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.
Yokoi
K
K
Department of Pharmacology, Cancer Research Institute, Japan.
Mukaida
N
N
Harada
A
A
Watanabe
Y
Y
Matsushima
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015415:Biomarkers; D004487:Edema; D019446:Endotoxemia / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D016209:Interleukin-8 / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000032:analysis; D011650:Pulmonary Alveoli / Q000473:pathology / Q000503:physiopathology; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D016209:Interleukin-8; D008070:Lipopolysaccharides; D009195:Peroxidase