Janus kinase inhibition prevents cancer- and myocardial infarction-mediated diaphragm muscle weakness in mice.
Am J Physiol Regul Integr Comp Physiol
; 310(8): R707-10, 2016 Apr 15.
Article
em En
| MEDLINE
| ID: mdl-26864813
ABSTRACT
Respiratory dysfunction is prevalent in critically ill patients and can lead to adverse clinical outcomes, including respiratory failure and increased mortality. Respiratory muscles, which normally sustain respiration through inspiratory muscle contractions, become weakened during critical illness, and recent studies suggest that respiratory muscle weakness is related to systemic inflammation. Here, we investigate the pathophysiological role of the inflammatory JAK1/3 signaling pathway in diaphragm weakness in two distinct experimental models of critical illness. In the first experiment, mice received subcutaneous injections of PBS or C26 cancer cells and were fed chow formulated with or without the JAK1/3 inhibitor R548 for 26 days. Diaphragm specific force was significantly reduced in tumor-bearing mice receiving standard chow; however, treatment with the JAK1/3 inhibitor completely prevented diaphragm weakness. Diaphragm cross-sectional area was diminished by â¼25% in tumor-bearing mice but was similar to healthy mice in tumor-bearing animals treated with R548. In the second study, mice received sham surgery or coronary artery ligation, leading to myocardial infarction (MI), and were treated with R548 or vehicle 1 h postsurgery, and once daily for 3 days. Diaphragm specific force was comparable between sham surgery/vehicle, sham surgery/R548 and MI/R548 groups, but significantly decreased in the MI/vehicle group. Markers of oxidative damage and activated caspase-3, mechanisms previously identified to reduce muscle contractility, were not elevated in diaphragm extracts. These experiments implicate JAK1/3 signaling in cancer- and MI-mediated diaphragm weakness in mice, and provide a compelling case for further investigation.
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Base de dados:
MEDLINE
Assunto principal:
Transtornos Respiratórios
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Diafragma
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Neoplasias do Colo
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Debilidade Muscular
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Inibidores de Proteínas Quinases
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Janus Quinase 1
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Janus Quinase 3
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Força Muscular
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Infarto do Miocárdio
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article