Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice

Abstract

Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS. Pulmonary leptin expression was analyzed by immunohistochemistry and real-time PCR. Pulmonary inflammation upon 4 wk CS exposure was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue of WT, ob/ob, and db/db mice. Immunohistochemical analysis revealed leptin expression in bronchial epithelial cells, pneumocytes, alveolar macrophages, and bronchial/vascular smooth muscle cells. The 4 and 24 wk CS exposure increased leptin expression in bronchial epithelial cells and pneumocytes versus air-exposed WT mice (p < 0.05). The 4 wk CS exposure resulted in increased accumulation of neutrophils, dendritic cells, macrophages, and lymphocytes in BALF and lung tissue of WT, ob/ob, and db/db mice. CS-exposed ob/ob and db/db mice showed in general higher numbers of neutrophils and lower numbers of CD4+, CD8+, and dendritic cells versus CS-exposed WT mice. Consistently, CXCL1 levels were enhanced in BALF of CS-exposed ob/ob and db/db mice versus WT mice (p < 0.05). Exogenous leptin administration completely restored the skewed inflammatory profile in ob/ob mice. These data reveal an important role of leptin in modulating innate and adaptive immunity after CS inhalation in mice.

A Comparative Study of Lung Host Defense in Murine Obesity Models. Insights into Neutrophil Function

“…Several animal models of obesity have been used to investigate the effects of obesity and associated comorbidities on the pulmonary immune response related to both acute and chronic lung diseases, including bacterial (11,12,18,19,27,29) and viral (9,28,39,40) respiratory infections, airway hyperresponsiveness (8,(41)(42)(43)(44)(45)(46), ARDS (5,7,12,30), pulmonary fibrosis (26), and chronic obstructive pulmonary disease (31). The most commonly employed mouse models of obesity include DIO, the hyperphagic mutant db/db, CPE fat/fat , and ob/ob strains.…”

Loss of Phosphatase and Tensin Homolog (PTEN) Induces Leptin-mediated Leptin Gene Expression

“…LEP binds to the leptin receptor (LEPR) and activates multiple intracellular signaling pathways (1,2). Elevated levels of LEP in the lung and serum are associated with, and potentially exacerbate, severity and progression of lung diseases, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), airway remodeling associated with asthma, and lung cancer (3)(4)(5)(6)(7)(8)(9). In patients, circulating and airway LEP concentrations negatively correlate with lung function (10).…”

“…Increased LEP expression and secretion following lung injury promotes fibroproliferation, contributing to pulmonary fibrosis (11), particularly in the setting of hyperoxia-induced ALI (11,12). Pulmonary LEP is also increased in asymptomatic smokers and in mice exposed to cigarette smoke where it modulates innate and adaptive immune cell recruitment (4,7). In contrast, resistance to the effects of LEP attenuates lung disease pathology, whereas reduction in LEP levels is a strong predictive factor in the improvement of lung function (13,14).…”

Documento de consenso SEPAR-ALAT sobre vacunación antineumocócica en fumadores

“…En otros análisis se comprobó que el humo del tabaco atenuaba la respuesta inflamatoria de las células respiratorias. Efectivamente, se ha comprobado que el tabaco inhibe la respuesta de los receptores tipo Toll II (TLR2), del factor nuclear KB (NF-KB), la proliferación de células CD4 (LTCD4), la maduración de células dendríticas y la capacidad de opsonización [32][33][34][35][36] . Luego, teniendo en cuenta estos datos obtenidos tanto en estudios in vivo como in vitro, parece claro que el humo del tabaco causa alteración de la respuesta inmunológica de las células respiratorias.…”