Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia

Rationale: Prostaglandin (PG) E-2, 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 PGE(2) 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 PGE(2)-mediated inhibition of both Collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE(2) resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE(2), 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 PGE(2) suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.