Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia.
BACKGROUND
Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator.


OBJECTIVE
To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts.


METHODS
Fibroblasts were grown in vitro from well characterized control (n = 7), UIP (n = 17), or other DPLD (n = 13) lung tissue. The effects of PGE2 on fibroblast proliferation and collagen expression were determined.


RESULTS
Only 3 of 12 UIP fibroblast lines exhibited PGE2-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE2 resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE2, whereas other DPLD fibroblasts manifested a degree of resistance intermediate to control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A.


CONCLUSIONS
The recognition that UIP fibroblasts manifest variable refractoriness to PGE2 suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.
Huang
Steven K
SK
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Wettlaufer
Scott H
SH
Hogaboam
Cory M
CM
Flaherty
Kevin R
KR
Martinez
Fernando J
FJ
Myers
Jeffrey L
JL
Colby
Thomas V
TV
Travis
William D
WD
Toews
Galen B
GB
Peters-Golden
Marc
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000473:pathology
D024042:Collagen Type I; D000242:Cyclic AMP; D015232:Dinoprostone