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

Regional hypoxia, associated with hemorrhage, is thought to induce a variet y of alterations in immune cell function, including upregulation of macroph age-inducible nitric oxide synthase (iNOS) expression and activity (NO prod uction). Furthermore, NO may cause immune cell dysfunction similar to that associated with hemorrhagic shock. However, it remains unknown whether hypo xia per se in the absence of any blood loss is a sufficient stimulus to cau se iNOS expression and NO production by macrophages. To study this, male Sp rague-Dawley rats (275-325 g) were placed in a plastic box flushed with a g as mixture containing 5% O-2-95% N-2 for 60 min. Peritoneal and splenic mac rophages were isolated 0-5.5 h thereafter, and blood samples were obtained. Nitrite and nitrate (stable degradation products of NO) production by sple nic and peritoneal macrophages cultured for 48 h was significantly increase d 3 and 5.5 h after hypoxemia. The increase in NO production by macrophages was preceded by elevated expression of iNOS mRNA at 1.5 h after hypoxia. A dditionally, interferon-gamma (IFN-gamma) levels in plasma from rats subjec ted to hypoxemia were significantly elevated soon after the insult (0-1.5 h posthypoxemia), suggesting a causal relationship between IFN-gamma product ion and upregulation of iNOS activity, mie propose that a hypoxemia-induced increase in macrophage iNOS activity following hemorrhage may in part be r esponsible for the observed immune dysfunction. Thus attempts to suppress m acrophage iNOS activity after this form of trauma may be helpful in improvi ng immune function under those conditions.