Effects Of All Trans Retinoic Acid On Oxidative Stress In The Wistar Rat Models Of Chronic Obstructive Pulmonary Emphysema

Introduction:Chronic obstructive pulmonary diseases (COPD) is the most common respiratory system diseases induced by many factors. Lesions begin with the lungs , performance for airway nonspecific inflammation and persistent airway obstruction, gradually accumulated other systems, which is harm to people's health seriously. It is estimated from the World Health Organization (WHO) that by 2020 COPD will be the 5th of top ten health problems over the worldwide, which is just 12th in the 1990s. In the United States, COPD is the 4th death causes, and in a higher tendency; In China, now adults COPD prealence approximately 3%,which means about 25 million people in the nationwide, and one million COPD patients will be die every year.Pulmonary emphysema is the main pathological type of COPD. There is no effective drug to prevent the progressive loss of lung parenchyma at present. The destory of elastic fiber breaks alveoli attachment, enlarges airspace, decreases gas exchange surface area and damages the elastic recoil in lung, so it plays a main role in the progress of this disease. The significant problem in clinical studies is how to explain the mechanism of forming pulmonary emphysema, and then find the effective methods to cure and prevent COPD, which is worth to discuss.All trans retinoic acid(ATRA), the biologically active metabolite of vitamin A,has extensive biological effects, such as participation modulate inflammatory cells, immune cell activation and promote development organization epithelial cell proliferation, differentiation.It is normally used to treat skin disease and the blood system tumors. Recently,It induces alveolar formation and increase elastic recoil in adult rat lung with elastase-induced emphysema, especially reduce matrix metalloproteinases expression, balance the MMPs/TIMPs level. But the reports of fuction of oxidation /antioxidation are rare, its mechanism needs to be a lot of experiments confirm and clarify, consummates the theoretical basis of ATRA treatment on pulmonary emphysema.Objective:1.To construct the emphysema model with Wistar rats by a single intratracheally instillation of porcine pancreatic elastase (PPE).2. To evaluate the effects of the all trans retinoic acid (ATRA) with different concentrations on alveolar repair , arterial blood gas and lung volume in emphysema rats.3.measure the lung tissue and plasma superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in emphysema rats with different concentrations of ATRA.Analysis the correlation of oxidative stress and disease, reveals the pathogenesis of emphysema from the oxidant / antioxidant . Learn more about the effects of the different concentration of ATRA treatment of emphysema, and discuss the mechanism of anti-oxidative of ATRA treatment.Methods:In this work, 60 male Wistar rats,which the body weights between 220 and 250g, were randomly divided into Controls group(N, n=10), Emphysema group(E, n=10), Cottonseed oil group(C, n=10), Low-dose ATRA treatment group(L, n=10), Middle-dose ATRA treatment group(M, n=10)and High-dose ATRA treatment group (H, n=10). Except group N, we constructed the rat models of emphysema by a single intratracheally instillation of porcine pancreatic elastase (PPE). Then treated with high, middle and low dose of ATRA (500μg/ml/kg, 1000μg/ml/kg,2000μg/ml/kg)and cottonseed oil 1ml/kg by intra-abdominal injection daily. 30 days later, The analysis of artery blood gas , lung volume, the alveolar morphology, plasma SOD and MDA, lung tissue SOD and MDA content of rats were performed. Experimental results were compared among group N,E,C,L,M and H.Results:1,Analysis of artery blood gasGroup E ,C, L,M, H are significantly lower than group N in PaO2 and SaO2 (P < 0.05), higher than N group in PaCO2 (P < 0.05); Group L are significantly higher than group E in PaO2 and SaO2 (P < 0.05), but Lower than group E in PaCO2 and closed to group N (P > 0.05).2,Lung volume and the alveolar morphologyIn lung volume ,group E ,C, L,M, H are significantly higher than group N (P < 0.05), Group E has no difference with group E (P >0.05), Group L,M are significantly lower than group E (P < 0.05). In the MLI and MAA of alveolar morphology, group E ,C, M, H are significantly higher than group N (P < 0.05), Group L are significantly lower than group E (P < 0.05),Group M,H has no difference with group E (P >0.05).3,Lung tissue oxidative stressIn lung tissue SOD ,group E ,C, L,M, H are significantly higher than group N (P < 0.05), Group L are significantly higher than any other group (P < 0.05). In lung tissue MDA, group E ,C,L, M, H are significantly higher than group N (P < 0.05), but group L,M are significantly lower than group E (P < 0.05).In plasma SOD ,group E ,C, L,M, H are significantly higher than group N (P < 0.05), Group L,M, H are no significantly difference of each other (P >0.05),but higher than group E ,C, N . In plasma MDA, group E ,C,L, M, H are significantly higher than group N (P < 0.05), group L,M are significantly lower than group E (P < 0.05). Group H are significantly higher than any other group (P < 0.05).Conclusion:1.It is succeeded in a single intratracheally instillation of porcine pancreatic elastase to construct the emphysema model in Wistar rats.2.Plasma SOD, lung tissue SOD and arterial PO₂ significantly correlated linearly; plasma MDA , lung tissue MDA and arterial PO₂ have a significant negative linear correlation. It shows oxidative stress is an important factor in reducing arterial PO₂ and play an important role in the pathogenesis of emphysema.3.MDA content in plasma and lung showed similar trends after intraperitoneal injection of ATRA treatment,it indicated that the body and the tissue are present the same levels of oxidative stress in emphysema rats;Come to SOD, obvious changes in the lung tissue, but weak changes in plasma, perhaps there are more retinoic acid receptors in the lung tissue and have better responsiveness all-trans retinoic acid.4.The treatment of Low-dose ATRA might significantly promote antioxidant effect, alveolar repair and remedy pulmonary malfunction; the Middle-dose ATRA has certain effect;but negative effect was observed from High-dose ATRA treatment group;cottonseed oil have no effects on Emphysema Rats.As we can see, antioxidant may be an important mechanism of ATRA treatment in emphysema and low concentrations of ATRA has a better antioxidant and best effect,which worth to further study.