Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF- B and MAPK/ERK mechanisms

Jarrar, Doraid, Joachim F. Kuebler, Loring W. Rue, III, Sadis Matalon, Ping Wang, Kirby I. Bland, and Irshad H. Chaudry. Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NFB and MAPK/ERK mechanisms. Am J Physiol Lung Cell Mol Physiol 283: L799–L805, 2002; 10.1152/ajplung.00465.2001.—The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AM ) chemokine and cytokine release after hemorrhage and sepsis is regulated by NFB and MAPK. Adult male rats underwent soft tissue trauma and hemorrhagic shock ( 90 min) followed by crystalloid resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation. AM were harvested, and TNF, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNFlevels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NFB, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AM were stimulated with LPS with or without inhibitors of NFB and MAPK. Serum TNFand IL-6 levels and spontaneous AM TNFand MIP-2 release were elevated (P 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NFB increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NFB or the upstream MAPK significantly decreased LPS-stimulated AM activation. Because enhanced release of inflammatory mediators by AM may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions.