Resistance To Emphysema By Enhancing BMP/Wnt Signaling In Mice Induced By Cigarette Smoking

Pulmonary emphysema,is a chronic respiratory disease and mostly caused by cigarette smoking,occupational hazards and air pollution.However,due to lack of effective target drugs for emphysema in clinical treatment and the pathogenesis remians unclear,which seriously threatens the physical and mental health of patients.To clarify the pathogenesis of emphysema is very important for prevention and treatment of the disease.Currently,the model of emphysema induced by cigarette smoking in mice is generally accepted and it can effectively simulate human emphysema.Our previous studies found that overexpression of the Noggin gene in alveolar type II epithelial cells showed a phenotype similar to human emphysema and we confirmed that the phenotype was related to down-regulation of BMP and Wnt signaling activity.Therefore,the aim of this study is to investigate whether upregulation of BMP and Wnt signaling pathway activity can resist the development of emphysema induced by cigarette smoking in mice.Here,we further clarify the role of these two signaling pathways in the pathogenesis of emphysema.Firstly,we successfully constructed the model of emphysema induced by cigarette smoking.The results showed that local alveolar expansion and a little breakage of the lung interval occurred in the lung tissues after one or two months of smoke exposure.After three or six months of smoke exposure,the lung tissues were significantly dilated,and the lung interval was broken.The mean linear intercept of the alveoli was significantly higher than that of the control group.Pathological indicators showed that smoke exposure could cause extensive degradation of elastin,collagen and E-cadherin in lung tissue of mice;inflammatory factors such as TNF-?,IL-18 and IL-1? increased significantly;cell proliferation and apoptosis showed remarkable abnormalities.These results indicate that smoke exposure in mice can cause abnormal morphological and physiological indicators that similar to human emphysema.Secondly,BRE-gal and Top-gal transgenic mice,which can respectively indicate BMP and Wnt signaling pathway activity,were exposed to cigarette smoking for 3 months.And X-gal staining showed that the activities of BMP and Wnt signaling pathways in lung tissue of smoke-exposed mice were significantly down-regulated.It suggest that BMP and Wnt signaling pathways are closely related to emphysema induced by smoke exposure.Finally,three mice lines which increased BMP and Wnt signaling activities alone or simultaneously in alveolar type II epithelial cells were exposed in smoke for 3 months.Morphological observation showed that the lung tissue structure remained normal,and the average alveolar lining interval was not different from the control group.After detecting the alveolar type II epithelial cell marker SP-C by immunofluorescence,we found the number of alveolar type II epithelial cells and the secretion of SP-C protein were both significantly decreased in wild-type mice compared with the control group.Furthermore,either increased the activity levels of BMP/Wnt signaling alone or simultaneously,the proliferation level of alveolar type II epithelial cells and the secreting level of SP-C protein in mutant mice were as well as in control mice after 3 months of smoke exposure.In total,our data suggest that increased the levels of BMP or Wnt signaling activity in alveolar type II epithelial cells could prevent the damaged of mouse alveolar type II epithelial cells caused by smok exposure,allowing cells to maintain normal structure and function.The increasing activity of BMP or Wnt signaling also has a certain resistance and protective effect on emphysema.These results will provide a new theoretical basis for further study of the pathogenesis of emphysema,and also provide a potential drug target for the prevention and treatment of the disease in the future.