Abstract. The mes rat is from an inbred mutant colony of rats with spontaneous eosinophilia. In order to investigate the pathogenesis of the mes rat, the histopathology and hematology for 76 mes rats were examined at several weeks of age. Tissue eosinophilia developed at 8 weeks of age when the blood eosinophil was 500 cells per microliter or more. Subsequently, eosinophilia progressed with age, and splenic eosinophilopoiesis and erythropoiesis appeared simultaneously. Many inflammatory lesions were induced after 10 weeks of age when the blood eosinophils became 1,000 cells per microliter or more. Gastroenteritis and mesenteric lymphadenitis were seen in 44 of 47 (94%) and 31 of 47 (66%) rats, respectively, after 10 weeks of age. Aortitis that deteriorated with age was found in 19 of 39 (49%) rats after 12 weeks of age. Hepatic fibrosis was found in four rats that exhibited severe eosinophilia and anemia. These results are comparable to the features of a hypereosinophilic syndrome in humans and other animals.

-Expression of hepatic cytochrome P450 (CYP) isoforms was compared in Sprague-Dawley (SD) and Wistar (WI) rats, which are commonly used strains in preclinical studies. Basal CYP1A1, -tively). Treatment with phenobarbital, a potent CYP inducer, increased the predominance of expression increased microsomal total P450 contents and smooth-surface endoplasmic reticulum in the centrilobular -rats exhibited predominantly arylhydrocarbon receptor, pregnane X receptor, and constitutive androstane WI rats was observed, possibly related to nuclear receptor-mediated induction. Considering the pharmacokinetic and toxicological importance of CYP1A and CYP3A, different outcomes might arise depending on the rat strains used in preclinical studies of drugs metabolized typically or mainly by both isoforms.

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Donor organ damage caused by cold preservation is a major problem affecting liver transplantation. Cold preservation most easily damages liver sinusoidal endothelial cells (LSECs), and information about the molecules modulating LSECs function can provide the basis for new therapeutic strategies. Adrenomedullin (AM) is a peptide known to possess anti-apoptotic and anti-inflammatory properties. AM is abundant in vascular endothelial cells, but levels are comparatively low in liver, and little is known about its function there. In this study, we demonstrated both AM and its receptors are expressed in LSECs. AM treatment reduced LSECs loss and apoptosis under cold treatment. AM also downregulated cold-induced expression of TNF, IL1, IL6, ICAM1 and VCAM1. AM reduced apoptosis and expression of ICAM1 and VCAM1 in an in vivo liver model subjected to cold storage. Conversely, apoptosis was exacerbated in livers from AM and RAMP2 (AM receptor activity-modifying protein) knockout mice. These results suggest that AM expressed in LSECs exerts a protective effect against cold-organ damage through modulation of apoptosis and inflammation.

The Matsumoto Eosinophilic Shinshu (MES) rat originated from an inbred mutant colony of rats with spontaneous eosinophilia. As part of an investigation of the pathogenesis of the MES rat, we examined the haematology data for 106 males and 88 females and age-associated changes using an automated haematology analyser, flow cytometric analysis and morphological examination. The data at 10 weeks of age showed the MES rats had higher counts for eosinophils and neutrophils, slightly higher counts for lymphocytes, monocytes, basophils, and large unstained cells (LUCs), and slightly lower values for the erythrocytic parameters when compared with Sprague-Dawley (SD) rats. In data for MES rats aged 8 to 20 weeks, eosinophil counts increased with age up to 20 weeks together with some increased neutrophil counts. After 11 weeks of age, counts for lymphocytes, monocytes, basophils, and LUCs in the MES rats were also slightly increased. In female MES rats, flow cytometric analysis showed increased counts for pan-T+ cells, but blasts, abnormal granulocytes and lymphocytes were not detected morphologically. The MES rat characterized by the haematological findings could be a useful animal model for studies of hypereosinophilia.

ABSTRACT. Despite its explosive properties and toxicity to both animals and humans, diethyl ether is an agent long used in Japan in the anaesthesia jar method of rat anaesthetises. However, in response to a recent report from the Science Council of Japan condemning diethyl ether as acceptable practice, we searched for an alternative rat anaesthesia method that provided data continuous with pre-existing regular toxicology studies already conducted under diethyl ether anaesthesia. For this, we examined two candidates; 30% isoflurane diluted with propylene glycol and pentobarbitone. Whereas isoflurane is considered to be one of the representatives of modern volatile anaesthetics, the method of propylene glycol-diluted 30% isoflurane used in this study was our modification of a recently reported method revealed to have several advantages as an inhalation anaesthesia. Intraperitoneal pentobarbitone has long been accepted as a humane method in laboratory animal anaesthesiology. These 2 modalities were scrutinized in terms of consistency of haematology and blood chemistry with previous results using ether. We found that pentobarbitone required a much longer induction time than diethyl ether, which is suspected to be the cause of fluctuations in several haematological and blood chemical results. Conversely, only calcium ion concentration showed a slight difference from traditional results in the case of 30% isoflurane. Additionally, serum prolactin and corticosterone levels indicated that 30% isoflurane induced less stress than ether, confirming that 30% isoflurane can both provide results consistent with diethyl ether, while at the same time remove its disadvantages. As such 30% isoflurane appears to be a strong alternative anaesthetic agent for future regular toxicology studies in Japan.

Summary The Matsumoto Eosinophilic Shinshu (MES) rat is an inbred mutant strain that spontaneously develops systemic hypereosinophilia with eosinophilic inflammatory lesions similar to those associated with hypereosinophilic syndrome in humans and other mammals. To elucidate the pathogenic mechanisms that underlie these features of MES rats, we examined the pattern of cytokine gene expression in mesenteric lymph nodes (MLNs), the thymus, and peripheral blood mononuclear cells as well as the blood clinicopathology and MLN lymphocytic subsets of these animals. MES rats exhibited both leucocytosis, attributable in large part to hypereosinophilia and neutrophilia, and immunoglobulin M (IgM) and IgA gammaglobulinaemia, with increased titres of IgM autoantibodies to nuclear antigens. Reverse transcription and polymerase chain reaction analysis revealed that the amounts of interleukin (IL)‐5, IL‐4, eotaxin, and interferon‐γ mRNAs were increased in the MLN lymphocytes of MES rats compared with the corresponding values for Sprague‐Dawley rats. Intraperitoneal administration of a monoclonal antibody specific for IL‐5 resulted in an immediate suppression of hypereosinophilia and a delayed suppression of neutrophilia in MES rats. Flow cytometry revealed an increased percentage of CD3+ CD4– CD8– T lymphocytes in MLNs of MES rats. Our results suggest that the hypereosinophilia of MES rats results from an increased production of IL‐5, and that the eosinophilic inflammatory lesions of these animals, which are largely restricted to the gut, may be related both to cytokine overexpression in MLNs and to T helper 1 and 2 immunological responses.

Endogenous alphaCGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of Con A. alphaCGRP could be a useful therapeutic target for the treatment of chronic hepatitis.