Prevention of endotoxemia-induced acute respiratory distress syndrome-like lung injury in rabbits by a monoclonal antibody to IL-8.

We have herein established an endotoxemia-induced acute respiratory distress syndrome (ARDS)-like lung injury administered a sublethal dose of lipopolysaccharide (LPS) intravenously 36 hours after the intratracheal instillation of heat-killed Streptococcus pyogenes (OK-432). At 36 hours after OK-432 priming, a mild infiltration into the lungs, consisting of a small number of neutrophils and macrophages, was observed without destruction of pulmonary architecture. A subsequent challenge with a sublethal dose of LPS induced pathologic changes characteristic of ARDS--such as extensive edema in alveolar lumina, marked infiltration composed of a large number of neutrophils and a few macrophages, fibrin deposit in alveolar space, and destruction of pulmonary architecture--resulting in severe hypoxemia. Concomitantly, LPS challenge after priming with OK-432 induced a marked elevation of IL-8 levels in serum and bronchoalveolar lavage fluid with local IL-8 production in lungs, as revealed by immunohistochemical analysis. An anti-IL-8 antibody treatment almost completely prevented pulmonary edema, destruction of pulmonary architecture, and impairment in gas exchange as well as neutrophil infiltration in lungs; there was also a significant reduction in the rate of acute lethality. These results provide evidence that IL-8 has a pivotal role in the induction of ARDS associated with endotoxemia, probably by recruiting and activating neutrophils locally.