Diminished Prostaglandin E₂Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

Abstract

Rationale: Patients with idiopathic pulmonary fibrosis (IPF), a progressive disease with a dismal prognosis, exhibit an unexplained disparity of increased alveolar epithelial cell (AEC) apoptosis but reduced fibroblast apoptosis. Objectives: To examine whether the failure of patients with IPF to upregulate cyclooxygenase (COX)-2, and thus the antifibrotic mediator prostaglandin (PG)E 2 , accounts for this imbalance. Methods: Fibroblasts and primary type II AECs were isolated from control and fibrotic human lung tissue. The effects of COX-2 inhibition and exogenous PGE 2 on fibroblast and AEC sensitivity to Fas ligand (FasL)-induced apoptosis were assessed. Measurements and Main Results: IPF lung fibroblasts are resistant to FasL-induced apoptosis compared with control lung fibroblasts. Inhibition of COX-2 in control lung fibroblasts resulted in an apoptosis-resistant phenotype. Administration of PGE 2 almost doubled the rate of FasL-induced apoptosis in fibrotic lung fibroblasts compared with FasL alone. Conversely, in primary fibrotic lung type II AECs, PGE 2 protected against FasL-induced apoptosis. In human control and, to a greater extent, fibrotic lung fibroblasts, PGE 2 inhibits the phosphorylation of Akt, suggesting that regulation of this prosurvival protein kinase is an important mechanism by which PGE 2 modulates cellular apoptotic responses. Conclusions: The observation that PGE 2 deficiency results in increased AEC but reduced fibroblast sensitivity to apoptosis provides a novel pathogenic insight into the mechanisms driving persistent fibroproliferation in IPF.

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

“…Previous studies have shown that cycloheximide alone is insufficient to induce fibroblast apoptosis (11,35), a finding that was confirmed in a subset of experiments for each of the different fibroblast populations studied. Together, these findings are consistent with prior studies showing that normal fibroblasts are relatively resistant to Fas-mediated apoptosis, that IPF lung fibroblasts have increased resistance to Fas-mediated apoptosis compared with normal lung fibroblasts, and that cycloheximide "sensitizes" normal and IPF fibroblasts to undergo robust apoptosis upon Fas activation (8,10,12,(33)(34)(35)(37)(38)(39). Additionally, these findings demonstrate that IMR-90 and CCL-210 fibroblasts exhibit Fas-induced apoptotic responses that are indistinguishable from primary normal lung fibroblasts isolated from lung explants.…”

“…Another recent report similarly showed that X-linked inhibitor of apoptosis (XIAP or BIRC4) is highly expressed within the mesenchymal cells of fibroblastic foci but not in the overlying epithelium (12). PGE 2 treatment suppressed XIAP and enhanced Fas-mediated apoptosis in lung fibroblasts, supporting a potential mechanistic role for XIAP in fibroblast survival (12).…”

“…IPF is characterized by the accumulation of fibroblasts and myofibroblasts, which aggregate in clusters termed "fibroblastic foci," the number of which correlates with patient mortality (13, 15). Although several studies have shown that fibroblasts within fibroblastic foci lack evidence of apoptosis, the mechanisms responsible for this apparent resistance to apoptosis are not clear (12,16,17).Parallels have been made between the biologic mechanisms observed in IPF and cancer (18,19). The inhibitor of apoptosis (IAP) protein family contains eight different members that contain at least one baculovirus IAP repeat (BIR) domain, which is critical for the ability of these proteins to interact with caspases and prevent apoptosis in vitro (20).…”

“…IPF is characterized by the accumulation of fibroblasts and myofibroblasts, which aggregate in clusters termed "fibroblastic foci," the number of which correlates with patient mortality (13, 15). Although several studies have shown that fibroblasts within fibroblastic foci lack evidence of apoptosis, the mechanisms responsible for this apparent resistance to apoptosis are not clear (12,16,17).…”

“…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).…”