The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AMΦ) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-κB 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. AMΦ were harvested, and TNF-α, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-α levels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NF-κB, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AMΦ were stimulated with LPS with or without inhibitors of NF-κB and MAPK. Serum TNF-α and IL-6 levels and spontaneous AMΦ TNF-α and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NF-κB increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NF-κB or the upstream MAPK significantly decreased LPS-stimulated AMΦ activation. Because enhanced release of inflammatory mediators by AMΦ may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions.