Hard G C, Snowden R T
MRC Toxicology Unit, Carshalton, Surrey, United Kingdom.
Toxicol Pathol. 1991;19(2):88-97. doi: 10.1177/019262339101900202.
Since recognition during the last decade that certain renal carcinogens can initially cause an accumulation of hyaline (protein) droplets in proximal tubules of male rats, it has become appropriate to establish whether this phenomenon of protein overload can also occur in rodent kidneys unrelated to chemical treatment. Kidney tissue from a number of selected rodent studies held in the National Toxicology Program (NTP) or Food and Drug Administration (FDA) archives were evaluated for hyaline droplet accumulation in proximal tubules. The survey concentrated on rats and mice of both sexes bearing hematopoietic tumors, as our preliminary observations had suggested this direction of study. The tissues of 101 Sprague-Dawley, 25 Osborne-Mendel, and 70 Fischer 344 rats and 96 B6C3F1 mice were examined. These animals provided an assortment of tumors including histiocytic sarcoma, lymphocytic lymphoma, mononuclear cell leukemia, and sarcoma. Hyaline droplet accumulation, primarily involving the P2 segment of proximal tubules, was diagnosed in 96% of rats with histiocytic sarcoma (74/77 cases in Sprague-Dawley, 17/18 in Osborne-Mendels, 7/7 in Fischers) and in 55% of B6C3F1 mice with histiocytic sarcoma (18/33 cases). There appeared to be a qualitative correlation between hyaline droplet accumulation and degree of tumor burden. Thus, in cases negative for hyaline droplets, the tumor was often confined to a single location, while increasing involvement of proximal segments beyond P2 occurred with more extensive multi-organ dissemination of the tumor. By immunohistochemistry on 11 cases of rat and 8 cases of mouse histiocytic sarcoma, the protein in hyaline droplets was identified as lysozyme, a known major secretory product of monocytes and macrophages. The hyaline droplets were negative for alpha 1-antitrypsin, alpha 2u-globulin, rat or mouse immunoglobulin, and albumin. More sparsely scattered droplets and granules present in proximal tubules of Fischer rats with mononuclear cell leukemia were negative for lysozyme but positive for either iron or lipofuscin pigment. The study establishes a clear association between renal tubule hyaline droplet and lysozyme accumulation in rats and mice with histiocytic sarcoma. Hyaline droplets secondary to neoplasia should be distinguished from chemically-induced hyaline droplet nephropathy in the male rat involving alpha 2u-globulin.
自从在过去十年间认识到某些肾致癌物最初可导致雄性大鼠近端小管中出现透明（蛋白）滴积累以来，确定这种蛋白过载现象是否也会在与化学处理无关的啮齿动物肾脏中发生就变得很有必要。对保存在国家毒理学计划（NTP）或食品药品监督管理局（FDA）档案中的一些选定啮齿动物研究的肾脏组织进行了评估，以检测近端小管中透明滴的积累情况。由于我们的初步观察结果表明了这个研究方向，所以该调查集中在患有造血系统肿瘤的雌雄大鼠和小鼠身上。检查了101只斯普拉格 - 道利大鼠、25只奥斯本 - 孟德尔大鼠、70只费希尔344大鼠以及96只B6C3F1小鼠的组织。这些动物患有多种肿瘤，包括组织细胞肉瘤、淋巴细胞淋巴瘤、单核细胞白血病和肉瘤。在患有组织细胞肉瘤的大鼠中，96%（斯普拉格 - 道利大鼠74/77例、奥斯本 - 孟德尔大鼠17/18例、费希尔大鼠7/7例）被诊断出有透明滴积累，主要累及近端小管的P2段；在患有组织细胞肉瘤的B6C3F1小鼠中，55%（18/33例）出现透明滴积累。透明滴积累与肿瘤负荷程度之间似乎存在定性相关性。因此，在透明滴阴性的病例中，肿瘤通常局限于单个部位，而随着肿瘤在多器官更广泛的扩散，近端小管P2段以外的部分受累程度增加。通过对11例大鼠和8例小鼠组织细胞肉瘤进行免疫组织化学分析，发现透明滴中的蛋白为溶菌酶，这是单核细胞和巨噬细胞已知的主要分泌产物。透明滴对α1 - 抗胰蛋白酶、α2u - 球蛋白、大鼠或小鼠免疫球蛋白以及白蛋白均呈阴性。在患有单核细胞白血病的费希尔大鼠近端小管中更稀疏分布的滴和颗粒对溶菌酶呈阴性，但对铁或脂褐素色素呈阳性。该研究明确了患有组织细胞肉瘤的大鼠和小鼠肾小管透明滴与溶菌酶积累之间的关联。肿瘤继发的透明滴应与雄性大鼠中涉及α2u - 球蛋白的化学诱导性透明滴肾病相区分。
