Rationale: 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.

Objectives: To determine whether leptin resistance, a feature of diabetes, prevents fibroproliferation after lung injury.

Methods: 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)-β₁–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-β₁ levels.

Measurements and Main Results: 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-β₁, 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-β₁ through a mechanism that required PPARγ. In patients with ARDS, BAL leptin levels were elevated and correlated with TGF-β₁ 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.

Conclusions: Leptin signaling is required for bleomycin-induced lung fibrosis. Leptin augments TGF-β₁ signaling in lung fibroblasts by inhibiting PPARγ. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients.