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Diminished Prostaglandin E₂ Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis

¹ Centre for Respiratory Research, University College London, Rayne Institute, London; ² Section of Airways Disease, National Heart and Lung Institute, Imperial College, London; and ³ Royal Brompton Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Robin J. McAnulty, Ph.D., Centre for Respiratory Research, University College London, Rayne Building, 5 University Street, London, WC1E 6JJ, UK. E-mail: r.mcanulty{at}ucl.ac.uk

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 up-regulate cyclooxygenase (COX)-2, and thus the antifibrotic mediator prostaglandin (PG)E₂, 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 PGE₂ 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 PGE₂ almost doubled the rate of FasL-induced apoptosis in fibrotic lung fibroblasts compared with FasL alone. Conversely, in primary fibrotic lung type II AECs, PGE₂ protected against FasL-induced apoptosis. In human control and, to a greater extent, fibrotic lung fibroblasts, PGE₂ inhibits the phosphorylation of Akt, suggesting that regulation of this prosurvival protein kinase is an important mechanism by which PGE₂ modulates cellular apoptotic responses.

Conclusions: The observation that PGE₂ deficiency results in increased AEC but reduced fibroblast sensitivity to apoptosis provides a novel pathogenic insight into the mechanisms driving persistent fibroproliferation in IPF.

Key Words: alveolar epithelial cell • fibroblast • pathogenesis • Fas ligand • Akt

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Excess epithelial cell apoptosis and fibroblast resistance to apoptosis are believed to contribute to the fibroproliferation that characterizes idiopathic pulmonary fibrosis (IPF). The mechanism underlying this imbalance in apoptosis is unknown. What This Study Adds to the Field The diminished capacity of patients with IPF to produce prostaglandin (PG)E2 results in increased sensitivity of alveolar epithelial cells to Fas ligand–induced apoptosis but induces fibroblast resistance to the same stimulus.

 

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