Jaime Eduardo Davino-Chiovatto1, Manoel Carneiro Oliveira-Junior2, BreAnne MacKenzie2, Alana Santos-Dias2, Ana Roberta Almeida-Oliveira2, Jefferson Comin Jonco Aquino-Junior2, Auriléia Aparecida Brito1, Nicole Cristine Rigonato-Oliveira1, Nilsa Regina Damaceno-Rodrigues3, Ana Paula Ligeiro Oliveira1, Alessandro Pereira Silva4, Fernanda Marciano Consolim-Colombo1, Flavio Aimbire5, Hugo Caire Castro-Faria-Neto6, Rodolfo Paula Vieira7. 1. Nove de Julho University (UNINOVE), São Paulo, SP, Brazil. 2. Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE), São José dos Campos, SP, Brazil. 3. University of São Paulo, School of Medicine, Department of Pathology (LIM 59), São Paulo, SP, Brazil. 4. Post-graduation Program in Biomedical Engineering, University of Mogi das Cruzes, Mogi das Cruzes, SP, Brazil. 5. Federal University of Sao Paulo (UNIFESP), São José dos Campos, SP, Brazil. 6. Laboratory of Immunopharmacology, Osvaldo Cruz Institute (IOC), Osvaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil. 7. Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE), São José dos Campos, SP, Brazil; Universidade Brasil, Post-graduation Program in Bioengineering and in Biomedical Engineering, São Paulo, SP, Brazil; Federal University of Sao Paulo (UNIFESP), Post-graduation Program in Sciences of Human Movement and Rehabilitation, Santos, SP, Brazil; Anhembi Morumbi University, School of Medicine, Avenida Deputado Benedito Matarazzo 4050, São José dos Campos, SP, Brazil. Electronic address: rodrelena@yahoo.com.br.
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 (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.
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.
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