Effect Of Fluvastatin On Airway Remodeling In Asthmatic Rats And Its Mechanism

Background Asthma,a chronic disease, characterized by airway hyper reactivity, inflammation, and remodeling and is an extraordinarily common cause of pulmonary impairment in world. It recently suggested airway remodeling that occurs in asthma make a prominent role for the perpetuation of airway inflammation and induction of the chronic features of asthma. This assertion is supported by observations that numerous agents that are elevated in the asthmatic airway after exposure to relevant inflammatory agents are mitogenic to ASMCs in vitro and stimulate expresses of adhesion molecules and secretes numerous cytokines. Furthermore, ASM mass is increased in the bronchi of severe chronic asthmatic subjects, and this increased mass is due to hyperplasia. Consequently , to control the asthma in clinic practice ,much research should center on how to inhabit the airway remodeling.Statins is new and man-made HMG-CoA reductase inhibitors. Statins may exert biological effects other than their cholesterol-lowering actions , including inhibition of Ras activation by preventing isoprenylation. A recent study has shown that lipid-soluble HMG-CoA reductase inhibitors prevent angiotensin II–induced hypertrophy at least in part through inhibition of p21ras/mitogen-activated protein kinase A pathway in neonatal cardiac myocytes in vitro. Plasma membrane localization of GTP-binding proteins such as Ras is crucial for their biological activity,which is related closely with cell proliferation. In fact , their prenylation is dependent on the formation of mevalonate-derived isoprenoid compounds. It has been previously demonstrated that the inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase interferes with Ras anchorage to cell membrane and its activation by reducing the pool of farnesyl groups. Presently, in vivo effects of HMG-CoA reductase inhibitors on Ras signaling and on downstream cell-cycle regulators are still not well defined.PART ONEAIM :To investigate the effect of hydroxy-methylglutaryl-CoA(HMG-CoA) reductase inhibitor, fluvastatin, on airway remodeling in asthmatic rats.METHODS: The male Sprague-Dawly rats were randomly divided into 4 groups with 10 rats in each group:the normal control group(A),the model group(B), the dexamethasone treated group(C)and the fluvastatin treated group( D).The asthmatic rat model was established by intraperitoneal injection and repeated inhalation of 10g/L ovalbumin. The changes of collagen typeⅢ, proliferation cell nuclear antigen (PCNA) and p21ras contents in the airway wall were detected by immunohistochemical methods, and the internal perimeter of bronchi(Pi) and the area of bronchial smooth muscle (WAm) were measured by the computerized image analysis system.RESULTS:①Fluvastatin inhibited the proliferation in airway remodeling: The WAm /Pi,the contents of collagen typeⅢand PCNA in group D (4.44±0.95μm2/μm], 32±6 and 38±10, respectively.) were lower than group B(7.01±1.54μm2/μm,55±8 and 68±12, respectively.) ,the difference being significant (all P<0.05);②Fluvastatin was less effective in inhibition on the course of airway remodeling than dexamethasone: The WAm /Pi , the contents of collagen typeⅢand PCNA in group D were higher than group C[(3.14±1.06)μm2/μm,21±6, 26±6] , the difference being significant(all P<0.05).③The contents of p21ras in group D (24±11) were lower, as compared with group B(57±10,P<0.05). A close correlation was demonstrated between p21ras and PCNA(rs=0.685, P<0.05).The same positive correlation was found between p21ras and collagen typeⅢ(rs=0.530, P<0.05). CONCLUSION: Fluvastatin could delay the course of airway remodeling in asthmatic rats, which is related partly to the inhibition of p21ras.But the inhibition of fluvastatin on the course of airway remodeling is less effective than the inhibition of dexamethasone. PART TWOObjective :To investigate the effect of hydroxymethylglutaryl-CoA(HMG-CoA) reducase inhibitor, fluvastatin, on airway remodeling in asthma.Methods: Air-way smooth muscle cells (ASMC) in rats were cultured in vitro.The proliferation of ASMC were detected with MTT method. Flow cytometry was used to detect the cell cycle.Results: The stimulative effects of histamine and serum on the proliferation of ASMC were prevented by Flu . There was concentration-dependent and time-dependent inhibition to the cell proliferation. OD value was obviously decreased ,compared with control group. But 10 -4mol·L -1 Flu group(0.31±0.02) is not significantly different, compared with the dexamethasone group(0.31±0.04) (P>0.05)。Flow cytometry indicate that Flu significantly blocked the cell cycle progression in G1 phase. Compared with the control group,the counts of cell in G1 phase increase significantly. Conclusion: Fluvastatin could inhibit the proliferation of the ASMCs in vitro and such effects are concentration-dependent and time-dependent. The effects of fluvastatin(10 -4mol·L -1)in vitro is not different from the dexamethasone(2×10-6 mol·L-1)significantly. Fluvastatin could delay the course of airway remodeling in asthma.