血铀浓度与肾损伤的关联性研究

目的研究人群血铀浓度与肾损伤间的关联。方法在湖南省4个铀矿分布地区开展病例对照研究, 分别纳入102例肾损伤病例和102例对照为病例组和对照组。使用条件logistic回归模型分析血铀浓度与肾损伤间的关联, 用限制性立方样条回归分析二者间的剂量反应关系。采用线性回归模型及Spearman相关来分析血铀浓度与肾损伤指标间的关联。结果全体研究对象血铀的中位浓度为8.94 ng/L, 病例组为10.19 ng/L。分析结果表明, 血铀可能是肾损伤的危险因素, 二者间存在剂量反应关系, 且呈非线性关联(χ2=5.15, P<0.05)。血铀浓度高暴露组发生肾损伤的危险性是低暴露组的4.21倍。血铀浓度与肾小球滤过率、血肌酐及β2微球蛋白等肾损伤指标关联密切(r=0.211、-0.142、0.195, P<0.05)。结论本研究表明血铀浓度与人群肾损伤之间存在统计学关联, 该结果可为肾损伤的预防提供流行病学依据。     

Induction of rat liver parenchymal cell apoptosis by hepatic myofibroblasts via transforming growth factor beta

The induction of apoptosis of rat liver parenchymal cells (PC) by transforming growth factor beta (TGF-beta)-expressing transforming fat-storing cells (FSC), i.e., myofibroblasts (MFB), was studied under culture conditions and compared with the apoptotic effect of human recombinant TGF-beta₁. MFB were obtained by subculture of FSC. The TGF-beta concentration in the conditioned medium of myofibroblast (MFBcM) determined with the Mink cell proliferation inhibition assay was <0.25 ng/mL/24 in the native medium, but 1.9 ng/mL24 h after transient acidification. MFBcM added in various dilutions and for different times to PC monolayers induced progressive cell detachment from the plastic support and increase of lactate dehydrogenase (LDH) activity in the medium. The reduction of mitochondrial dehydrogenase activity in PC (XTT or WST-1 test) was an early sign of MFBcM-induced functional impairment of PC. Short term exposure of PC with MFBcM for 3 hours was sufficient to induce the deleterious effects on PC, but neither native (nonactivated) MFBcM nor conditioned medium of untransformed FSC (FSCcM), in which TGF-beta was not detectable, were able to impair function and viability of PC. Activated MFBcM increased strongly (up to 21-fold) the concentration of oligonucleosomal DNA fragments both in the adherent and detached fraction of PC. Internucleosomal DNA fragments (DNA ladder) were demonstrated by electrophoresis of extracted DNA on agarose gels and by in situ end-labeling of DNA breaks (TUNEL reaction) only in MFBcM-exposed PC. MFBcM-treated PC exhibited intense fluorescence after staining with DNA-binding dye Hoechst 33342 and an increased number of cells with fragmented nuclei. All these criteria point to MFBcM-generated apoptosis of cultured PC, which were found to be very similar to those induced by human recombinant TGF-beta₁. The exclusive role of active TGF-beta in MFBcM as mediator of the apoptotic effects of MFB was proven by preincubation of the conditioned medium with human recombinant latency-associated peptide, which reversed completely MFBcM induced reduction of the XTT-test and the MFBcM-generated increase of oligonucleosomal DNA fragments. Partial reversibility was reached by preincubation of the medium with recombinant soluble type II TGF-beta receptor. The data let us conclude that transformed FSC, i.e., MFB in damaged liver, could participate in the mechanisms of PC apoptosis by paracrine loops involving TGF-beta. (Hepatology 1996 Mar;23(3):571-81)