XANTHINE OXIDASE-DERIVED OXYGEN RADICALS INCREASE LUNG CYTOKINE EXPRESSION IN MICE SUBJECTED TO HEMORRHAGIC-SHOCK

Acute inflammatory lung injury often complicates hemorrhagic shock, a systemic ischemia-reperfusion syndrome. Because oxygen radicals are generated during ischemia-reperfusion, and oxygen radicals can activate nuclear regulatory factors that affect transcription of proinflammatory cytokines, we examined the premise that oxygen radicals increase interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) expression in lung mononuclear cells after hemorrhage. Intraparenchymal pulmonary mononuclear cells isolated 1 h after hemorrhage from control mice had increased levels of mRNA for IL-1 beta (P < 0.001) and TNF-alpha (P < 0.05) compared with cells from sham-hemorrhaged mice. Hemorrhaged mice treated with the oxygen radical scavenger dimethylthiourea (DMTU) had decreased levels of mRNA for IL-1 beta in pulmonary mononuclear cells, compared with hemorrhaged controls (P < 0.05). In hemorrhaged mice depleted of xanthine oxidase (XO) by a tungsten-enriched diet, pulmonary mononuclear cell mRNA levels for IL-1 beta and TNF-alpha were significantly decreased (P < 0.01 and 0.05, respectively), compared with cells from hemorrhaged control mice fed a normal diet. Similarly, mRNA transcripts for IL-1 beta and TNF-alpha among pulmonary mononuclear cells from hemorrhaged mice treated with allopurinol, an inhibitor of XO, were also significantly reduced (P < 0.05 and 0.001, respectively), compared with hemorrhaged control mice not treated with allopurinol. Our results indicate that XO-derived oxygen radicals contribute to the increased expression of mRNA for IL-1 beta and TNF-alpha, which occurs among pulmonary mononuclear cell populations immediately after hemorrhage. This pathophysiologic mechanism may contribute to the frequent development of acute lung injury after blood loss and trauma and may provide a link between ischemia-reperfusion injury and increased proinflammatory lung cytokine responses.