Experimental Study On All-trans Retinoic Acid Promoting Alveolar Repair In Emphysematous Rats And Rabbits After Lung Volume Reduction Surgery

Pulmonary emphysema is a common disease severely threatening human health in worldwide. 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. All-trans retinoic acid(ATRA), the biologically active metabolite of vitamin A, plays an important role in lung development, mature and maintaining alveolar architectural stability. It induces alveolar formation and increase elastic recoil in adult rat lung with elastase-induced emphysema, so it is probably an effective drug for treatment of pulmonary emphysema, but the mechanism is unclear. Lung volume reduction surgery(LVRS) is an palliative treatment for severe pulmonary emphysema. The melioration of pulmonary function after LVRS is only last 2 years and decrease quickly after 2 years. The mechanism of LVRS treatment for pulmonary emphysema is still uncertain. Most studies about LVRS to date focus on the adaption of respiratory muscule such as diaphragm but few about the remanent lung. The research results from compensatory lung growth after pneumonectomy show that alveolar can be repaired or regenerated in some special circumstance. Both the proper strengthen force and ATRA are the stimulators for alveolar repair or regeneration. The deposition of elastin in lung is regulated by tropoelastin gene and the destory of elastic fiber was mainly regulated by the imbalance between matrix meatlloproteinase-9(MMP-9) and tissuse inhibitor-1 of matrix meatlloproteinase(TIMP-1) in cigarrette smoking-induced emphysema. The present study investigates the effects and its probable mechanisms of ATRA and LVRS on pulmonary emphysema. Firstly, the emphysematous animal model was estab-lished in rats induced by cigarette smoking plus porcine pancreatic elastase intratracheal instillation. Secondly, pulmonary function, artery blood gas analysis and alveolar mor-phometry were compared between the normal rats, emphysematous rats, emphysematous rats injected intraperitoneally with cottonseeds oil and emphysematous rats injected intrap-eritoneally with ATRA dissolution in cottonseeds oil. Additionaly, regulation of tropoelastin, MMP-9 and TIMP-1 by ATRA was studied by immunohistochemistry, ELISA, Western-blot and RT-PCR. Thirdly, the emphysematous rabbits were treated with LVRS and followed with ATRA intraperitoneally injection. Pulmonary function, artery blood gas analysis and alveolar morphometry were compared in normal rabbits, emphysematous rabbits, sham op-eration rabbits, LVRS rabbits, LVRS rabbits injected intraperitoneally with cottonseeds oil and LVRS rabbits injected intraperitoneally with ATRA. Additionaly, regulation of tropoe-lastin, MMP-9 and TIMP-1 by LVRS and ATRA were also studied by immunohistochemis-try, ELISA, Western-blot and RT-PCR. The following is our results: 1. emphysematous rat model similar to human emphysema caused by long-term ciga-rette smoking was successfully induced with cigarette smoking plus porcine pancreatic elastase intratracheal instillation during 3 months. 2. Though no melioration of artery blood gas analysis was achieved, pulmonary func-tion and alveolar morphometry were meliorated in emphysematous rats after treated with ATRA. ATRA upregulates the expression of tropoelastin and TIMP-1, downregulates the expression of MMP-9. The ratio between MMP-9 and TIMP-1 was balanced. As a result, deposition of elastin was increased and destroy of elastic fiber was decreased, alveolar was repaired and elastic recoil of lung was recovered. 3. Pulmonary function, artery blood gas analysis and alveolar morphometry were all meliorated in emphysematous rabbitts after treated with LVRS. LVRS upregulates the tro-poelastin mRNA expression and increase the elastin deposition, alveolar was repaired and elastic recoil of lung was recovered. LVRS has no effect on the mRNA expression of MMP-9 and TIMP-1. 4. Pulmonary function and alveolar morphometry were meliorated after treated with ATRA in LVRS rabbits but the change of artery blood gas analysis was not statistically sig-nificant. ATRA significantly enhance the effect of LVRS on emphysema. ATRA upregu-lates the expression of tropoelastin and balances the ratio between MMP-9 and TIMP-1 in LVRS rabbits.Our results suggest that: 1. The emphysematous animal model simmlar to human emphysema can be induced by cigarette smoking plus intratracheal instillation elastolyic proteins within a short term. 2. ATRA promotes alveolar repair and increases elastic recoil in emphysematous rats lung. ATRA may upregulate the expression of tropoelastin and balance the ratio between MMP-9 and TIMP-1. 3. LVRS increases elastic recoil in emphysematous rabbits lung. Strengthen force after LVRS may upregulate the expression of tropoelastin. 4. ATRA promotes more alveolar repair and elastic recoil increase in emphysematous rabbits after LVRS by upregulating the expression of tropoelastin and balancing the ratio between MMP-9 and TIMP-1.