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Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice
Published on: January 16, 2015
p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice
Satoshi Marumo, Yuma Hoshino1, Hirofumi Kiyokawa
1Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan. yuma@kuhp.kyoto-u.ac.jp.
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-1β, 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.
Insights
p38 mitogen-activated protein kinase (p38 MAPK) activation correlates with susceptibility to cigarette smoke-induced emphysema. Inhibiting p38 MAPK effectively reduced lung inflammation and injury in mice, suggesting it as a therapeutic target for COPD.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Inflammation Research
Background:
- Chronic obstructive pulmonary disease (COPD) necessitates novel anti-inflammatory agents.
- p38 mitogen-activated protein kinase (p38 MAPK) is implicated in COPD pathogenesis.
- The therapeutic efficacy of p38 MAPK inhibitors for COPD remains unestablished.
Purpose of the Study:
- To investigate the link between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema.
- To determine if p38 MAPK inhibition mitigates lung inflammation and injury in murine models of CS exposure.
Main Methods:
- Compared p38 MAPK activation, lung inflammation, and injury in emphysema-susceptible (C57BL/6) and resistant (NZW) mice under acute and chronic CS exposure.
- Administered a selective p38 MAPK inhibitor (SB203580) to C57BL/6 mice to assess its effects on CS-induced lung pathology.
Main Results:
- Emphysema-susceptible mice exhibited significantly higher CS-induced lung inflammation, apoptosis, and oxidative DNA damage.
- p38 MAPK activation and upregulation were observed in susceptible mice following CS exposure, but not in resistant mice.
- SB203580 treatment significantly reduced CS-induced lung inflammation, proteinase expression, oxidative DNA damage, and apoptosis.
Conclusions:
- Cigarette smoke selectively activates p38 MAPK in emphysema-susceptible mice.
- Selective inhibition of p38 MAPK ameliorates lung inflammation and injury in a murine model of CS exposure.
- p38 MAPK pathways represent a potential molecular target for COPD treatment.
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