INHIBITION OF PLEURAL MESOTHELIAL CELL COLLAGEN-SYNTHESIS BY NITRIC-OXIDE

The pleural mesothelial cell has a critical role in repairing the meso thelium after injury via its ability to produce connective tissue macr omolecules. We have recently shown that proinflammatory cytokines and lipopolysaccharide induce pleural mesothelial cells to produce nitric oxide. The present study examined the effect of nitric oxide on pleura l mesothelial cell protein synthesis. Rat pleural mesothelial cells we re exposed to various combinations of tumor necrosis factor, interleuk in-l, interferon-gamma, and lipopolysaccharide or to the nitric oxide donors: 6-morpholino-sydnonimine, S-nitroso-N-acetyl-D,L-penicillamine , sodium nitroprusside, and spermine-NC adduct for 24-48 h. Nitrate an d nitrite (an index of nitric oxide production) and net collagen and n oncollagen protein production (uptake of H-3-proline into collagenase- sensitive protein) were then determined. Net collagen production was s ignificantly inhibited by the cytokine-lipopolysaccharide combinations tested. Collagen inhibition paralleled the time course of increased n itric oxide production. The inhibition of collagen production was also significantly reversed by the addition of N-G-nitro-L-arginine methyl ester, and was reproduced by the addition of a 5:1 molar excess of L- arginine to N-G-nitro-L-arginine methyl ester. Additionally, nitric ox ide-generating compounds significantly inhibited collagen production i n a dose-dependent manner compared to unexposed control cells. Net col lagen production was inhibited to a greater degree than noncollagen pr otein synthesis. These results suggest that nitric oxide may be a sign ificant mediator of PMC collagen production during conditions of signi ficant pleural inflammation.