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Hyperoxia-induced emphysematous changes in subacute phase of endotoxin-induced lung injury in rats

¹Department of Surgery, Tokyo Metropolitan Komagome Hospital and Departments of ²Medicine, ³Surgery, and ⁵Pathology, Keio University School of Medicine, Tokyo and ⁶Pharmacia Keio Research Laboratory, Tokyo 160-8582; ⁴Department of Immunology & Inflammation, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Company, Ltd., Osaka 532-8514 Japan

Submitted 11 September 2003 ; accepted in final form 3 March 2004

We examined the effects of prolonged hyperoxia (75% O₂) on lung structure and collagen metabolism in the subacute phase of lung injury induced by continuous infusion of endotoxin (LPS) in a rat model. Experimental groups included control, endotoxin alone, endotoxin plus hyperoxia, and hyperoxia alone. Endotoxin-treated rats received a bolus of LPS (10 mg/kg iv) followed by 500 µg·kg^–1·day^–1 in continuous infusion for 10 days. The bronchoalveolar lavage (BAL) fluid/plasma albumin concentration ratio, an index of capillary permeability, and neutrophil and macrophage counts in BAL fluid were highest in the endotoxin plus hyperoxia group. On pathological examination, prolonged hyperoxia exacerbated destruction of the alveolar wall and caused most prominent emphysematous changes in the endotoxin plus hyperoxia group. Lung tissue hydroxyproline concentration was significantly decreased in the hyperoxia group and increased in the endotoxin group. The latent forms of MMP-2 and MMP-9 increased in BAL fluid of the endotoxin- and/or hyperoxia-treated groups, whereas the activities of collagenase and gelatinase, and the active form of MMP-2 were all increased in the hyperoxia-treated groups. Added to endotoxin, prolonged hyperoxia degraded collagen, the major structural component of basement membranes, and caused emphysematous changes associated with activation of collagenase and MMP-2. Our observations suggest that, in the subacute phase of endotoxin-induced lung injury, prolonged hyperoxia causes pulmonary emphysematous changes with persistent injury to the alveolar capillary barrier. Collagenase and MMP-2 activated by hyperoxia, together with MMP-9, may play prominent roles in disruption of the alveolar basement membranes and degradation of collagen lining the alveolar walls.

emphysema; matrix metalloproteinase

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