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Métodos Terapêuticos e Terapias MTCI
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1.
Inflammation ; 40(3): 788-797, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28194607

RESUMO

Exposure to ozone has been associated with airway inflammation and glucocorticoid insensitivity. This study aimed to observe the capacity of anti-murine interleukin-17A monoclonal antibody (IL-17mAb) to reverse ozone-induced glucocorticoid insensitivity and to detect its effects with glucocorticoids in protecting against airway inflammation. After C57/BL6 mice were exposed to ozone (2.5 ppm; 3 h) for 12 times over 6 weeks, PBS, IL-17mAb (50 ug/ml), dexamethasone (2 mg/kg), and combination administration of IL-17mAb (50 ug/ml) and dexamethasone (2 mg/kg) were intraperitoneally injected into mice at a dose of 0.1 ml, respectively, for 10 times over 5 weeks. At sacrifice, lung histology, airway inflammatory cells, levels of related cytokines in bronchoalveolar lavage fluid (BALF), and serum were analyzed, airway inflammatory cell infiltration density and mean linear intercept (Lm) were measured, the expression of IL-17A mRNA, glucocorticoid receptors (GR), NF-κB, and p38 mitogen-activated protein kinase (MAPK) phosphorylation were determined. We found that combination administration markedly reduced ozone-induced total inflammatory cells, especially neutrophils; inhibited levels of cytokines, including IL-8, IL-17A, and TNF-α in BALF; and suppressed airway inflammatory cell infiltration density and Lm. Additionally, combination administration significantly elevated levels of IFN-γ in BALF, decreased the dexamethasone-induced increase of IL-17A mRNA, and increased the expression of GR and decrement of NF-κB and p38MAPK phosphorylation, which are also related to glucocorticoids insensitivity. Collectively, combination administration shows profound efficacy in inhibiting certain cytokines, and IL-17 mAb partly improved the glucocorticoids insensitivity via modulating the enhanced production rate and improving expression of IL-17A induced by glucocorticoids administration and p38MAPK, NF-κB signaling pathway.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Glucocorticoides/farmacologia , Interleucina-17/imunologia , Ozônio/toxicidade , Animais , Anticorpos Monoclonais/farmacologia , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Camundongos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Neutrófilos/imunologia , Neutrófilos/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Biomed Pharmacother ; 83: 247-256, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27380433

RESUMO

Exposure to ozone has led to airway inflammation and airway hyperresponsiveness, which potential mechanisms relate to ozone-induced oxidative stress. IL-17 is a growing target for autoimmune and inflammatory diseases. The aim of the study was to examine the inhibitory effects of anti-murine interleukin-17A monoclonal antibody (IL-17mAb) on adverse effects of ozone which are noted above. After C57/BL6 mice were exposed to ozone (2.5ppm; 3h) for 12 times over 6 weeks, IL-17mAb, PBS was intraperitoneally injected into mice 1h after ozone or air exposure for 6 weeks and mice were studied 24h after final exposure, monitoring bronchial responsiveness, airway inflammatory cells, lung histology, levels of neutrophil-related chemokine and proinflammatory cytokines in bronchoalveolar lavage (BAL) fluid and serum, the expression of IL-17A mRNA and protein, glucocorticoid receptors (GR), and the phosphorylation of p38MAPK in lung tissues. The administration of IL-17mAb reduced the ozone-induced increases in total cells, especially neutrophils; decreased levels of cytokines, including IL-8 in BAL fluid, IL-8 and IL-17A in serum; mitigated the severity of airway hyperresponsiveness; attenuated lung inflammation scores and histologic analysis confirmed the suppression of lung inflammation, compared with the administration of a control PBS. Exposure to ozone results in increases in IL-17A production rate, mRNA and protein levels of IL-17A and the protein level of GR. These effects were halted and reversed by IL-17mAb treatment. Furthermore, IL-17mAb also reduced the phosphorylation of p38MAPK. Therefore, we conclude that IL-17mAb may be a useful therapy in ozone-related diseases, including COPD.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Interleucina-17/imunologia , Pneumonia/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Doença Crônica , Citocinas/sangue , Enfisema/sangue , Enfisema/tratamento farmacológico , Enfisema/patologia , Enfisema/fisiopatologia , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ozônio , Pneumonia/sangue , Pneumonia/patologia , Pneumonia/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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