蛋白激酶在微血管通透性中的作用

微血管内皮细胞层是一层半选择通透性屏障,可以调节血液中的液体、溶质和血浆蛋白进入组织间隙。在炎症刺激作用下,可通过旁细胞途径和跨细胞途径引起内皮通透性上升。旁细胞通路主要由内皮细胞间的紧密连接、黏附连接和细胞与外基质的黏着斑组成。炎症介质,如脂多糖和肿瘤坏死因子α可激活多种蛋白激酶。活化的蛋白激酶主要包括Rho相关的卷曲蛋白激酶、肌球蛋白轻链激酶、蛋白激酶C、酪氨酸激酶和丝裂原活化蛋白激酶等,参与引发内皮屏障生化和结构改变,旁细胞通路开放,导致通透性上升。该文对上述蛋白激酶在微血管通透性中作用机制的研究进展进行综述。     

The role of T cell antagonism and original antigenic sin in genetic immunization

To counter highly mutable pathogens like HIV-1, a number of vaccines are being developed to deliver multiple mutant forms of viral Ags to provoke multivalent antiviral CTLs. However, it is uncertain whether such multiple mutant epitope vaccines will generate the diverse CTL responses desired or will instead create immune interference. To characterize the role of immune interference by mutant epitopes in this process, we have tested a "worst case" scenario in which the immunodominant epitope of OVA (SIINFEKL) and its in vitro TCR antagonist (SIINFEDL) have been used to genetically immunize C57BL/6 mice. We demonstrate here that sequential delivery of these mutant epitopes provokes original antigenic sin in CD8 T cells as demonstrated by attenuation of CTLs, intracellular IFN-gamma production, and MHC I peptide-tetramer staining. By contrast, simultaneous exposure of the immune system to this agonist/antagonist pair not only fails to generate T cell antagonism in vivo, but also avoids original antigenic sin. These observations suggest that simultaneous immunization with vaccines containing mutant epitopes, even T cell antagonists, can indeed generate a diverse array of T cell responses and that at least some immune interference can be avoided by delivering mutant Ags to the immune system simultaneously.     

ADH-induced water permeability: what role for the microtubular network?

1. ADH-induced intramembrane particle aggregates in the apical membrane of the epithelial cells are specifically related to water permeability in the epithelium. 2. Colchicine and nocadozole (both of which bind to tubulin) inhibit ADH-induced osmotic water flow in the amphibian bladder. 3. Microtubules may be involved in the translocation of the aggrephores prior to their insertion into the plasma membrane.     

The role of free radical generation in increasing cerebrovascular permeability

The brain endothelium constitutes a barrier to the passive movement of substances from the blood into the cerebral microenvironment, and disruption of this barrier after a stroke or trauma has potentially fatal consequences. Reactive oxygen species (ROS), which are formed during these cerebrovascular accidents, have a key role in this disruption. ROS are formed constitutively by mitochondria and also by the activation of cell receptors that transduce signals from inflammatory mediators, e.g., activated phospholipase A₂ forms arachidonic acid that interacts with cyclooxygenase and lipoxygenase to generate ROS. Endothelial NADPH oxidase, activated by cytokines, also contributes to ROS. There is a surge in ROS following reperfusion after cerebral ischemia and the interaction of the signaling pathways plays a role in this. This review critically evaluates the literature and concludes that the ischemic penumbra is a consequence of the initial edema resulting from the ROS surge after reperfusion.     

The temperature dependence of erythrocyte water diffusion permeability

1. The activation energy of the diffusion water exchange in red blood cells increases with temperature. 2. Fetal blood has a higher activation energy for diffusion water exchange than adult blood. 3. Treatment of red cells with p-chloromercuribenzoate alters the activation energy and apparently allows a lipid and a protein pore pathway to be resolved. The permeability and activation energy of the treated cells is in the range found for lipid membranes; and the difference between treated and untreated cells, the "protein" pathway, has a diffusion activation energy comparable with that of free water. 4. A resolution of the discrepancies between the NMR methods of measuring diffusion water exchange is suggested.     

The role of the mitochondrial permeability transition in cell death

The mitochondrial permeability transition (MPT) is a non-selective inner membrane permeabilization that occurs in response to increased calcium load and redox stress. Currently, two models of the MPT exist including the, largely hypothetical, native proteinaceous pore model and the oxidized inner membrane protein model which may reflect the extremes in a continuum of changes that occur to the inner membrane prior to its permeabilization. Here I discuss evidence that the MPT per se leads to necrosis, but not cytochrome c release and apoptosis. However, data also suggest that signaling crosstalk between the MPT and Bcl-2 family proteins occurs indicating an important role for the MPT in apoptosis.     

线粒体通透性转换孔在缺血后处理中的作用和机制

心肌细胞急性缺血后,及时再灌注能够挽救缺血心肌细胞的活力、减少梗死面积、促进心肌细胞功能恢复。但是再灌注是一把“双刃剑”,它产生大量活性氧类（reactive oxygen species,ROS）和Ca2＋超载,开放线粒体通透性转换孔（mitochondrial permeability transition pore,mPTP）,使线粒体肿胀,外膜破裂导致心肌细胞坏死。mPTP是线粒体非特异性的转换孔,由电压依赖性阴离子通道（voltage-dependent anion channel,VDAC）、腺苷酸转位蛋白（adeninenucleotide translocator,ANT）和亲环蛋白D（cyclophilin D,CYPD）组成。mPTP关闭维持线粒体结构完整,是缺血心肌细胞功能恢复的先决条件。缺血后处理通过减少再灌注早期ROS大量释放和拮抗Ca^2＋超载、释放内源性介质、激活再灌注损伤补救激酶（reperfusion injury salvage kinase,RISK）、抑制mPTP开放,从而保护心肌细胞。