Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis.
BACKGROUND
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.


OBJECTIVE
To examine whether the failure of patients with IPF to up-regulate 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.


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.
Maher
Toby M
TM
Centre for Respiratory Research, University College London, Rayne Building, 5 University Street, London WC1E 6JJ, UK. r.mcanulty@ucl.ac.uk
Evans
Iona C
IC
Bottoms
Stephen E
SE
Mercer
Paul F
PF
Thorley
Andrew J
AJ
Nicholson
Andrew G
AG
Laurent
Geoffrey J
GJ
Tetley
Teresa D
TD
Chambers
Rachel C
RC
McAnulty
Robin J
RJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000502:physiology; D014945:Wound Healing / Q000502:physiology
D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone