Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition

Recent studies support the concept that pulmonary granulomatous inflammatio n directed by interferon (IFN)-gamma, interleukin (IL)-12, and nitric oxide usually resolves In the absence of fibrosis. To determine whether nitric o xide participates in modulating the fibrotic response during the developmen t of pulmonary granulomas in response to purified protein derivative (PPD), mice presensitized to PPD received daily intraperitoneal injections of N-G -nitro-D-arginine-methyl ester (D-NAME), N-G-nitro-L-arginine-methyl ester (L-NAME), or aminoguanidine after delivery of PPD-coated beads to the lungs . Eight days later, morphometric analysis of lung granulomas revealed that L-NAME-treated mice when challenged with PPD in vitro for 36 hours had the largest pulmonary granulomas and the greatest collagen deposition among the treated groups. In addition, equivalent numbers of dispersed lung cells fr om L-NAME- and aminoguanidine-treated mice produced significantly higher le vels of IL-4, monocyte chemoattractant protein (MCP)-1, and macrophage infl ammatory protein (MIP)-1 alpha and significantly lower levels of eotaxin co mpared with D-NAME-treated mice. Cultures of dispersed lung cells from L-NA ME-treated mice also produced significantly more IL-10 and less IL-12 compa red with similar numbers of dispersed lung cells from D-NAME-treated mice. Cultures of isolated lung fibroblasts from L-NAME-treated mice expressed hi gher levels of C-C chemokine receptor 2 (CCR2) and CCR3 mRNA and contained less MCP-1 and eotaxin protein than a similar number of fibroblasts from D- NAME-treated mice. Thus, nitric oxide appears to regulate the deposition of extracellular matrix in lung granulomas through the modulation of the cyto kine and chemokine profile of these lesions. Alterations in the cytokine, c hemokine, and procollagen profile of this lesion may be a direct effect of nitric oxide on the pulmonary fibroblast and provide an important signal fo r regulating fibroblast activity during the evolution of chronic lung disea se.