RGD Reference Report - Leptin Promotes Fibroproliferative ARDS by Inhibiting Peroxisome Proliferator-activated Receptor-{gamma} - Rat Genome Database

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Leptin Promotes Fibroproliferative ARDS by Inhibiting Peroxisome Proliferator-activated Receptor-{gamma}

Authors: Jain, M  Budinger, GS  Lo, A  Urich, D  Rivera, SE  Ghosh, AK  Gonzalez, A  Chiarella, SE  Marks, K  Donnelly, HK  Soberanes, S  Varga, J  Radigan, KA  Chandel, NS  Mutlu, GM 
Citation: Jain M, etal., Am J Respir Crit Care Med. 2011 Feb 11.
RGD ID: 5128773
Pubmed: PMID:21317313   (View Abstract at PubMed)
PMCID: PMC3266063   (View Article at PubMed Central)
DOI: DOI:10.1164/rccm.201009-1409OC   (Journal Full-text)

RATIONALE: Diabetic patients have a lower incidence of ARDS and those that 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 TGF-beta1-mediated transcription in primary normal human lung fibroblasts. Bronchoalveolar lavage fluid (BAL) samples from patients with ARDS and ventilated controls were obtained for measurement of leptin and active TGF-beta1 levels. RESULTS: Diabetic mice (db/db) were resistant to lung fibrosis. The db/db mice had higher levels of PPARgamma, an inhibitor of the transcriptional response to TGF-beta1, 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-beta1 through a mechanism that required PPARgamma. In patients with ARDS, BAL leptin levels were elevated and correlated with TGF-beta1 levels. Overall, there was no significant relationship between BAL leptin levels and clinical outcomes; however in non-obese patients, higher BAL leptin levels were associated with fewer intensive care unit- and ventilator-free days and a higher mortality. CONCLUSIONS: Leptin signaling is required for bleomycin induced lung fibrosis. Leptin augments TGF-beta1 signaling in lung fibroblasts by inhibiting PPARgamma. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
adult respiratory distress syndrome disease_progressionIDA 5128773respiratory system fluid/secretion RGD 
adult respiratory distress syndrome disease_progressionISOLEP (Homo sapiens)5128773; 5128773respiratory system fluid/secretion RGD 
pulmonary fibrosis  ISOLepr (Mus musculus)5128773; 5128773associated with Diabetes Mellitus and Type 2RGD 
pulmonary fibrosis  IMP 5128773associated with Diabetes Mellitus and Type 2RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lep  (leptin)
Lepr  (leptin receptor)

Genes (Mus musculus)
Lep  (leptin)
Lepr  (leptin receptor)

Genes (Homo sapiens)
LEP  (leptin)
LEPR  (leptin receptor)


Additional Information