Mechanisms of Inflammation: Role of CD34 and Podocalyxin in Neutrophil Recruitment

炎症是宿主对生物、化学或物理攻击的先天防御反应。炎症是由细菌、病毒和寄生虫感染引起的。炎症是肝脏（如肝炎）、关节（如关节炎）和肺（如肺炎和哮喘）等器官中许多疾病的基础。炎症的特点是防御细胞如中性粒细胞和单核细胞在血液中被激活。被激活的细胞，如中性粒细胞，从血液中进入器官对抗细菌。中性粒细胞通过与内皮细胞的相互作用从血管中迁移。内皮细胞排列在血管壁的内部。活化的中性粒细胞通过产生自由基等化学物质来杀死细菌。活化的中性粒细胞过度迁移到组织中会导致由中性粒细胞产生的自由基和其他化学物质对组织造成严重损害。中性粒细胞产物引起的组织损伤，如果过量，会导致发病率和死亡率。为了保持平衡，确保中性粒细胞利大于弊，我们需要保持中性粒细胞的抗微生物作用，同时，微调它们向组织的迁移，以防止组织损伤。这可以通过控制中性粒细胞的迁移来实现。

Inflammation is a host's innate defense response to biological, chemical or physical insults. Inflammation is induced through infections with bacteria, viruses and parasites. Inflammation underlies many diseases in organs such as the liver (e.g., hepatitis), joints (e.g., arthritis) and lungs (e.g., pneumonia and asthma). Inflammation is characterized by the activation of defense cells such as neutrophils and monocytes while in the blood stream. Activated cells such as neutrophils move from the blood into the organs to fight bacteria. Neutrophils migrate from the blood vessels through interactions with the endothelial cells. Endothelial cells line the inside of the walls of blood vessels. Activated neutrophils kill bacteria through production of chemicals such as free oxygen radicals. Excessive migration of activated neutrophils into the tissues results in significant tissue damage from free oxygen radicals and other chemicals produced by the neutrophils. The tissue damage caused by products of neutrophils, if excessive, contributes to morbidity and mortality. In order to maintain balance and insure that neutrophils do more good than harm, we need to maintain the anti-microbial actions of the neutrophils, and at the same time, fine-tune their migration into the tissues to prevent tissue damage. This can be potentially accomplished through control of migration of the neutrophils. Neutrophil migration occurs through various steps such as slowing, rolling on the endothelium, firm adhesion with the endothelium and finally migration out of the blood vessels. One of the very early events in the migration of neutrophils into the tissues is the interaction between the neutrophils and the endothelium. This interaction is facilitated through the formation of projections (called pseudopods) on the neutrophil membrane through reorganization of cell skeleton proteins such as F-actin. The mechanisms that lead to the cytoskeletal changes in neutrophils are not fully understood. I propose to study the roles of CD34 and podocalyxin (PC) proteins in these processes to eventually discover molecular mechanisms to control neutrophil migration. The studies include evaluation of the mechanisms that influence the expression of CD34 and PC in neutrophils and endothelial cells as well as the study of the role of these proteins in the interactions of neutrophils with the endothelium. The studies will be conducted with an array of in vitro and in vivo methods to investigate the cell morphology, molecules and outcomes: confocal and electron immunocytochemistry; western blots; flow cytometry; endothelial and neutrophil cultures; mouse models of inflammation in cremaster muscle and lungs. Taken together, my trainees and I will conduct studies that range from isolated cultured neutrophil and endothelial cells to two different animal models of inflammation to understand the fundamental nature of the neutrophil migration. The data from these studies are expected to show hitherto unknown roles for CD34 and PC in the formation of pseudopods on neutrophils, which facilitate interactions with endothelial cells lining the inside walls of the blood vessels. Because these initial membrane contacts are critical for the eventual migration of neutrophils, these data will advance our knowledge and contribute towards the development of new molecular management models of inflammatory diseases for animals and humans.