期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 183, 期 11, 页码 1490-1498出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201009-1409OC
关键词
acute lung injury; fibrosis; lung; diabetes mellitus
资金
- American Lung Association
- Northwestern University Clinical and Translational Sciences Institute (NUCATS) [NCCR] [UL1 RR025741]
- Northwestern Memorial Foundation
- Scleroderma Research Foundation
- Genentech
- Cystic Fibrosis Foundation
- Millennium Pharmaceuticals
- [ES015024]
- [ES013995]
- [HL071643]
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)-beta(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-beta(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-gamma (PPAR gamma), an inhibitor of the transcriptional response to TGF-beta(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-beta(1) through a mechanism that required PPARg. In patients with ARDS, BAL leptin levels were elevated and correlated with TGF-beta(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-beta(1) signaling in lung fibroblasts by inhibiting PPARg. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients.
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