TY - JOUR
T1 - Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ
AU - Jain, Manu
AU - Budinger, G. R.Scott
AU - Lo, Amy
AU - Urich, Daniela
AU - Rivera, Stephanie E.
AU - Ghosh, Asish K.
AU - Gonzalez, Angel
AU - Chiarella, Sergio E.
AU - Marks, Katie
AU - Donnelly, Helen K.
AU - Soberanes, Saul
AU - Varga, John
AU - Radigan, Kathryn A.
AU - Chandel, Navdeep S.
AU - Mutlu, Gökhan M.
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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.
AB - 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.
KW - Acute lung injury
KW - Diabetes mellitus
KW - Fibrosis
KW - Lung
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U2 - 10.1164/rccm.201009-1409OC
DO - 10.1164/rccm.201009-1409OC
M3 - Article
C2 - 21317313
AN - SCOPUS:79957945650
SN - 1073-449X
VL - 183
SP - 1490
EP - 1498
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 11
ER -