Inducible nitric oxide synthase knockout mice exhibit resistance to the multiple organ failure induced by zymosan

In the present study, by comparing the responses in wild-type mice (+/+) an d mice lacking (-/-) the inducible (or type 2) nitric oxide synthase (iNOS) , we investigated the role played by iNOS in the development of non-septic shock. A severe inflammatory response characterized by peritoneal exudation , high peritoneal levels of nitrate/nitrite, and leukocyte infiltration int o peritoneal exudate was induced by zymosan administration in iNOS +/+ mice . This inflammatory process coincided with the damage of lung, liver, and s mall intestine, as assessed by histological examination. Lung, small intest ine, and liver myeloperoxidase (MPO) activity, indicative of neutrophil inf iltration and lipid peroxidation, were significantly increased in zymosan-t reated iNOS +/+ mice. Peritoneal administration of zymosan in the iNOS +/mice induced also a significant increase in the plasma levels of nitrite/ni trate and in the levels of peroxynitrite at 18 h after zymosan challenge. I mmunohistochemical examination demonstrated a marked increase in the immuno reactivity to nitrotyrosine and to poly ADP-ribose synthetase (PARS) in the lung, liver, and intestine of zymosan-treated iNOS +/+ mice. The intensity and degree of nitrotyrosine and PARS were markedly reduced in tissue secti on from zymosan-iNOS -/- mice. Zymosan-treated iNOS -/- mice showed a signi ficantly decreased mortality and inhibition of the development of peritonit is. In addition, iNOS -/- mice showed a significant protection on the devel opment of organ failure since tissue injury and MPO were reduced in lung, s mall intestine, and liver. Furthermore, a significant reduction of suppress ion of mitochondrial respiration, DNA strand breakage, and reduction of cel lular levels of NAD(+) was observed in ex vivo macrophages harvested from t he peritoneal cavity of iNOS -/- mice subjected to zymosan-induced non-sept ic shock. in vivo treatment with aminoguanidine (300 mg/kg 1 and 6 h after zymosan administration) significantly prevents the inflammatory process. Ta ken together, our results clearly demonstrate that iNOS plays an important role in zymosan-induced non-septic shock.