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

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 PGE ₂-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.