A low level of TNF-alpha mediates hemorrhage-induced acute lung injury viap55 TNF receptor

Acute lung injury after hemorrhagic shock (HS) is associated with the expre ssion of tumor necrosis factor (TNF)-alpha in the lung. However, the role o f TNF-alpha and its receptors in this pulmonary disorder remains obscure. T his study examined the temporal relationship of pulmonary TNF-alpha. produc tion to neutrophil accumulation during HS and determined the role of TNF-al pha in neutrophil accumulation and lung leak. HS was induced in mice by rem oval of 30% of total blood volume. Lung TNF-alpha was measured by ELISA. Ne utrophil accumulation was detected by immunofluorescent staining, and micro vascular permeability was assessed using Evans blue dye. Although HS induce d a slight and transient increase in lung TNF-alpha, neutrophil accumulatio n preceded the increase in TNF-alpha. However, lung neutrophil accumulation and lung leak were abrogated in TNF-alpha knockout mice, and both were res tored by administration of recombinant TNF-alpha to TNF-alpha knockout mice before HS. Neutrophil accumulation and lung leak were abrogated in mice la cking the p55 TNF-alpha receptor, but neither was influenced by p75 TNF-alp ha receptor knockout. This study demonstrates that a low level of pulmonary TNF-alpha is sufficient to mediate HS-induced acute lung injury during HS and that the p55 TNF-alpha receptor plays a dominant role in regulating the pulmonary inflammatory response to HS.