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p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice.
Marumo, Satoshi; Hoshino, Yuma; Kiyokawa, Hirofumi; Tanabe, Naoya; Sato, Atsuyasu; Ogawa, Emiko; Muro, Shigeo; Hirai, Toyohiro; Mishima, Michiaki.
Afiliação
  • Hoshino Y; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan. yuma@kuhp.kyoto-u.ac.jp.
BMC Pulm Med ; 14: 79, 2014 May 07.
Article em En | MEDLINE | ID: mdl-24885161
ABSTRACT

BACKGROUND:

There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure.

METHODS:

In acute and chronic CS exposure, the activation and expression of p38 MAPK in the lungs, as well as lung inflammation and injury (proteinase production, apoptosis, and oxidative DNA damage), were compared between two mouse strains C57BL/6 (emphysema-susceptible) and NZW (emphysema-resistant). The selective p38 MAPK inhibitor SB203580 (45 mg/kg) was administrated intra-peritoneally to C57BL/6 mice, to examine whether it ameliorated cigarette smoke-induced lung inflammation and injury.

RESULTS:

Acute CS-induced lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2), proteinase expression (MMP-12 mRNA), apoptosis, and oxidative DNA damage were significantly lower in NZW than C57BL/6 mice. p38 MAPK was significantly activated and up-regulated by both acute and chronic CS exposure in C57BL/6 but not NZW mice. mRNA expression of p38 MAPK was also upregulated in C57BL/6 by chronic CS exposure and tended to be constitutively suppressed in NZW mice. SB203580 significantly attenuated lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2, protein levels of KC, MIP-1α, IL-1ß, and IL-6), proteinase expression (MMP-12 mRNA), oxidative DNA damage, and apoptosis caused by acute CS exposure.

CONCLUSIONS:

Cigarette smoke activated p38 MAPK only in mice that were susceptible to cigarette smoke-induced emphysema. Its selective inhibition ameliorated lung inflammation and injury in a murine model of cigarette smoke exposure. p38 MAPK pathways are a possible molecular target for the treatment of chronic obstructive pulmonary disease.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Enfisema Pulmonar / Poluição por Fumaça de Tabaco / Proteínas Quinases p38 Ativadas por Mitógeno / Suscetibilidade a Doenças Limite: Animals Idioma: En Revista: BMC Pulm Med Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Enfisema Pulmonar / Poluição por Fumaça de Tabaco / Proteínas Quinases p38 Ativadas por Mitógeno / Suscetibilidade a Doenças Limite: Animals Idioma: En Revista: BMC Pulm Med Ano de publicação: 2014 Tipo de documento: Article