Effect Of Tranilast On Airway Remodeling Of Experimental COPD Rats

Chronic Obstructive Pulmonary Disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive, related with abnormal inflammatory response to some noxious particles or gas. It is generally acknowledged now that chronic continuity inflammation and airway remodeling are the main pathological changes of COPD. COPD is the fourth major cause of chronic morbidity and mortality throughout the world. It is important to investigate the pathogenesis of COPD for prevention and treatment of this disease.Connective tissue growth factor is a multi-functional matricellular protein that can regulate extracellurlar matrix(ECM) production,and differentiation. CTGF may be a new molecular target for therapeutic intervention in fibrotic disease.Tranilast , as an anti-allergic agent, can stabilize the epicyte of mast cells and basophils and inhibit the release of the hypersensitive mediator. In recent years, it has been reported that tranilast can affect some cytokines, such as TGF-β, PDGF, MCP-1. So it can be used to treat organs fibrotic disease, atherosclerosis, and so on. The study intends to investigate the effect of tranilast on COPD airway remodeling through intervention on experimental COPD rats.Part 1. Establishing rat chronic obstructive pulmonary disease model and the effect of tranilast on its pathomorphologyObjective: To observe the effect of tranilast on experimental COPD rats, especially on collagen and pathologic configuration.Methods: Forty-eighth SD rats were divided into two groups in random: untreated model group, tranilast-treated group. Other eight rats were control group. The COPD rat model was established by passive smoking and intratracheal instillation of lipopolysaccharide(LPS), and then treated with sterile saline or tranilast (400mg·kg^-1·d^-1) respectively. Eight rats in each group were killed in 7th, 14th, 28th day after the beginning of proceeding. Bronchoalveolar lavage fluid(BALF) were collected and the total and differential cells were counted. The distribution and the ratio of typeⅠto typeⅢcollagen in the lung tissue were determined using a sirius red polarizing microscopy morphometry method. Lung tissues were observed by hemotoxylin and eosin stain, then the image analysis were made.Results: The total cells and the AM ratio in BALF of tranilast-treated group significantly decreased in comparison with those in model group(P<0.05). In comparison with control group,model group collagen deposition increased and predominant typeⅠcollagen presented in 28th day. TypeⅠcollagen deposition in treated group was lower than that in model group but still higher than that in control group. Image analysis suggested that the airway wall thickness,the vessel thickness and the ratio of gland thickness/airway wall thickness were significantly smaller than that in model group(P<0.05).Conclusion: Tranilast can lessen airway remodeling of COPD rat models by lighten airwayinflammation through inhibiting AM and inhibit collagen synthesizePart 2. Effect of tranilast on expression of connective tissue growth factor in experimental COPD ratsObjective: To investigate the effect of tranilast on the expression of connective tissue growth factor (CTGF) in experimental chronic obstructive pulmonary disease (COPD) rats.Methods: Forty-eighth SD rats were divided into two groups in random: untreated model group, tranilast-treated group. Other eight rats were control group. The COPD rat model was established by passive smoking and intratracheal instillation of lipopolysaccharide(LPS), and then treated with sterile saline or tranilast (400mg·kg^-1·d^-1) respectively. Eight rats in each group were killed in 7th, 14th, 28th day after the beginning of proceeding. Immunohistochemistry methods were performed to detect the expression of CTGF in COPD rats and compare with that in the control group.Results: The expression of CTGF in COPD rats increased compare with that in the control group. Immunohistochemical analyses revealed that CTGF protein couldn't be detected in control group , model 7d group and tranilast-treated 7d group. While CTGF can be detected positive in 14d group, maximum level in 28d group in the model groups and tranilast-treate groups. In contrast, the expression of CTGF in tranilast-treated 28d group (2.8±0.3) decreased dramatically compare with that in the model 28d group (3.8±0.4 )( p<0.05).Conclusions: LPS and passive smoking can induce the high expression of CTGF in the airway of COPD rats. But tranilast may lessen the airway remodeling in COPD rats by inhibit CTGF expression in some sense.