Involvement of nitric oxide in the pathogenesis of adult respiratory syndrome (ARDS) and the regulation of ARDS by osteopontin

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Adult respiratory distress syndrome (ARDS) is a noncardiogenic lung edema. Recent studies suggest that nitric oxide (NO) mediated by inducible NO synthase (iNOS) in activated macrophages is involved in the pathogenesis of ARDS. Osteopontin (OPN) is a phosphorylated glycoprotein produced by a variety of cells including macrophages. Recent findings that OPN inhibits iNOS expression led us to test the hypothesis that OPN may be a counter-regulator for iNOS in development of ARDS. To address this hypothesis, we examined expression of endogenous OPN and iNOS in the lung of a mouse model of ARDS (ARDS mice) and in a murine macrophage cell line, RAW 264.7 cells, by treatment of cells with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Mice were given LPS intratracheally to produce ARDS mice. Coinduction of iNOS and OPN mRNA was observed in the lung of ARDS mice. Interestingly, OPN mRNA was induced more slowly than iNOS mRNA. Stimulation of RAW 264.7 cells with LPS and IFN-γresulted in an increase of iNOS mRNA to maximum at 12 h after stimulation. In contrast, OPN mRNA was induced more slowly than iNOS mRNA, as was also seen in the lung of ARDS mice. Induced OPN mRNA is closely associated with increased iNOS mRNA because expression of both OPN and iNOS mRNA in RAW 264.7 cells was markedly suppressed by addition of the specific iNOS inhibitor or the NOS inhibitor. In addition, the No-releasing agent spermine NONOate enhanced induction of OPN mRNA, suggesting that NO generated by iNOS up-regulates the endogenous OPN in macrophages stimulated with LPS and IFN-γ. This up-regulation of endogenous OPN may represent a negative feedback system acting to reduce iNOS expression and may contribute, at least in part, to protect the lungs from LPS-mediated tissue injury.