| Autor: |
Jain M, Budinger GR, 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, Jain, Manu, Budinger, G R Scott, Lo, Amy, Urich, Daniela, Rivera, Stephanie E |
| Zdroj: |
American Journal of Respiratory & Critical Care Medicine; 6/1/2011, Vol. 183 Issue 11, p1490-1498, 9p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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