HEMORRHAGE INCREASES CYTOKINE EXPRESSION IN LUNG MONONUCLEAR-CELLS INMICE - INVOLVEMENT OF CATECHOLAMINES IN NUCLEAR FACTOR-KAPPA-B REGULATION AND CYTOKINE EXPRESSION

The expression of proinflammatory and immunoregulatory cytokines rapid ly increases in the lungs after hemorrhage, and such alterations contr ibute to the frequent development of acute inflammatory lung injury in this setting. Blood loss also produces elevations in catecholamine co ncentrations in the pulmonary and systemic circulation, In the present experiments, we used alpha- and beta-adrenergic receptor blockade to examine in vivo interactions between hemorrhage-induced adrenergic sti mulation and pulmonary cytokine expression, Treatment of mice with the alpha-adrenergic receptor antagonist phentolamine prevented not only the elevation in mRNA levels of IL-1 beta, TNF-alpha, and TGF-beta 1, the increase in IL-1 beta protein, but also the activation of nuclear factor (NF)-kappa B and cyclic AMP response element binding protein, w hich occurred in lung cells of untreated animals during the first hour after hemorrhage. in contrast, treatment before hemorrhage with the b eta-adrenergic receptor antagonist propranolol was associated with inc reases in mRNA levels for IL-1 beta, TNF-alpha, and TGF-beta 1, which were greater than those present in untreated hemorrhaged mice, and did mot prevent hemorrhage-associated increases in lung IL-1 beta protein , Treatment with propranolol prevented hemorrhage-induced phosphorylat ion of cyclic AMP response element binding protein, but increased hemo rrhage-associated activation of NF-kappa B. These results demonstrate that hemorrhage initially increases pulmonary cytokine expression thro ugh alpha- but not beta-adrenergic stimulation, and suggest that such alpha-adrenergic-mediated effects occur through activation of the tran scriptional regulatory factor NF-kappa B.