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

Authors: Jain, Manu; Budinger, G R Scott; Lo, Amy; Urich, Daniela; Rivera, Stephanie E; Ghosh, Asish K; Gonzalez, Angel; Chiarella, Sergio E; Marks, Katie; Donnelly, Helen K; Soberanes, Saul; Varga, John; Radigan, Kathryn A; Chandel, Navdeep S; Mutlu, Gökhan M

Published In Am J Respir Crit Care Med, (2011 Jun 01)

Abstract: 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)-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. 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-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. CONCLUSIONS: 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.

PubMed ID: 21317313 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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