Turner Terry T, Bang Hyun J, Lysiak Jeffery L
Departments of Urology and Cell Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
J Urol. 2004 Dec;172(6 Pt 2):2574-8. doi: 10.1097/01.ju.0000144203.30718.19.
We review the work of our laboratory in discovering the pathophysiological mechanisms that underpin testicular response to testicular torsion. Evidence from animal models is used to discover pathways that might be amenable to manipulation by therapeutic regimens.
Rats and mice were subjected to 1 and 2 hours of testicular torsion, respectively. Preliminary experiments determined that those are the times of torsion in those species that produce severe testicular atrophy and germ cell apoptosis. A variety of biochemical and molecular biological techniques were used to determine the mechanism(s) leading to spermatogenic disruption and germ cell apoptosis.
Testicular torsion can eliminate spermatogenesis despite return blood flow, continued Sertoli cell function and perhaps the continued production of testosterone by Leydig cells, although the latter point is not completely resolved. Torsion repair is followed by a period of germ cell apoptosis, accumulation of testicular neutrophils and increased testicular oxidative stress. Testicular vascular E-selectin expression is increased after torsion repair as are a number of cytokines important to the recruitment of neutrophils. Elements of the c-Jun-N-terminal kinase pathway are important in this process. The presence of neutrophils leads to intratesticular oxidative stress, and oxidative stress has been significantly reduced by intravenous infusion of oxygen radical scavengers at the time of torsion repair.
Testicular torsion causes loss of spermatogenesis and a significant increase in germ cell apoptosis due to an increase in testicular oxidative stress concomitant with reperfusion. Oxidative stress arises with recruitment of neutrophils, and the recruitment of neutrophils occurs due to E-selectin expression on the surface of the testicular venules after torsion repair. The cytokines, tumor necrosis factor-alpha and interleukin-1beta, activate the stress related kinase pathway to E-selectin expression after torsion repair. Oxidative stress is relieved by infusion of oxygen radical scavengers, which results in a significant salvage of testicular function.
我们回顾了本实验室在发现支撑睾丸扭转后睾丸反应的病理生理机制方面的工作。利用动物模型的证据来发现可能适合通过治疗方案进行调控的途径。
分别对大鼠和小鼠进行1小时和2小时的睾丸扭转。初步实验确定这是导致这些物种严重睾丸萎缩和生殖细胞凋亡的扭转时间。使用了多种生化和分子生物学技术来确定导致生精破坏和生殖细胞凋亡的机制。
尽管恢复了血流、支持细胞功能持续存在，或许间质细胞仍持续产生睾酮（尽管后一点尚未完全明确），但睾丸扭转仍可消除精子发生。扭转修复后会经历一段生殖细胞凋亡期、睾丸中性粒细胞积聚以及睾丸氧化应激增加。扭转修复后睾丸血管E-选择素表达增加，同时一些对中性粒细胞募集很重要的细胞因子也增加。c-Jun-N-末端激酶途径的元件在这一过程中很重要。中性粒细胞的存在导致睾丸内氧化应激，在扭转修复时静脉输注氧自由基清除剂可显著降低氧化应激。
睾丸扭转导致精子发生丧失和生殖细胞凋亡显著增加，这是由于再灌注时睾丸氧化应激增加所致。氧化应激随着中性粒细胞的募集而产生，中性粒细胞的募集是由于扭转修复后睾丸小静脉表面E-选择素的表达。细胞因子肿瘤坏死因子-α和白细胞介素-1β在扭转修复后激活与应激相关的激酶途径以促进E-选择素表达。输注氧自由基清除剂可减轻氧化应激，从而显著挽救睾丸功能。
