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 ge nerated during ischemia-reperfusion, and oxygen radicals can activate nuclear regulatory factors that affect transcription of proinflammator y cytokines, we examined the premise that oxygen radicals increase int erleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha ) expression in lung mononuclear cells after hemorrhage. Intraparenchy mal pulmonary mononuclear cells isolated 1 h after hemorrhage from con trol mice had increased levels of mRNA for IL-1 beta (P < 0.001) and T NF-alpha (P < 0.05) compared with cells from sham-hemorrhaged mice. He morrhaged mice treated with the oxygen radical scavenger dimethylthiou rea (DMTU) had decreased levels of mRNA for IL-1 beta in pulmonary mon onuclear cells, compared with hemorrhaged controls (P < 0.05). In hemo rrhaged mice depleted of xanthine oxidase (XO) by a tungsten-enriched diet, pulmonary mononuclear cell mRNA levels for IL-1 beta and TNF-alp ha were significantly decreased (P < 0.01 and 0.05, respectively), com pared with cells from hemorrhaged control mice fed a normal diet. Simi larly, mRNA transcripts for IL-1 beta and TNF-alpha among pulmonary mo nonuclear cells from hemorrhaged mice treated with allopurinol, an inh ibitor of XO, were also significantly reduced (P < 0.05 and 0.001, res pectively), compared with hemorrhaged control mice not treated with al lopurinol. Our results indicate that XO-derived oxygen radicals contri bute 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 th e frequent development of acute lung injury after blood loss and traum a and may provide a link between ischemia-reperfusion injury and incre ased proinflammatory lung cytokine responses.