes of cell death, and distinctions are not always clear; however, almost all of the accumulated data in lung fibrosis relate to apoptotic cell death. 67,68 Apoptosis is mediated by the concerted action of a set of cysteine proteases known as caspases. There are two major pathways of apoptosis, the death receptor and mitochondrial pathways, which converge to activate effector caspases, caspase-3 and caspase-7, which execute the apoptotic cell death program.…”

“…There are two major pathways of apoptosis, the death receptor and mitochondrial pathways, which converge to activate effector caspases, caspase-3 and caspase-7, which execute the apoptotic cell death program. 67,68 Apoptosis has been shown to be the primary mechanism of myofibroblast elimination in granulation tissue during the resolution phase of normal wound repair. 69 Apoptosis has also been identified as a primary mechanism of myofibroblast removal in the bleomycin lung fibrosis model.…”

Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

“…28,29 Remarkably, fibroblasts in IPF lungs exhibit few signs of apoptosis. 2 We determined that the proapoptotic peroxidated lipid 4-HNE was present throughout IPF lungs, particularly in alveolar macrophages, and to a lesser extent, in type II alveolar epithelial cells, and fibroblasts/myofibroblasts (Supplemental Figure 1, …”

“…We affinitypurified IgG using a peptide affinity column. Horseradish peroxidase-, fluorescein isothiocyanate-, rhodamine-, and Cy5-conjugated F(abЈ) 2 fragments of donkey anti-goat, -rabbit, and -mouse IgG were from Jackson ImmunoResearch Laboratories (West Grove, PA). Alexa Fluor 488-or 594-conjugated anti-mouse, anti-rabbit, or anti-goat IgG, and 4Ј,6-diamidino-2-phenylindole diacetate (DAPI) were from Molecular Probes/Invitrogen (Carlsbad, CA).…”

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

“…Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3,4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5,6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7)(8)(9)(10)(11)(12).…”