The antineoplastic platinum complexes cisplatin and its analogues are widely used in the chemotherapy of a variety of human malignancies, and are especially active against several types of cancers. Nedaplatin is a second-generation platinum complex with reduced nephrotoxicity. However, their use commonly causes nephrotoxicity due to a lack of tumor tissue selectivity. Several recent studies have provided significant insights into the molecular and histopathological events associated with nedaplatin nephrotoxicity. In this review, we summarize findings concerning the renal histopathology and molecular pathogenesis induced by antineoplastic platinum complexes, with a particular focus on the comparative nephrotoxicity of cisplatin and nedaplatin in rats.
The placenta grows rapidly for a short period with high blood flow during pregnancy and has multifaceted functions, such as its barrier function, nutritional transport, drug metabolizing activity and endocrine action. Consequently, the placenta is a highly susceptible target organ for drug- or chemical-induced adverse effects, and many placenta-toxic agents have been reported. However, histopathological examination of the placenta is not generally performed, and the placental toxicity index is only the placental weight change in rat reproductive toxicity studies. The placental cells originate from the trophectoderm of the embryo and the endometrium of the dam, proliferate and differentiate into a variety of tissues with interaction each other according to the development sequence, resulting in formation of a placenta. Therefore, drug- or chemical-induced placental lesions show various histopathological features depending on the toxicants and the exposure period, and the pathogenesis of placental toxicity is complicated. Placental weight assessment appears not to be enough to evaluate placental toxicity, and reproductive toxicity studies should pay more attention to histopathological evaluation of placental tissue. The detailed histopathological approaches to investigation of the pathogenesis of placental toxicity are considered to provide an important tool for understanding the mechanism of teratogenicity and developmental toxicity with embryo lethality, and could benefit reproductive toxicity studies.
Many variables may affect the outcome of continuous infusion studies. The results largely depend on the experience of the laboratory performing these studies, the technical equipment used, the choice of blood vessels and hence the surgical technique as well the quality of pathological evaluation. The latter is of major interest due to the fact that the pathologist is not involved until necropsy in most cases, i.e. not dealing with the complicated surgical or in-life procedures of this study type. The technique of tissue sampling during necropsy and the histology processing procedures may influence the tissues presented for evaluation, hence the pathologist may be a source of misinterpretation. Therefore, ITO proposes a tissue sampling procedure and a standard nomenclature for pathological lesions for all sites and tissues in contact with the port-access and/or catheter system.
Two cases of spontaneous focal hepatic hyperplasia were observed in young female cynomolgus macaques (Macaca fascicularis). Grossly, a single raised nodule was observed in the left hepatic lobe. Histopathologically, the nodule compressed surrounding normal tissue; however, the hepatic cords within the nodule continued to those in the normal area except in part. Extensive fibrosis and absence of a normal hepatic triad were observed in the nodule. Thin fibrous septa radiating from the dense central stellate scarring and distended vessels were apparent in one animal. Hepatocytes in the nodule lacked cellular atypia, showed frequent PAS-positive eosinophilic inclusions in the cytoplasm and showed higher positive ratios for PCNA. The present cases resembled focal nodular hyperplasia reported in humans and a chimpanzee.
The histologic characteristics of a salivary mucocele in a beagle used in a toxicity study are described in this report. A pale yellowish cyst under the mandibular skin containing frothy mucus was observed at necropsy. Microscopically, numerous villous projections arose from the internal surface of the cyst and were lined by stratified epithelial-like macrophages, which were immunopositive for macrophage scavenger receptor A. A ruptured sublingual interlobar duct connected to the lumen was observed near the cyst. Luminal amorphous material showed a positive reaction with Alcian blue and periodic acid-Schiff staining as did mucin in the sublingual gland. Ultrastructurally, the epithelial-like macrophages had numerous vacuoles containing electron-lucent material, which was presumed to be lysosomal in origin, and had pseudopods on their cell surfaces interdigitating with those on the adjacent cells. This case report helps to understand the diversity of the background findings in beagles used in toxicity studies.
Vascular endothelial growth factor (VEGF) and its receptors have recently reported to be expressed in human osteoarthritis (OA), suggesting that VEGF could be implicated in the pathogenesis of this disease. In the present study, expression of VEGF in the articular cartilage was determined in three different OA models: medial meniscectomy and monoiodoacetate (MIA) injection in rats and age-associated spontaneous joint cartilage destruction in guinea pigs. VEGF was detected by immunohistochemical analysis in the regenerative and hypertrophic chondrocytes, perichondrium and osteophyte areas and chondrocyte clones. Stain intensity of VEGF immunoreactivity increased simultaneously with the degree of cartilage destruction and reparation. These results suggest that VEGF is a key factor in the articular cartilage in human OA and animal OA models.