Assessment for the mechanisms of anti-apoptotic effects of transcription factor MafB in alveolar macrophages of emphysematous lungs induced by cigarette smoke exposure

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Cigarette smoking is the most common risk factor for the development of chronic obstructive pulmonary disease (COPD), a severe worldwide medical problem. COPD is characterized physiologically by various levels of airflow obstruction, and pathologically by findings of pulmonary emphysema. In the lungs of smokers, oxidative stress rises due to increase of free radicals and oxidants. The functions of alveolar macrophages (Ams) are altered in such an environment, and their survival is prolonged against toxicities of cigarette smoke (CS) by an unknown mechanism. We previously demonstrated that transcriptional factor MafB was upregulated in Ams from CS-exposed mice. DNA binding capacity of MafB for Maf recognition element was also increased in Ams from those mice. Furthermore, we established a macrophage cell line that can overexpress MafB, and thereby clarified the role of MafB. Forced expression of MafB heightened cell viability and attenuated the occurrence of apoptosis in cells treated w … More ith CS-extract. After CS exposure Caspase-3 activity was inhibited in MafB overexpressing cells compared to control cells, while the release of cytochrome c in MafB overexpressing cells was not different from those of control cells. mRNA expression of caspase-3 was not altered by MafB overexpression. On the other hand, modulator of apoptosis 1 (Moap1) gene expression was significantly reduced by MafB overexpression. The expressions of other genes which are regulating caspase-3 activity, such as activated factor 1 (Apaf1), p21^<CIP1/WAF1>, BclX_L, and Bax, remained unchanged. These results suggest that enhanced MafB expression by oxidative stress inhibits AM cell death through caspase pathway, not through mitochondrial pathway.In order to evaluate the role of MafB further, we currently establish dominant-negative MafB expressing mice under the control of human scavenger receptor promoter that enables specific gene expression only in macrophages (manuscript under preparation). Using this mouse, we are assessing the role of MafB in vivo. Less