Am. J. Respir. Cell Mol. Biol., Volume 21, Number 1, July, 1999 128-136

Reactive Oxygen and Nitrogen Intermediates Increase Transforming Growth Factor-1 Release from Human Epithelial Alveolar Cells through Two Different Mechanisms

Agnes Bellocq, Elie Azoulay, Stefano Marullo, Antoine Flahault, Bruno Fouqueray, Carole Philippe, Jacques Cadranel, and Laurent Baud

Service d'Explorations Fonctionnelles and Unité INSERM 489, Service de Biostatistique et Informatique, and Service de Pneumologie and UPRES-A 1531, Hôpital Tenon; and UPRES-A 8068, Hôpital Cochin, Paris, France

Transforming growth factor (TGF)-1 is a growth factor involved in the mechanisms of lung repair and fibrosis that follow inflammatory processes. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) or reactive nitrogen intermediates (RNI) by inflammatory cells and the expression of TGF-1 by alveolar epithelial cells. Exposure of the A549 lung epithelial cell line to either an ROI generating system (xanthine and xanthine oxidase) or an RNI donor (S-nitroso-N-acetyl-penicillamine [SNAP]) promoted a time- and dose-dependent increase in TGF-1 release, as measured by a specific enzyme-linked immunosorbent assay. At the peak, the levels of TGF-1 were twice the control values. The induction of TGF-1 release by ROI was blunted by catalase and unaffected by superoxide dismutase, indicating the involvement of hydrogen peroxide. The response was also blunted by 5,6-dichloro-1--D-ribofuranosyl benzimidazole (DRB), a specific RNA polymerase II inhibitor, and accompanied by a corresponding increase in TGF-1 messenger RNA, as measured by quantitative/competitive reverse transcription polymerase chain reaction, suggesting the involvement of transcriptional mechanisms and possibly other downstream mechanisms. In contrast, RNI-induced TGF-1 release was unaffected by DRB and blunted by the protein synthesis inhibitor cycloheximide, suggesting the involvement of translational and post-translational mechanisms. This response required cyclic guanosine monophosphate (cGMP)- mediated processes because (1) immunoreactive cGMP accumulated in the culture medium of SNAP-treated cells; (2) SNAP-induced TGF-1 release was blunted by KT 5823, an inhibitor of cGMP-dependent protein kinase; and (3) similar increase in TGF-1 release was obtained by cell exposure to membrane-permeable dibutyryl-cGMP or to atrial natriuretic factor, a known agonist of particulate guanylate cyclase. These data suggest that in vitro exposure of human alveolar epithelial cells to ROI and RNI enhances TGF-1 release through different mechanisms. In vivo, this control may constitute a molecular link between inflammatory and fibrotic processes.

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