Chandra A M, Campbell G A, Reddy G, Qualls C W
Department of Anatomy, Pathology, and Pharmacology, College of Veterinary Medicine, Oklahoma State University, Stillwater, USA.
Vet Pathol. 1999 May;36(3):212-20. doi: 10.1354/vp.36-3-212.
1,3,5-Trinitrobenzene (TNB) is a soil and water contaminant at certain military installations. Encephalopathy in rats given 10 daily oral doses of TNB has been reported. The lesion was bilaterally symmetric vacuolation and microcavitation in the cerebellar roof nuclei, vestibular nuclei, olivary nuclei, and inferior colliculi. The contribution of the blood-brain barrier (BBB) in the genesis of these lesions remains uncertain. One of the main goals of the present work was to evaluate the functional state of the BBB. Male Fischer 344 rats (five rats/group) were euthanatized after four, five, six, seven, eight, or 10 daily doses of TNB (71 mg/kg). A different set of rats (five rats/group) was allowed to recover for 10 or 30 days after receiving 10 doses of TNB. Integrity of the BBB was assessed by immunohistochemical staining for extravasated plasma albumin on paraffin-embedded sections. Rats euthanatized after four to eight doses had no lesions, and albumin extravasation in the susceptible regions of the brain was minimal. Rats receiving 10 daily doses of TNB had bilaterally symmetric vacuolation and microcavitation in the cerebellar nuclei, vestibular nuclei, and inferior colliculi in association with multifocal, often confluent foci of extravasated albumin in susceptible nuclei. Albumin was present in vascular walls, extracellular space, and neurons. Immunoreactivity in neurons was of two types: cytoplasmic staining representing pinocytic uptake and homogeneous staining of the entire neuron (nucleus and cytoplasm) due to uncontrolled albumin leakage through the damaged cell membrane. In rats allowed to recover for 10 days, the microcavitated foci were infiltrated by glial and gitter cells. Albumin immunoreactivity was present as extracellular granular debris, and neuronal staining (for albumin) was mild. In rats allowed to recover for 30 days, immunoreactivity to albumin was not seen. This study demonstrates that TNB-mediated tissue damage is accompanied by breakdown of the BBB. The presence of vacuolation and associated extravasated serum proteins in TNB-treated rats is an indication of vasogenic brain edema, which appears to be a critical event in TNB toxicity. Additional studies are needed to determine the reason for selective regional vulnerability and brain microvascular susceptibility to TNB.
1,3,5-三硝基苯（TNB）是某些军事设施中的土壤和水污染物。据报道，给大鼠每日口服10次TNB后会出现脑病。病变表现为小脑顶核、前庭核、橄榄核和下丘双侧对称的空泡化和微腔形成。血脑屏障（BBB）在这些病变发生过程中的作用尚不确定。本研究的主要目标之一是评估血脑屏障的功能状态。雄性Fischer 344大鼠（每组5只）在每日给予4、5、6、7、8或10次TNB（71毫克/千克）后实施安乐死。另一组大鼠（每组5只）在接受10次TNB给药后分别恢复10天或30天。通过对石蜡包埋切片上渗出的血浆白蛋白进行免疫组织化学染色来评估血脑屏障的完整性。在给予4至8次剂量后实施安乐死的大鼠没有病变，并且大脑易感区域的白蛋白渗出极少。每日接受10次TNB给药的大鼠在小脑核、前庭核和下丘出现双侧对称的空泡化和微腔形成，同时在易感核中出现多灶性、常融合的白蛋白渗出灶。白蛋白存在于血管壁、细胞外间隙和神经元中。神经元中的免疫反应性有两种类型：细胞质染色代表胞饮摄取，以及由于白蛋白通过受损细胞膜不受控制地渗漏而导致整个神经元（细胞核和细胞质）的均匀染色。在恢复10天的大鼠中，微腔形成灶被胶质细胞和格子细胞浸润。白蛋白免疫反应性表现为细胞外颗粒碎片，并且神经元染色（针对白蛋白）较轻。在恢复30天的大鼠中，未观察到对白蛋白的免疫反应性。本研究表明，TNB介导的组织损伤伴随着血脑屏障的破坏。TNB处理的大鼠中出现的空泡化和相关的血清蛋白渗出表明存在血管源性脑水肿，这似乎是TNB毒性中的一个关键事件。需要进一步的研究来确定TNB选择性区域易损性和脑微血管易感性的原因。
