| Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ. | |
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MedLine Citation:
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PMID: 21317313 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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)-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. 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-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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-02-11 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: 183 ISSN: 1535-4970 ISO Abbreviation: Am. J. Respir. Crit. Care Med. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-06 Completed Date: 2011-08-15 Revised Date: 2012-01-26 |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: United States |
Other Details:
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Languages: eng Pagination: 1490-8 Citation Subset: AIM; IM |
Affiliation:
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Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bronchoalveolar Lavage Fluid Disease Models, Animal Female Humans Leptin / metabolism*, pharmacology* Lung / metabolism Male Mice Middle Aged PPAR gamma / metabolism* Respiratory Distress Syndrome, Adult / metabolism* Transforming Growth Factor beta / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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ES013995/ES/NIEHS NIH HHS; ES015024/ES/NIEHS NIH HHS; HL071643/HL/NHLBI NIH HHS; UL1 RR025741/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Leptin; 0/PPAR gamma; 0/Transforming Growth Factor beta |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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