Leptin Promotes Fibroproliferative Acute Respiratory Distress Syndrome by Inhibiting Peroxisome Proliferator–activated Receptor-γ

• Published in: American journal of respiratory and critical care medicine Vol. 183; no. 11; pp. 1490 - 1498
• Main 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.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.06.2011
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; B. Critical Care; Biological and medical sciences; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Emergency and intensive respiratory care; Female; Humans; Intensive care medicine; Leptin - metabolism; Leptin - pharmacology; Lung - metabolism; Male; Medical sciences; Mice; Middle Aged; PPAR gamma - metabolism; Respiratory Distress Syndrome, Adult - metabolism; Transforming Growth Factor beta - metabolism; Endocrinopathy; lung; Lung disease; Intensive care; Respiratory disease; Diabetes mellitus; Leptin; Fibrosis; Peroxisome; Respiratory distress; acute lung injury; Resuscitation
• DOI: 10.1164/rccm.201009-1409OC
• ISSN: 1073-449X; 1535-4970

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