Heinzelmann M, Mercer-Jones M A, Passmore J C
The Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY, USA.
Am J Kidney Dis. 1999 Aug;34(2):384-99. doi: 10.1016/s0272-6386(99)70375-6.
In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils' ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This review summarizes the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. Nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase is a membrane-associated enzyme that generates a family of reactive oxygen intermediates (ROI). There is increasing evidence that ROIs are implicated in glomerular pathophysiology: ROIs contribute to the development of proteinuria, alter glomerular filtration rate, and induce morphological changes in glomerular cells. Specific neutrophil granules contain microbicidal peptides, proteins, and proteolytic enzymes, which mediate the dissolution of extracellular matrix, harm cell structures or cell function, and induce acute and potentially irreparable damage. Although both ROI and neutrophil-derived proteases alone have the potential for tissue destruction, it is their synergism that circumvents the intrinsic barriers designed to protect the host. Even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of neutrophil-derived myeloperoxidase (MPO) and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage if not properly controlled. In addition, neutrophil-derived phospholipase products such as leukotrienes and platelet-activating factor contribute to vascular changes in acute inflammation and amplify tissue damage. Increasing evidence suggests that mesangial cells and neutrophils release chemotactic substances (eg, interleukin 8), which further promote neutrophil migration to the kidney, activate neutrophils, and increase glomerular injury. Also, the expression of adhesion molecules (eg, intercellular adhesion molecule 1 on kidney-specific cells and beta-2-integrins on leukocytes) has been correlated with the degree of injury in various forms of glomerulonephritis or after ischemia and reperfusion. Together, these results suggest that neutrophils and adhesion molecules play an important role in mediating tissue injury with subsequent renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase susceptibility to infection and sepsis.
在许多疾病和急性炎症性疾病中，病理过程的重要组成部分与中性粒细胞释放多种能够破坏正常细胞和溶解结缔组织的介质的能力有关。本综述总结了中性粒细胞造成组织破坏的机制以及促进这种作用的肾脏特异性因子的作用。烟酰胺腺嘌呤二核苷酸磷酸H（NADPH）氧化酶是一种膜相关酶，可产生一系列活性氧中间体（ROI）。越来越多的证据表明，ROI与肾小球病理生理学有关：ROI导致蛋白尿的发生，改变肾小球滤过率，并诱导肾小球细胞的形态变化。特定的中性粒细胞颗粒含有杀菌肽、蛋白质和蛋白水解酶，它们介导细胞外基质的溶解，损害细胞结构或细胞功能，并导致急性且可能无法修复的损伤。虽然单独的ROI和中性粒细胞衍生的蛋白酶都有造成组织破坏的可能，但它们的协同作用绕过了旨在保护宿主的内在屏障。即使少量的ROI在存在中性粒细胞衍生的髓过氧化物酶（MPO）的情况下也能产生次氯酸（HOCl），并启动抗蛋白酶的失活和潜在蛋白酶的激活，如果不加以适当控制，这会导致组织损伤。此外，中性粒细胞衍生的磷脂酶产物如白三烯和血小板活化因子会导致急性炎症中的血管变化并加剧组织损伤。越来越多的证据表明，系膜细胞和中性粒细胞会释放趋化物质（如白细胞介素8），这会进一步促进中性粒细胞向肾脏迁移，激活中性粒细胞，并加重肾小球损伤。此外，黏附分子（如肾脏特异性细胞上的细胞间黏附分子1和白细胞上的β-2整合素）的表达与各种形式的肾小球肾炎或缺血再灌注后的损伤程度相关。这些结果共同表明，中性粒细胞和黏附分子在介导组织损伤及随后的肾衰竭中起重要作用。相反，慢性肾衰竭会降低中性粒细胞功能，从而增加感染和败血症的易感性。
