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Title: Leptin resistance protects mice from hyperoxia-induced acute lung injury.

Authors: Bellmeyer, Amy; Martino, Janice M; Chandel, Navdeep S; Scott Budinger, G R; Dean, David A; Mutlu, Gökhan M

Published In Am J Respir Crit Care Med, (2007 Mar 15)

Abstract: RATIONALE: Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown. OBJECTIVES: To determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury. METHODS: Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O(2)) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo. MEASUREMENTS AND MAIN RESULTS: Lung leptin levels were increased both in wild-type and leptin receptor-defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared with wild-type mice. CONCLUSIONS: These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.

PubMed ID: 17185651 Exiting the NIEHS site

MeSH Terms: Animals; Bronchoalveolar Lavage Fluid/cytology; Cell Count; Cytokines/metabolism; Diabetes Mellitus, Type 2/metabolism; Hyperoxia/metabolism*; Leptin/administration & dosage; Leptin/metabolism*; Lung Injury*; Lung/metabolism*; Male; Mice; Mice, Inbred C57BL; Neutrophils/metabolism; Pulmonary Alveoli/metabolism; Pulmonary Edema/metabolism; Receptors, Cell Surface/metabolism; Receptors, Leptin; Survival Analysis

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