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

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

Research output: Contribution to journalArticle

60 Scopus citations

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)-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 mechanismthat 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 highermortality. 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.

Original languageEnglish (US)
Pages (from-to)1490-1498
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume183
Issue number11
DOIs
StatePublished - Jun 1 2011

Keywords

  • Acute lung injury
  • Diabetes mellitus
  • Fibrosis
  • Lung

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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