ABSTRACT
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 (10 μg/mouse), control + 48 h, LPS+48 h, and LPS 48 h+Montelukast (10 mg/kg). In addition, human neutrophils were incubated with LPS ( 1μg/mL) and treated with montelukast (10 μM). 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-alfa (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
Objetivos: Algunos lípidos proinflamatorios derivados de la enzima lipooxigenasa 1 son potentes quimioatrayentes de neutrófilos, un tipo celular con una implicación principal en el síndrome de distrés respiratorio agudo (SDRA), para el que no hay tratamiento efectivo. Considerando los efectos beneficiosos del inhibidor de los receptores de leucotrienos montelukast en otras enfermedades pulmonares, se investigó si este fármaco era capaz de atenuar la inflamación en un modelo de ratón de SDRA y de reducir la activación de los neutrófilos humanos inducida por LPS. Métodos: Se utilizaron 35 ratones C57BL/6 distribuidos en los siguientes grupos: control (PBS) + 24 h, LPS+(24 h [10 μg/ratón]), control + 48 h y LPS 48 h + montelukast (10 mg/kg). Por otro lado, se incubaron neutrófilos humanos con LPS (1 μg/ml) y se trataron con montelukast (10 μM). Resultados: La administración orotraqueal de montelukast redujo el número total de células (p < 0,05), de macrófagos (p < 0,05), de neutrófilos (p < 0,01), de linfocitos (p < 0,001) y los niveles totales de proteína en el lavado broncoalveolar (p < 0,05), así como de IL-6 (p < 0,05), CXCL1/KC (p < 0,05), IL-17 (p < 0,05) y TNF-alfa (p < 0,05). Además, el montelukast redujo los neutrófilos (p < 0,001), los linfocitos (p < 0,01) y los macrófagos (p < 0,01) en el parénquima pulmonar. Asimismo, restauró los niveles de VEGF en el lavado broncoalveolar (p < 0,05) y disminuyó la expresión del receptor LTB4 (p < 0,001) y de NF-κB (p < 0,001), una diana downstream del LPS, en los leucocitos del parénquima pulmonar. Por último, redujo la producción de IL-8 por parte de los neutrófilos humanos tratados con LPS. Conclusión: En conclusión, el montelukast atenuó de manera eficaz tanto la inflamación pulmonar inducida por LPS en un modelo de ratón de SDRA como en neutrófilos humanos estimulados con LPS
Subject(s)
Animals , Mice , Leukotriene Antagonists/therapeutic use , Lipopolysaccharide Receptors/administration & dosage , Pneumonia/chemically induced , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/complications , Pneumonia/drug therapy , Pneumonia/veterinary , Cytokines/therapeutic use , Bronchoalveolar Lavage/veterinary , Anti-Asthmatic Agents/therapeutic useABSTRACT
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.
Subject(s)
Acetates/pharmacology , Leukotriene Antagonists/pharmacology , Neutrophil Activation/drug effects , Pneumonia/prevention & control , Quinolines/pharmacology , Animals , Bronchoalveolar Lavage , Capillary Permeability/drug effects , Cyclopropanes , Cytokines/analysis , Cytokines/drug effects , Humans , Leukocyte Count , Lipopolysaccharides , Lung/cytology , Lymphocytes/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , NF-kappa B/drug effects , NF-kappa B/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Pneumonia/chemically induced , Receptors, Leukotriene B4/drug effects , Receptors, Leukotriene B4/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/etiology , Sulfides , Time Factors , Vascular Endothelial Growth Factor A/metabolismABSTRACT
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.
