内源性二氧化硫对野百合碱诱导肺动脉高压大鼠肺血管炎性反应的调节作用

Effects of endogenous sulfur dioxide on pulmonary vascular inflammation in rats with monocrotaline - induced pulmonary hypertension

目的探讨内源性二氧化硫（SO2）对野百合碱（MCT）诱导肺动脉高压大鼠肺血管炎性反应的调节作用。方法雄性Wistar大鼠32只，随机数字表法分成4组，每组8只：对照组、MCT组、MCT＋L-天冬氨酸-β-异羟肟酸（HDX）组及MCT＋s02组。MCT组、MCT＋HDX组和MCT＋S0：组大鼠腹腔注射MCT（60mr／kg，第1天），对照组注射同样剂量的9g／L盐水，MCT＋HDX组给予HDX25mg／kg，灌胃，第0、7、14天），MCT＋S0：组每天腹腔注射SO2供体[亚硫酸钠（Na2SO3）与亚硫酸氢钠（NaHSO。）摩尔比3：1]。采用右心导管法测定肺动脉平均压（mPAP），采用免疫组织化学方法检测肺小动脉内皮细胞炎症分子细胞间黏附分子-1（ICAM-1）及核因子-κB（NF-κB）信号转导通路关键分子p65和NF-κB抑制蛋白（IKBct）的表达。结果4组大鼠mPAP、肺小动脉内皮细胞中ICAM-1、Iκβα及p65表达比较差异有统计学意义（mPAP：F=53．334，P〈0．01；ICAM-1：F=183．82，P〈0．01；IKBα：F=142．89，P〈0．01；p65：F=105．46，P〈0．01）。与对照组相比，MCT组大鼠mPAP显著升高，肺小动脉内皮细胞ICAM．1及p65蛋白表达升高，IKBα蛋白表达降低；与MCT组大鼠相比，MCT＋SO2组大鼠mPAP显著降低，肺小动脉内皮细胞ICAM-1和p65蛋白表达均降低，Iκβα蛋白表达增加；MCT＋HDX组大鼠mPAP显著升高，肺小动脉内皮细胞ICAM-1及p65蛋白表达均增强，IKBct表达降低。结论内源性SO2可抑制MCT诱导肺动脉高压大鼠肺小动脉内皮细胞中NF-κB信号通路，抑制肺血管炎性反应，拮抗肺动脉高压的形成。

Objective To investigate the effects of endogenous sulfur dioxide （ SO2 ） on pulmonary vascular in- flammation in rats with monoerotaline （MCT） - induced pulmonary hypertension. Methods Thirty - two Wistar rats were randomly divided into 4 groups（ n = 8 for each group） ： control group, MCT group, MCT ＋ L - aspartie acid - β - hydroxamate（HDX） group,and MCT ＋ SO2 group. Rats in the MCT group, MCT ＋ HDX group, and MCT ＋ SO2 group were subcutaneously injected with MCT（60 mg/kg） on the first day. For rats in MCT ＋ HDX group, HDX （25 mg/kg, on day 0,7 and 14） was given orally after injection of MCT;and rats in MCT ＋ SO2 group were subcutaneously injected with the SO2 donor sodium sulfite/sodium bisulfate（ Na2SO3/NaHSO3, and mole ratio was adjusted to approximately 3 ： 1 ） each day. Rats in the control group received only the same volume of solvent vehicle only. After 3 weeks, mean pulmonary artery pressure（mPAP） of each rat was evaluated by using a right cardiac catheterization procedure. Immunohistoehemistry was used to detect the expression of inflammatory related factor intercellular adhesion molecule - 1 （ ICAM - 1 ） and the key molecules of nuclear factor -κB （ NF - κB ） signal transduetion pathway, including p65 and inhibitor of NF - κB （IKBot） in the small pulmonary artery endothelial cells. Results The differences in mPAP, expression of ICAM - 1, IκBα and p65 in the small pulmonary artery endothelial cells were found among the 4 groups （mPAP：F =53. 334,P 〈0.01 ;ICAM - 1 ：F = 183.82 ,P 〈0. 01 ; IκBα ： F = 142.89,P 〈 0.01 ;p65 ： F = 105.46,P 〈 0.01 ）. The mean pulmonary artery pressure（mPAP） was significantly raised in MCT group rats as compared with that of the control group along with upregulated expressions of ICAM - 1 protein and p65 protein in small pulmonary artery endothelial ceils, while the expression of IκBα protein in small pulmonary artery endothelial cells was significantly low. After administration of HDX,the mPAP and the expression of ICAM - 1 protein and p65 protein in small pulmonary artery endothelial cells further increased compared with those of MCT group, while the expression of IκBα protein in small pulmonary artery endothelial cells was significantly lower than that of MCT group. Whereas with treatment of So2 deriva- tives,the mPAP,the expression of ICAM - I protein and p65 protein in small pulmonary artery endothelial cells were significantly lower than those of MCT group ,while the expression of IκBα protein in small pulmonary artery endothelialcells increased significantly compared with that of MCT group. Conclusions Endogenous So2 might inhibit the activation of NF - κB pathway in the small pulmonary artery endothelial cells, attenuate the pulmonary vascular inflammation and prevent the MCT -induced pulmonary hypertension in rats.