Abstract
BackgroundThere 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.MethodsIn 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.ResultsAcute 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.ConclusionsCigarette 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.
Highlights
There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 mitogen-activated protein kinases (MAPKs)) 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
The bronchoalveolar lavage fluid (BALF) neutrophil counts were significantly increased in both strains, but to a significantly lesser extent in NZW mice compared with C57BL/6 mice (Figure 1D)
This study demonstrated that cigarette smoking activated p38 MAPK only in mice that were susceptible to cigarette smoke (CS)-induced emphysema, and that the selective inhibition of p38 MAPK ameliorated lung injury and inflammation in a murine model of CS exposure
Summary
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. There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. 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. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide [1], and further increases in its prevalence and mortality are predicted [2]. COPD is characterized by airway obstruction and progressive lung inflammation associated with the influx of inflammatory cells [3]. Lung inflammation is further amplified by oxidative stress and excess proteinases in the lung. These mechanisms lead to characteristic COPD pathological changes [4]. Emphysema can be developed without enhancing inflammation in some animal models [5,6], the central pathogenesis of human COPD is still believed to be chronic lung inflammation
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