Hypoxemia in the absence of blood loss upregulates iNOS expression and activity in macrophages

Regional hypoxia,associated with hemorrhage, is thought to induce a variety ofalterations in immune cell function, including upregulation ofmacrophage-inducible nitric oxide synthase (iNOS) expression andactivity (NO production). Furthermore, NO may cause immune celldysfunction similar to that associated with hemorrhagic shock. However,it remains unknown whether hypoxia per se in the absence of any bloodloss is a sufficient stimulus to cause iNOS expression and NOproduction by macrophages. To study this, male Sprague-Dawley rats(275-325 g) were placed in a plastic box flushed with a gasmixture containing 5% O₂-95%N₂ for 60 min. Peritoneal andsplenic macrophages were isolated 0-5.5 h thereafter, and bloodsamples were obtained. Nitrite and nitrate (stable degradation productsof NO) production by splenic and peritoneal macrophages cultured for 48 h was significantly increased 3 and 5.5 h after hypoxemia. The increasein NO production by macrophages was preceded by elevated expression ofiNOS mRNA at 1.5 h after hypoxia. Additionally, interferon-(IFN-) levels in plasma from rats subjected to hypoxemia weresignificantly elevated soon after the insult (0-1.5 hposthypoxemia), suggesting a causal relationship between IFN-production and upregulation of iNOS activity. We propose that ahypoxemia-induced increase in macrophage iNOS activity followinghemorrhage may in part be responsible for the observed immunedysfunction. Thus attempts to suppress macrophage iNOS activity afterthis form of trauma may be helpful in improving immune function underthose conditions.