肝纤维化动物模型研究进展

肝纤维化是肝损伤后的修复反应,涉及一系列复杂的细胞及分子机制,如何制作和选择与人类肝纤维化相似的动物模型,不仅是深入研究肝纤维化发病机制的重要基础,也是筛选防治肝纤维化药物的有效手段.文章介绍了目前常用的几种肝纤维化动物模型的造模方法,即给实验动物施以不同性质、不同剂量以及不同作用方式的肝毒剂,造成不同类型的肝纤维化模型.通过比较各种方法的致病机理、造模途径、效果、优缺点和各自用途,提出了肝纤维化动物模型的选择依据及研究方向.     

MMP13和TIMP2在肝缺血再灌注损伤介导肝纤维化进程中的动态变化及作用

探讨肝缺血再灌注损伤(HIRI)介导肝纤维化进程中基质金属蛋白酶-13(MMP13)和基质金属蛋白酶组织抑制剂2(TIMP2)的动态变化及作用。将70只C57雄性小鼠随机分为假手术组(Sham组)及肝缺血再灌注组(I/R 0 h组、I/R 3 h组、I/R 6 h组、I/R 72 h组、I/R 7 d组及I/R 15 d组)。夹闭肝门静脉、左叶和中叶的肝动脉,缺血90 min后开夹,分别再灌0、3、6、72 h、7 d及15 d,处死小鼠。检测小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)的水平;测定肝组织中羟脯氨酸(Hyp)的含量;免疫组化法检测肝组织中α-平滑肌肌动蛋白(α-SMA)表达量;RT-PCR检测肝组织MMP13和TIMP2 mRNA的表达水平;HE染色观察肝纤维化程度。结果显示,与Sham组相比,I/R 0 h、I/R 3 h及I/R 6 h组血清ALT、AST升高(P<0.05),I/R 72 h、I/R 7 d及I/R 15 d组下降(P<0.05)。I/R各组肝组织Hyp含量随再灌注时间延长逐渐升高,其中I/R 72 h、I/R 7 d、I/R 15 d组显著高于Sham组(P<0.05)。免疫组化显示,肝组织α-SMA的蛋白表达量随再灌注时间延长而逐渐增加。RT-PCR显示,I/R各组MMP13 mRNA的表达水平呈先高后低的趋势,与Sham组相比,I/R 0 h、I/R 3 h组显著升高(P<0.05)。而TIMP2的表达为先低后高,与Sham组相比,I/R 72 h、I/R 7 d及I/R 15 d组显著升高(P<0.05)。HE染色结果与上述变化趋势相一致。结果表明,在HIRI介导肝纤维化形成过程中MMP13与TIMP2呈动态的协同作用,共同促进肝纤维化的发生发展,是肝纤维化形成的关键因素。     

肝龙胶囊联合水飞蓟宾胶囊对肝纤维化大鼠的治疗作用

观察肝龙胶囊联合水飞蓟宾胶囊对肝纤维化大鼠的治疗效果,探讨肝龙胶囊是否对水飞蓟宾胶囊抗肝纤维化具有增效的作用。用猪血清制备大鼠肝纤维化模型,水飞蓟宾胶囊临床给药剂量单用及联合不同剂量肝龙胶囊处理肝纤维化大鼠,通过试剂盒及酶联免疫吸附试验(ELISA)检测大鼠血清和肝组织内肝纤维化标志物透明质酸(hyaluronic acid,HA)、层黏素(laminin,LN)、血清Ⅲ型前胶原氨基端肽(procollagenⅢN-termi,PCⅢ)、Ⅳ型胶原(typeⅣcollagen,Ⅳ-C)及转化生长因子β1(transforming growth factor-β,TGF-β1)、Ⅰ型胶原(collagen typeⅠ,Col-Ⅰ)的含量,以及肝脏内丙二醛(malondialdehyde,MDA)、谷草转氨酶(glutamic oxaloacetic transaminase,AST)、谷丙转氨酶(Cereal third transaminase,ALT)、γ-谷氨酰转肽酶(γ-glutamyl transpeptidase,γ-GT)的含量。与模型组比较,各治疗组中大鼠血清肝纤维化标志物的含量均低于模型组(P<0.05);肝龙胶囊与水飞蓟素联合用药与单用水飞蓟宾组相比,可使大鼠血清内HA和TGF-β1的含量显著降低(P<0.05);大鼠肝脏组织中除PCⅢ外,其余血清肝纤维化标志物的含量治疗组均低于模型组。肝组织中的γ-GT和ALT高剂量联合给药组显著降低,AST无显著差异,MDA中剂量联合给药组显著升高。说明肝龙胶囊可增强水飞蓟宾胶囊对猪血清性肝纤维化大鼠的抗肝纤维化作用。     

细粒棘球蚴感染羊肝脏包囊纤维化形成的病理形态学观察

为了探讨细粒棘球蚴感染羊肝脏包囊纤维化形成的病理学过程,本研究通过病理组织学、细胞化学和超微形态学的诊断方法,对羊感染细粒棘球蚴后肝脏的病理组织学变化,以及肝组织纤维化和包囊形成过程进行病理学观察。结果显示:原头蚴感染肝组织后病变沿感染组织的血管周围产生,相继出现肝细胞萎缩、变性、坏死;同时病变组织血管壁出现纤维组织分解、血管管壁出芽,增生出的纤维组织伸向周围炎症区域,血管管腔及炎区大量嗜酸性粒细胞浸润,增生的胶原纤维沿残存的肝细胞周围围绕病变组织,最终形成包囊壁。该研究结果为进一步阐释细粒棘球蚴感染羊肝脏包囊纤维化形成的病理机制奠定了坚实的基础。     

免疫调节剂SCA对感染血吸虫小鼠诱导的肝病变及纤维化作用的影响

进一步研究免疫调节剂 SCA对感染小鼠诱导的抗肝内血吸虫卵肉芽肿病变及血吸虫性纤维化作用的调节动态和分子机制。结果证明 :小鼠感染后 49～ 77d时 ,实验鼠肉芽肿的平均面积和体积均显著小于感染对照鼠 (P <0 .0 1 ) ,实验组之间无显著性差异 (P >0 .0 5) ;在感染后 49d和 63 d时 ,实验鼠的 IL-2和 IL-4收稿日期 :2 0 0 3- 0 4 - 0 3基金项目 :江苏省教育厅资金项目 (0 1KJD310 - 0 0 1)作者简介 :骆　伟 (195 4 - ) ,女 ,苏州市人 ,苏州大学医学院寄生虫学教研室副教授 ,主要从事寄生虫感染免疫学方面的研究工作。水平均显著高于对照鼠 ,并均显示相当高水平的 IL-1 0 ;在感染后 77d时 ,实验鼠的 IL-1 0水平显著高于对照鼠 (P <0 .0 5)。表明免疫调节剂 SCA能诱导明显的抗肝内血吸虫卵肉芽肿效应和血吸虫性纤维化作用 ,其分子机制与 CD4 亚群的 Th1型 (IL -2 )和 Th2型 (IL -4和 IL -1 0 )细胞因子应答的调节动态密切相关 ,提示 SCA具有明显的实用价值和应用前景     

Pathophysiology of pruritus

In spite of the research that has been performed, pruritus remains a poorly understood sensation. It is important to remember that the majority of information presented here is derived from observations of human subjects. One can only speculate as to how much of this information can be extrapolated to pruritus in animals. Pruritus is closely intertwined with pain and touch. Pain and pruritus sensations are carried on A delta and C fibers, ascend on the lateral spinothalamic tract, and terminate in various brain centers, including the thalamus and the cortex. The gate control theory of pain and pruritus describes the substantia gelatinosa cells as "swinging gates" to modify peripheral input and result in stimulation of higher centers. Central factors reduce or amplify the perception of these cutaneous sensations. Histamine is the classic mediator of pruritus, although it is still unknown whether a final common mediator of pruritus exists. Numerous other mediators include proteases, peptides, substance P, opiate peptides, prostaglandins, and leukotrienes. These may have pruritic properties directly, or may act as histamine liberators to cause pruritus.     

Pathophysiology of gravidity

Regulating processes during embryonal and fetal growth are discussed (genes, hormones). Due to viral infections there can be disorder of fetal life (resorption, mumification, abortion and malformations). Mucosal Disease is hold up as an example to describe that it depends on the moment of infection, on the development of immunologic competence and on the qualities of the virus, what happens after infection. The development of immunologic competence is considered carefully. An infection with Mucosal Disease-virus can find expression in disorders of intrauterine development, malformations, manifest nerval symptoms and death because of viral reproduction in the fetus. Pathogenesis of the disturbance of the development of the central nervous system and of the skin are discussed in detail. Infection with Mucosal Disease-virus and infection with Blue Tongue-virus are compared. Different to the development of these viruses is the IBR-virus, with propagates mainly in trophoblasts. This virus causes fetal death because of anoxia or brings about necrosis in the fetus. Similar to this virus is the virus of Aujeszky's Disease, different to this virus is the Hog Cholera-virus. Except of abortion and still-birth, after infection with this virus suckling pigs can be born, which show hypoplasia of the cerebellum or dysmyelogenesis. Furthermore they can be immunologically tolerant. In conclusion there is a comment on the Parvovirus infection, which results in the SMEDI-Syndrome (stillbirth, mumification, embryonic-death, infertility): effect of infection of gametes via sperm is infertility, because there is no decomposition of corpus luteum graviditatis, the sow acts as if she is pregnant. The economical loss is extremely high.     

Pathophysiology and management of arthritis.

This article primarily reviews the pathophysiology, diagnosis, and therapy of osteoarthritis but also briefly discusses immune-mediated arthritides. Given the frequency of occurrence of arthritis in veterinary patients, it is crucial that clinicians be aware of the mechanisms of the disease and be comfortable with diagnosis and treatment. Unfortunately,there is a great deal of information still to be learned in regards to management of these cases. Because of the rapid and continuing research gains, it behooves clinicians to maintain a current awareness of the related literature.     

Pathophysiology of navicular syndrome

Navicular syndrome is a degenerative disorder of the distal half of the flexor surface of the proximal sesamoid bone that is predisposed by faulty foot conformation. In horses that become symptomatic, the faulty conformation results in sustained application of nonphysiologic pressure by the deep digital flexor tendon against the flexor cortex of the bone. This force stimulates an intense bone remodeling response in order to attenuate the pressure. An unfortunate sequela of this response is active hyperemia and edema formation in the medullary cavity of the bone. The edema is organized by fibrous tissue resulting in venous entrapment, venous hypertension, vascular bone pain, and the onset of clinical signs.     

Pharmacologic manipulation of fertility.

The professional application of agents to the manipulation of fertility of cows requires basic and applied knowledge of the physiologic mechanisms that are affected and of the pharmacologic agents that are used. In all areas of the pharmacologic manipulation of fertility, the achievement is less than the ideal, and further research is required to improve the efficiency of treatments. The induction of estrus in acyclic animals can involve a reduction in the depth of anestrus, pretreatment with progestagen to ensure estrous behavior and the formation of a normal corpus luteum, and then treatment with exogenous gonadotropin. Responsiveness to treatment can be variable and reflects the depth of anestrus of the animals. Improved treatment regimens require a knowledge of the basic mechanisms involved with the depth of anestrus, a means of assessing the depth of anestrus, and an understanding of the hormonal requirements of ovarian follicles for development and maturation in animals at different depths of anestrus. The optimal precision in the synchronization of estrus (and ovulation) in cyclic animals requires the synchronization of both follicular waves and the end of progestational phase. The end of progestational phase can be synchronized effectively using prostaglandin F2a (or analogs), or by treatment with progestagens with or without luteolytic agents. Procedures to synchronize follicular waves need to be established. The induction of superovulation can be achieved readily using gonadotropins prior to estrus synchronization using prostaglandin F2a. The responses to standard treatments in terms of ovulation rates and yield of transferable embryos are highly variable. The development of procedures to reduce this variability requires an understanding of the intra-ovarian mechanisms involved in recruitment of follicles for a wave of follicular growth, in the selection of dominant follicles for further development, and in the mechanisms controlling follicular atresia. Cystic ovarian disease can be treated effectively using HCG or GnRH (follicular cysts) or prostaglandin F2a (luteal cysts). The basic mechanisms resulting in failure of estrogen positive feedback on LH secretion (that results in cystic follicles) remain to be determined. Small but significant increases in pregnancy rates can be achieved treating cows with prostaglandin during the post-partum period, with prostaglandin to induce estrus for insemination, with GnRH or HCG at estrus, and with GnRH or progestagen treatment during diestrus. Beneficial effects of treatment have been shown in some trials but not in others.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pathophysiology of calcium and phosphorus disorders.

Hypocalcemia and hypophosphatemia are relatively common in periparturient cows. This article reviews the etiologic factors that contribute to the development of these conditions. The physiologic role of magnesium in calcium homeostasis and the physiologic effect of dietary cation-anion difference at the cellular level are discussed in depth. A theory to explain the development of periparturient hypophosphatemia is developed.