Leptin Promotes Fibroproliferative Acute Respiratory Distress Syndrome by Inhibiting Peroxisome Proliferator–activated Receptor-γ

Jain, Manu; Budinger, G. R. Scott; Lo, Amy A.; Urich, Daniela; Rivera, Eleanor; Ghosh, Asish K.; González, Ángel; Chiarella, Sergio E.; Marks, Keith H; Donnelly, Helen K.; Soberanes, Saul; Varga, John; Radigan, Kathryn A.; Chandel, Navdeep S.; Mutlu, Gökhan M.

doi:10.1164/rccm.201009-1409oc

Cited by 91 publications

(91 citation statements)

References 66 publications

(79 reference statements)

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“…Previous reports have also shown that leptin and leptin receptor are expressed in airway epithelium (24), and bronchial expression of leptin is increased in chronic obstructive pulmonary disease (25,26). Leptin seems to be involved in embryonic lung growth and maturation (27,28), and in fibroproliferative responses in the lung to bleomycin (29). Furthermore, polymorphisms in leptin and leptin receptor have been associated with differences in lung function (30,31).…”

Section: Discussionmentioning

confidence: 94%

Obesity and Asthma

Sideleva¹,

Suratt²,

Black³

et al. 2012

Am J Respir Crit Care Med

289

159

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Rationale: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese. Objectives: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity. Methods: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time. Measurements and Main Results: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P , 0.01), with increased expression of leptin (P , 0.01) and decreased adiponectin (p , 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho ¼ 20.8; P , 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery. Conclusions: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.

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Section: Discussionmentioning

confidence: 94%

Obesity and Asthma

Sideleva¹,

Suratt²,

Black³

et al. 2012

Am J Respir Crit Care Med

289

159

View full text Add to dashboard Cite

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“…Bellmeyer and coworkers (13) found that exogenously administered leptin causes ALI in mice and that leptin resistance protects mice from hyperoxia-induced lung injury. Jain and coworkers (12) showed that leptin levels in bronchoalveolar lavage fluid are increased in patients with ALI, and that leptin promotes fibroproliferative ALI by increasing transforming growth factor-b1 transcription in a peroxisome proliferator-activated receptor-g-dependent fashion (12), suggesting that leptin may not only promote ALI, but may contribute to lung fibrosis in response to injury, possibly shedding light on a mechanistic link between PGD and small airways fibrosis (obliterative bronchiolitis) after lung transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggests that obesity is a novel risk factor for ALI among the critically ill (9,10), perhaps by altering the milieu of proinflammatory and antiinflammatory cytokines produced by adipose tissue (so-called "adipokines") (11)(12)(13), such as leptin and adiponectin. Leptin in particular has been shown to play a role in the development of ALI in a hyperoxia mouse model and to contribute to the fibroproliferative stage of the acute respiratory distress syndrome (12,13).…”

mentioning

confidence: 99%

Obesity and Primary Graft Dysfunction after Lung Transplantation

Lederer¹,

Kawut

Wickersham

et al. 2011

Am J Respir Crit Care Med

136

102

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Rationale: Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation. Objectives: To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation. Methods: We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios. Measurements and Main Results: Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30-50%) for each 5 kg/m 2 increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sexadjusted P ¼ 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass. Conclusions: Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

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“…Shore and coworkers have previously shown that leptin infusion increases airway reactivity in lean mice; this is not related to increases in allergic airway inflammation, suggesting that leptin may be having effects in pathways quite distinct from those involved in allergic asthma (16). The observation that leptin was inversely related to lung function as measured by FEV 1 is also intriguing, given reports that leptin is involved in lung development (17,18) and may regulate fibroproliferative responses in the lung (19). Further studies evaluating the mechanistic relevance of elevated TNFa and leptin in airway disease in obese individuals with asthma are needed.…”

mentioning

confidence: 99%