Objective: To examine the temporal relationship of pulmonary TNF-alpha production to acute lung injury (ALI) during hemorrhagic shock (HS).
Methods: HS was induced in mice by removal of 30% of calculated total blood volume. Lung TNF-alpha was measured by ELISA. Lung neutrophil accumulation was detected by immunofluorescent staining, and pulmonary microvascular permeability was assessed using Evans blue dye.
Results: While HS induced a slight and transient increase in lung TNF-alpha, neutrophil accumulation preceded the change in lung TNF-alpha. However, lung neutrophil accumulation and the increase in microvascular permeability were abrogated in TNF-alpha knockout mice, and both were restored by administration of low dose TNF-alpha to TNF-alpha knockout mice prior to HS. Both neutrophil accumulation and microvascular leak were abrogated in p55 TNF-alpha receptor knockout mice, while p75 TNF-alpha receptor knockout mice behaved similar to wild type.
Conclusion: A low level of pulmonary TNF-alpha is sufficient to mediate HS-induced acute lung injury and that the p55 TNF-alpha receptor plays a dominant role in regulating the pulmonary inflammatory response to HS. The results suggest that anti-TNF-alpha strategies for the control of the pulmonary inflammatory response to HS can be directed toward antagonizing the p55 TNF-alpha receptor.