Montelukast, Leukotriene Inhibitor, Reduces LPS-Induced Acute Lung Inflammation and Human Neutrophil Activation

Davino-Chiovatto, Jaime Eduardo; Oliveira-Junior, Manoel Carneiro; MacKenzie, BreAnne; Santos-Dias, Alana; Almeida-Oliveira, Ana Roberta; Aquino-Junior, Jefferson Comin Jonco; Brito, Auriléia Aparecida; Rigonato-Oliveira, Nicole Cristine; Damaceno-Rodrigues, Nilsa Regina; Oliveira, Ana Paula Ligeiro; Silva, Alessandro Pereira; Consolim-Colombo, Fernanda Marciano; Aimbire, Flavio; Castro-Faria-Neto, Hugo Caire; Vieira, Rodolfo Paula

doi:10.1016/j.arbr.2019.10.002

Archivos de Bronconeumología (English Edition)

ISSN: 1579-2129

Archivos de Bronconeumologia is a scientific journal that preferentially publishes prospective original research articles whose content is based upon results dealing with several aspects of respiratory diseases such as epidemiology, pathophysiology, clinics, surgery, and basic investigation. Other types of articles such as reviews, editorials, a few special articles of interest to the society and the editorial board, scientific letters, letters to the Editor, and clinical images are also published in the Journal. It is a monthly Journal that publishes a total of 12 issues and a few supplements, which contain articles belonging to the different sections.

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Current Contents/Clinical Medicine, JCR SCI-Expanded, Index Medicus/Medline, Excerpta Medica/EMBASE, IBECS, IME, SCOPUS, IBECS

Jaime Eduardo Davino-Chiovattoa,◊, Manoel Carneiro Oliveira-Juniorb,◊, BreAnne MacKenzieb,◊, Alana Santos-Diasb, Ana Roberta Almeida-Oliveirab, Jefferson Comin Jonco Aquino-Juniorb, Auriléia Aparecida Britoa, Nicole Cristine Rigonato-Oliveiraa, Nilsa Regina Damaceno-Rodriguesc, Ana Paula Ligeiro Oliveiraa, Alessandro Pereira Silvad, Fernanda Marciano Consolim-Colomboa, Flavio Aimbiree, Hugo Caire Castro-Faria-Netof, Rodolfo Paula Vieirab,g,h,i,

Corresponding author

rodrelena@yahoo.com.br

Corresponding author.

a Nove de Julho University (UNINOVE), São Paulo, SP, Brazil

b Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE), São José dos Campos, SP, Brazil

c University of São Paulo, School of Medicine, Department of Pathology (LIM 59), São Paulo, SP, Brazil

d Post-graduation Program in Biomedical Engineering, University of Mogi das Cruzes, Mogi das Cruzes, SP, Brazil

e Federal University of Sao Paulo (UNIFESP), São José dos Campos, SP, Brazil

f Laboratory of Immunopharmacology, Osvaldo Cruz Institute (IOC), Osvaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

g Universidade Brasil, Post-graduation Program in Bioengineering and in Biomedical Engineering, São Paulo, SP, Brazil

h Federal University of Sao Paulo (UNIFESP), Post-graduation Program in Sciences of Human Movement and Rehabilitation, Santos, SP, Brazil

i Anhembi Morumbi University, School of Medicine, Avenida Deputado Benedito Matarazzo 4050, São José dos Campos, SP, Brazil

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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.

Keywords:

Inflammation

Neutrophils

Acute lung injury

Leukotriene

Cytokines

Growth factors

Resumen

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)+24h, LPS+(24h [10μg/ratón]), control+48h y LPS 48h+montelukast (10mg/kg). Por otro lado, se incubaron neutrófilos humanos con LPS (1μg/ml) y se trataron con montelukast (10μM).

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-α (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.

Palabras clave:

Inflamación

Neutrófilos

Daño pulmonar agudo

Leucotrieno

Citoquinas

Factores de crecimiento