Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ.

<bold>Rationale: </bold>Diabetic patients have a lower incidence of acute respiratory distress syndrome (ARDS), and those who develop ARDS are less likely to die. The mechanisms that underlie this protection are unknown.<bold>Objectives: </bold>To determine whether leptin resistance, a feature of diabetes, prevents fibroproliferation after lung injury.<bold>Methods: </bold>We examined lung injury and fibroproliferation after the intratracheal instillation of bleomycin in wild-type and leptin-resistant (db/db) diabetic mice. We examined the effect of leptin on transforming growth factor (TGF)-β(1)-mediated transcription in primary normal human lung fibroblasts. Bronchoalveolar lavage fluid (BAL) samples from patients with ARDS and ventilated control subjects were obtained for measurement of leptin and active TGF-β(1) levels.<bold>Measurements and Main Results: </bold>Diabetic mice (db/db) were resistant to lung fibrosis. The db/db mice had higher levels of peroxisome proliferator-activated receptor-γ (PPARγ), an inhibitor of the transcriptional response to TGF-β(1), a cytokine critical in the pathogenesis of fibroproliferative ARDS. In normal human lung fibroblasts, leptin augmented the transcription of profibrotic genes in response to TGF-β(1) through a mechanism that required PPARγ. In patients with ARDS, BAL leptin levels were elevated and correlated with TGF-β(1) levels. Overall, there was no significant relationship between BAL leptin levels and clinical outcomes; however, in nonobese patients, higher BAL leptin levels were associated with fewer intensive care unit- and ventilator-free days and higher mortality.<bold>Conclusions: </bold>Leptin signaling is required for bleomycin-induced lung fibrosis. Leptin augments TGF-β(1) signaling in lung fibroblasts by inhibiting PPARγ. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients. [ABSTRACT FROM AUTHOR]