RESUMEN
OBJECTIVES: Some pro-inflammatory lipids derived from 1 lipooxygenase enzyme are potent neutrophil chemoattractant, a cell centrally involved in acute respiratory distress syndrome (ARDS); a syndrome lacking effective treatment. Considering the beneficial effects of the leukotriene receptor inhibitor, montelukast, on other lung diseases, whether montelukast attenuates inflammation in a mouse model of ARDS, and whether it reduces LPS stimulated activation of human neutrophils was investigated. METHODS: Thirty-five C57Bl/6 mice were distributed into control (PBS)+24h, LPS+24h (10µg/mouse), control+48h, LPS+48h, and LPS 48h+Montelukast (10mg/kg). In addition, human neutrophils were incubated with LPS (1µg/mL) and treated with montelukast (10µM). RESULTS: Oral-tracheal administration of montelukast significantly attenuated total cells (P<.05), macrophages (P<.05), neutrophils (P<.01), lymphocytes (P<.001) and total protein levels in BAL (P<.05), as well as IL-6 (P<.05), CXCL1/KC (P<.05), IL-17 (P<.05) and TNF-α (P<.05). Furthermore, montelukast reduced neutrophils (P<.001), lymphocytes (P<.01) and macrophages (P<.01) in the lung parenchyma. In addition, montelukast restored BAL VEGF levels (P<.05). LTB4 receptor expression (P<.001) as well as NF-κB (P<.001), a downstream target of LPS, were also reduced in lung parenchymal leukocytes. Furthermore, montelukast reduced IL-8 (P<.001) production by LPS-treated human neutrophils. CONCLUSION: In conclusion, montelukast efficiently attenuated both LPS-induced lung inflammation in a mouse model of ARDS and in LPS challenged human neutrophils.
Asunto(s)
Acetatos/farmacología , Antagonistas de Leucotrieno/farmacología , Activación Neutrófila/efectos de los fármacos , Neumonía/prevención & control , Quinolinas/farmacología , Animales , Lavado Broncoalveolar , Permeabilidad Capilar/efectos de los fármacos , Ciclopropanos , Citocinas/análisis , Citocinas/efectos de los fármacos , Humanos , Recuento de Leucocitos , Lipopolisacáridos , Pulmón/citología , Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neumonía/inducido químicamente , Receptores de Leucotrieno B4/efectos de los fármacos , Receptores de Leucotrieno B4/metabolismo , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/etiología , Sulfuros , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PURPOSE: Obesity results in decreased lung function and increased inflammation. Moderate aerobic exercise (AE) reduced lung inflammation and remodeling in a variety of respiratory disease models. Therefore, this study investigated whether AE can attenuate a diet-induced obesity respiratory phenotype; including airway hyper-responsiveness (AHR), remodeling and inflammation. METHODS: Sixty C57Bl/6 male mice were distributed into four groups: control lean (CL), exercise lean (EL), obese (O) and obese exercise (OE) groups (2 sets of 7 and 8 mice per group; nâ¯=â¯15). A classical model of diet-induced obesity (DIO) over 12â¯weeks was used. AE was performed 60â¯min/day, 5â¯days/week for 5â¯weeks. Airway hyperresponsiveness (AHR), lung inflammation and remodeling, adipokines and cytokines in bronchoalveolar lavage (BAL) was determined. RESULTS: A high fat diet over 18â¯weeks significantly increased body weight (pâ¯<â¯.0001). Five weeks of AE significantly reduced both AHR and pulmonary inflammation. AHR in obese mice that exercised was reduced at the basal level (pâ¯<â¯.05), vehicle (PBS) (pâ¯<â¯.05), 6.25 MCh mg/mL (pâ¯<â¯.05), 12.5 MCh mg/mL (pâ¯<â¯.01), 25 MCh mg/mL (pâ¯<â¯.01) and 50 MCh mg/mL (pâ¯<â¯.05). Collagen (pâ¯<â¯.001) and elastic (pâ¯<â¯.001) fiber deposition in airway wall and also smooth muscle thickness (pâ¯<â¯.001) were reduced. The number of neutrophils (pâ¯<â¯.001), macrophages (pâ¯<â¯.001) and lymphocytes (pâ¯<â¯.01) were reduced in the peribronchial space as well as in the BAL: lymphocytes (pâ¯<â¯.01), macrophages (pâ¯<â¯.01), neutrophils (pâ¯<â¯.001). AE reduced obesity markers leptin (pâ¯<â¯.001), IGF-1 (pâ¯<â¯.01) and VEGF (pâ¯<â¯.001), while increased adiponectin (pâ¯<â¯.01) in BAL. AE also reduced pro-inflammatory cytokines in the BAL: IL-1ß (pâ¯<â¯.001), IL-12p40 (pâ¯<â¯.001), IL-13 (pâ¯<â¯.01), IL-17 (pâ¯<â¯.001, IL-23 (pâ¯<â¯.05) and TNF-alpha (pâ¯<â¯.05), and increased anti-inflammatory cytokine IL-10 (pâ¯<â¯.05). CONCLUSIONS: Aerobic exercise reduces high fat diet-induced obese lung phenotype (AHR, pulmonary remodeling and inflammation), involving anti-inflammatory cytokine IL-10 and adiponectin.