title: Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Manu
authors.initials: M
authors.lastname: Jain
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Amy
authors.initials: A
authors.lastname: Lo
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Rivera
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Katie
authors.initials: K
authors.lastname: Marks
authors.forename: Helen K
authors.initials: HK
authors.lastname: Donnelly
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Radigan
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D047495:PPAR gamma / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D020738:Leptin; D047495:PPAR gamma; D016212:Transforming Growth Factor beta