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Published ahead of print on October 4, 2007, doi:10.1164/rccm.200706-963OC
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American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 66-74, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200706-963OC

Original Article

Variable Prostaglandin E2 Resistance in Fibroblasts from Patients with Usual Interstitial Pneumonia

Steven K. Huang1, Scott H. Wettlaufer1, Cory M. Hogaboam2, Kevin R. Flaherty1, Fernando J. Martinez1, Jeffrey L. Myers2, Thomas V. Colby3, William D. Travis4, Galen B. Toews1 and Marc Peters-Golden1

1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and 2 Department of Pathology, University of Michigan, Ann Arbor, Michigan; 3 Department of Pathology, Mayo Clinic, Scottsdale, Arizona; and 4 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York

Correspondence and requests for reprints should be addressed to Marc Peters-Golden, M.D., Division of Pulmonary and Critical Care Medicine, 1150 W. Medical Center Drive, 6301 MSRB III, Ann Arbor, MI. E-mail: petersm{at}umich.edu

Rationale: 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.

Objectives: 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.

Measurements and Main 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.

Key Words: collagen • cAMP • idiopathic pulmonary fibrosis • nonspecific interstitial pneumonia • proliferation


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Prostaglandin (PG) E2 is a potent inhibitor of cellular function in normal lung fibroblasts. There are no studies that have comprehensively examined the responsiveness to PGE2 in fibroblasts from patients with well-defined fibrotic lung disease.

What This Study Adds to the Field
Fibroblasts from the majority of patients with usual interstitial pneumonia exhibited resistance to the inhibitory effects of PGE2 on collagen expression and/or cell proliferation. Mechanistic explorations revealed several signaling defects that account for this resistance.

 



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