EVALUATION OF ANTI-ADHESION MOLECULE THERAPY AFTER MCA OCCLUSION IN THE RAT

我们的目标是：减少大脑中动脉后的缺血细胞损伤 选择性阻断白细胞黏附的大鼠大脑中动脉闭塞 分子受体(CD11b，LFA-1)，研究其作用机制 阻断这些受体可减少缺血细胞的损伤，并使 磁共振成像作为一种非侵入性的评估方法 缺血组织对治疗性干预的反应。至 为了实现这些目标，我们将采用与以下三个相关的实验 明确的目标。 目的1：抗(CD11b，LFA-1)单抗对小鼠肾小球滤过率的影响 将研究短暂性脑缺血大鼠的细胞损伤(2 小时)大脑中动脉闭塞。缺血细胞损伤将作为一项功能进行测量 抗体给药剂量和时间。假设：一个单克隆体 与整合素反应的抗体将减少缺血细胞损伤 作为抗体注射剂量和时间的函数进行测量。 假设：与整合素反应的单抗可降低 短暂性大脑中动脉闭塞后的缺血细胞损伤。目标2：机制 抗CD11b和抗LFA-1反应性抗体可减轻脑缺血 将对细胞损伤进行调查。2(A)；我们将测量并关联 中性粒细胞渗入脑缺血范围的时间分布 有缺血细胞损伤的组织。假设；白细胞的渗透， 主要是中性粒细胞，先于或伴随进入缺血组织 与缺血细胞损伤有关，并在 短暂性局灶性脑缺血。2(B)。我们将进行量化 局部脑血流量的放射自显影测量 短暂性大脑中动脉闭塞后。假设；中性粒细胞可能有助于 减少局部脑血流量对再灌注损伤中的缺血细胞损伤 流。2(C)：血脑屏障的通透性将为 在短暂性大脑中动脉闭塞后不同时间进行评估。假说； 中性粒细胞可能通过相互作用在一定程度上导致缺血细胞损伤 与毛细血管内皮细胞结合从而增加血管通透性 血脑屏障对水和神经毒性物质。目标3：我们将使用核磁共振 方法(灌注成像、扩散加权成像(DWI)、T1和T2 成像)，以评估生理变化和抗肿瘤疗效 整合素治疗干预。假设：具有有效的白细胞 抗黏附分子治疗的时间分布和价值 水的表观扩散常数(ADC)和脑血流量 将被修改，并且通过T2加权测量的病变体积 与没有抗体的动物相比，成像将会减少。

Our goals are; to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking leukocyte adhesion molecule receptors (CD11b, LFA-1), to investigate mechanisms by which blocking these receptors reduce ischemic cell damage, and to bring to fruition magnetic resonance imaging as a non-invasive method of assessing the response of ischemic tissue to a therapeutic intervention. To accomplish these goals we will employ experiments associated with three Specific Aims. Aim 1: The effect of anti-(CD11b, LFA-1) monoclonal antibodies on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage after transient MCA occlusion. Aim 2: Mechanisms by which the anti-CD11b and anti-LFA-1 reactive antibodies reduce ischemic cell damage will be investigated. 2(a); We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis; Infiltration of leukocytes, primarily neutrophils, into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. 2 (b). We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis; Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow. 2(c): The permeability of the blood-brain barrier (BBB) will be evaluated at various times after transient MCA occlusion. Hypothesis; Neutrophils may contribute in part to ischemic cell damage by interacting with the capillary endothelium and thereby increasing the permeability of the BBB to water and neurotoxic substances. Aim 3: We will employ NMR methodology (Perfusion Imaging, Diffusion Weighted Imaging (DWI), T1 & T2 Imaging) to assess the physiological changes and efficacy of the anti- integrin therapeutic intervention. Hypothesis: With effective leukocyte anti-adhesion molecule therapy, the temporal profiles and values of the apparent diffusion constant of water (ADC)w) and CBF in the ischemic tissue will be modified, and the volume of the lesion as measured by T2 weighted imaging will be reduced compared to animals without antibody.