Role of nitric oxide in acute lung inflammation: lessons learned from the inducible nitric oxide synthase knockout mouse.
OBJECTIVE
Acute lung inflammation is characterized by complex interactions among cytokines, chemokines, adhesion molecules, leukocytes, and other mediators. Proinflammatory cytokines have been implicated in the up-regulation of the inducible form of nitric oxide synthase (iNOS), which produces large amounts of nitric oxide (NO). Conversely, in some systems, NO regulates the expression of cytokines to affect leukocyte recruitment. Thus, the role of NO both exogenously administered and endogenously produced by iNOS in acute lung inflammation has not been fully elucidated. The current studies suggest a proinflammatory role for inhaled NO in a compartmentalized model of lung injury, whereas blocking of iNOS afforded protection. These results and other previous investigations have been complicated by the use of nonselective blockers of the iNOS isoform.


RESULTS
In an attempt to circumvent this, we examined the response of the lung to direct endotoxin challenge in mice in which iNOS had been genetically deleted (iNOS-/-). We observed a significant decrease in the inflammatory response in the iNOS-/- mice compared with wild-type mice as characterized by decreases in neutrophil accumulation and cytokine expression. Additionally, the lung cytokine response in the iNOS-/- mice was characterized by a significant increase in interleukin-12 and an inability to up-regulate interleukin-10.


CONCLUSIONS
Induction of NO may be a key mediator in driving the cytokine response to endotoxin toward an increased type-2 (interleukin-10) response and a diminished type-1 (interleukin-12) response.
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000633:toxicity; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D020318:Rats, Long-Evans; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D004731:Endotoxins; D007074:Immunoglobulin G; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat