A low level of TNF-α mediates hemorrhage-induced acute lung injury via p55 TNF receptor

Abstract

Acute lung injury after hemorrhagic shock (HS) is associated with the expression of tumor necrosis factor (TNF)-α in the lung. However, the role of TNF-α and its receptors in this pulmonary disorder remains obscure. This study examined the temporal relationship of pulmonary TNF-α production to neutrophil accumulation during HS and determined the role of TNF-α in neutrophil accumulation and lung leak. HS was induced in mice by removal of 30% of total blood volume. Lung TNF-α was measured by ELISA. Neutrophil accumulation was detected by immunofluorescent staining, and microvascular permeability was assessed using Evans blue dye. Although HS induced a slight and transient increase in lung TNF-α, neutrophil accumulation preceded the increase in TNF-α. However, lung neutrophil accumulation and lung leak were abrogated in TNF-α knockout mice, and both were restored by administration of recombinant TNF-α to TNF-α knockout mice before HS. Neutrophil accumulation and lung leak were abrogated in mice lacking the p55 TNF-α receptor, but neither was influenced by p75 TNF-α receptor knockout. This study demonstrates that a low level of pulmonary TNF-α is sufficient to mediate HS-induced acute lung injury during HS and that the p55 TNF-α receptor plays a dominant role in regulating the pulmonary inflammatory response to HS.