Initiation of and tolerance to neutrophil - mediated acute lung injury (ARDS): A yin-yang mechanism involving interleukin-1

Abstract

The significance of the increased interleukin 1 (IL-l) levels in lungs of ARDS patients is unknown. Our results indicate that IL-I can not only cause acute lung injury but also produce tolerance to acute lung injury. We found that lungs in rats given IL-I (50 ng) intratracheally promptly became edematous and that leak was associated with increases in NFKB activity, lung neutrophils, TNF, cytokine induced neutrophil chemoattractant (CINC) levels and oxidative stress. Paradoxically, we also found that rats pretreated with IL-1 had the same numbers of lung neutrophils, but developed less lung leak, compared to saline-pretreated rats following a subsequent instillation of IL-l intratracheally. Similarly, lungs isolated from rats pretreated with IL-l also developed less leak than saline-perfused isolated lungs that were subsequently perfused with neutrophils and given IL-I intratracheally. Likewise, rat lung microvascular endothelial cells (RLMEC,) pretreated with IL-1 in vitro resisted injury by stimulated neutrophils better than saline-pretreated RLMEC. IL-I pretreatment increased NFKB activation in RLMEC and overexpression of the mutant forms of IKB~ (S32136A) or IKBB (S19123A) decreased both NFKB activation and tolerance in IL-I pretreated RLMEC. Identification of these “yin yang” responses is relevant to the design and interpretation of approaches that increase or decrease IL-I in ARDS and other inflammatory disorders.