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

Manu Jain, GR 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 Chandel, Gökhan M. Mutlu

Research output: Contribution to journalArticle

52 Citations (Scopus)

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

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Peroxisome Proliferator-Activated Receptors
Adult Respiratory Distress Syndrome
Leptin
Transforming Growth Factors
Bronchoalveolar Lavage Fluid
Lung
Fibroblasts
Lung Injury
Fibrosis
Bleomycin
Mechanical Ventilators
Intensive Care Units
Cytokines

Keywords

  • Acute lung injury
  • Diabetes mellitus
  • Fibrosis
  • Lung

ASJC Scopus subject areas

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

Cite this

Jain, Manu ; Budinger, GR 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 ; Mutlu, Gökhan M. / Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ. In: American Journal of Respiratory and Critical Care Medicine. 2011 ; Vol. 183, No. 11. pp. 1490-1498.
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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.",
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Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ. / Jain, Manu; Budinger, GR 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; Mutlu, Gökhan M.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 183, No. 11, 01.06.2011, p. 1490-1498.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ

AU - Jain, Manu

AU - Budinger, GR 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

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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