The involvement of nitric oxide in a mouse model of adult respiratory distress syndrome.
The release of free radicals and pro-inflammatory cytokines such as nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) is commonly observed in adult respiratory distress syndrome (ARDS) following infection or exposure to microbial products. The aim of this study was to scrutinize the involvement of NO in ARDS in a mouse model determined by the sequential exposure to lipopolysaccharide (LPS) and formyl-norleucyl-phenylalanine (FNLP). Nitrite measurements in bronchoalveolar lavage fluids (BALF) and sera demonstrated that exposure to microbial products elicits large amounts of NO in LPS/FNLP-challenged mice. This release was significantly inhibited by infusion with the inducible NO synthase antagonist, aminoguanidine (AG). Our results show that LPS/FNLP exposure induces lung damage as demonstrated by protein and lactate dehydrogenase (LDH) increases in BALF. Liver damage was also detected in LPS/FNLP-challenged mice with increases in serum ornithine-carbamoyltransferase (OCT) levels. LPS/FNLP infusion led to elevated levels of the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) in the sera. LPS/FNLP also led to neutrophil adhesion in the lung vasculature, as seen by increased levels of myeloperoxydase. Interestingly, inhibition of NO release in challenged mice led to an important increase in markers of tissue damage in the lungs and livers, but a decrease in neutrophil recruitment. Infusion of AG in LPS/FNLP-challenged mice led to a much increased level of sera TNF alpha. These data suggest that after exposure to microbial products, NO generated as a result of activation of the inducible NO synthase blocks the full expression of tissue damage in the lungs.
Département de Pharmacologie, C.H.U.S., Université de Sherbrooke, Canada.
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Pheng
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Francoeur
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Denis
D000818:Animals; D015415:Biomarkers; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000097:blood; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000097:blood / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000503:physiopathology*
D015415:Biomarkers; D016207:Cytokines; D004151:Dipeptides; D008070:Lipopolysaccharides; C097577:N-formyl-norleucyl-phenylalanine; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D009195:Peroxidase; D009954:Ornithine Carbamoyltransferase