Genetic map of 12 polymorphic loci on rat chromosome 1.

Twelve polymorphic markers identified by restriction fragment length polymorphism (RFLP) analysis or simple sequence repeat (SSR) polymorphism analysis were assigned to rat chromosome 1 by linkage analysis of F2 intercross progeny of F344/N and LEW/N inbred rat strains. One linkage group, covering 46.3 cM, consisted of eight markers including five genes, TNT (fast skeletal troponin T), IGF2 (insulin-like growth factor 2), MYL2 (MLC2 gene for muscle myosin light chain 2), ALDOA (aldolase A), and HBB (hemoglobin beta-chain); one anonymous locus, D1N64; one marker related to the carboxypeptidase B gene, CARB07-related sequence; and one marker related to the parathyroid hormone gene, PTH-related sequence.

The origin of the autoimmune disease-resistant LER rat: an outcross between the buffalo and autoimmune disease-prone Lewis inbred rat strains.

The Lewis (LEW) rat strain is highly susceptible to a large number of experimentally induced inflammatory and autoimmune diseases. The Lewis resistant (LER) rat strain, which reportedly arose as a spontaneous mutation in a closed colony of LEW rats, is resistant to many of these disorders. The mechanism of resistance is not yet clear.

Coexpression of phosphotyrosine-containing proteins, platelet-derived growth factor-B, and fibroblast growth factor-1 in situ in synovial tissues of patients with rheumatoid arthritis and Lewis rats with adjuvant or streptococcal cell wall arthritis.

Fibroblast growth factor (FGF)-1 and PDGF-B-like factors have been implicated in the pathobiology of RA and animal models of this disease. Since the receptors for FGF-1 and PDGF are tyrosine kinases, we examined the expression of tyrosine phosphorylated proteins (phosphotyrosine, P-Tyr) in synovial tissues from patients with RA and osteoarthritis (OA), and rats with streptococcal cell wall (SCW) and adjuvant arthritis (AA). Synovia from patients with RA and LEW/N rats with SCW and AA arthritis, in contrast to controls, stained intensely with anti-P-Tyr antibody.

Linkage map of 10 polymorphic markers on rat chromosome 2.

Analysis of F2 intercross progeny of inbred F344/N x LEW/N rats led to the assignment of 10 polymorphic PCR-typable markers to rat chromosome 2. The markers form a single linkage group covering 47.9 cM with the following order: D2N1R-D2N28-FGG (gamma fibrinogen)-PKLR (liver and RBC pyruvate kinase)-ATP1A1 (the alpha-1 polypeptide of Na+/K+ transporting ATPase)-HSD3B (hydroxy-delta-5-steroid dehydrogenase)-D2N2R-D2N91-CAMKI (calmodulin-dependent protein kinase II)-D2N35.

Map of seven polymorphic markers on rat chromosome 14: linkage conservation with human chromosome 4.

Seven polymorphic markers identified by polymerase chain reaction (PCR) amplification, including markers for six genes--DRD1L (dopamine receptor, D1-like-2), GLUKA (glucokinase), PF4 (platelet factor 4), ALB (albumin), AFP (alpha-fetoprotein), and BSP (bone sialoprotein)--and one anonymous locus (D14N52), were mapped to a single 67-cM linkage group with F2 intercross progeny of F344/N and LEW/N inbred rat strains. Two of these markers, ALB and AFP, have previously been assigned to rat Chromosome (Chr) 14, allowing assignment of this entire linkage group. Five of the markers--DRD1L, PF4, ALB, AFP, and BSP--have been physically mapped to a large region of human Chr 4 encompassing the p arm and the q arm to band q28.

Genetic mapping of the athymic nude (RNU) locus in the rat to a region on chromosome 10.

The nude trait in the rat is transmitted in an autosomal recessive manner and is associated with thymic aplasia, T-cell deficiency, and hairlessness. Congenic rats homozygous for the RNU (Rowett nude) locus are important models in the study of inflammatory disease, tumor growth, and transplant rejection. The RNU locus has not been previously mapped, and the nature of the gene product is unknown.

Linkage map of seven polymorphic markers on rat chromosome 18.

A genetic linkage map of seven polymorphic markers was created with F2 intercross progeny of F344/N and LEW/N rats and assigned to rat Chromosome (Chr) 18. Five of the markers described were defined by simple sequence length polymorphisms (SSLPs) associated with five genes: transthyretin (TTR), trypsin inhibitor-like protein (TILP), beta 2 adrenergic receptor (ADRB2), olfactory neuron-specific G protein (OLF), and gap junction protein (GJA1). One marker was defined by a restriction fragment length polymorphism (RFLP) detected with a probe for the human colony stimulating factor 1 receptor (CSF1R) gene.

Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis.

Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, is also secreted in peripheral inflammatory sites, where it acts as a local proinflammatory agent. Arthritis-susceptible LEW/N rats have profoundly deficient hypothalamic CRH responses to inflammatory stimuli and other stressors. Arthritis-resistant F344/N rats, on the other hand, have a robust increase in hypothalamic CRH in response to the same stimuli.

Genetic map of nine polymorphic loci comprising a single linkage group on rat chromosome 10: evidence for linkage conservation with human chromosome 17 and mouse chromosome 11.

Seven genes and two anonymous markers were mapped to a single linkage group on rat chromosome 10 using progeny of an F2 intercross of Fischer (F344/N) and Lewis (LEW/N) inbred rats. Two genes, the neu oncogene or cellular homologue of the viral oncogene erbb2 (ERBB2) and growth hormone (GH) were mapped by Southern blot analysis of restriction fragment length polymorphisms. Five genes, embryonic skeletal myosin heavy chain (MYH3), androgen binding protein/sex hormone binding globulin (SHBG), asialoglycoprotein receptor (hepatic lectin)-1 (ASGR1), ATP citrate lysase (CLATP), and pancreatic polypeptide (PPY), and two anonymous markers, F16F2 and F10F1, were mapped using PCR amplification techniques.

The effect of norepinephrine on endotoxin-mediated macrophage activation.

The effect of norepinephrine (NE) on the production of tumor necrosis factor (TNF) by rat spleen macrophages was determined. Following activation with lipopolysaccharide, analysis of both secreted and cell-associated samples showed that TNF activity was significantly suppressed in the presence of 10 microM NE. With the addition of the beta-receptor antagonist propranolol a partial reversal of the suppressive effect of NE was noted whereas the addition of the mixed alpha-receptor antagonist phentolamine induced a more pronounced suppressive effect in the supernatant fraction.

Mechanisms and suppression of inflammatory demyelination.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system commonly used as a model for multiple sclerosis. In both of these diseases demyelination occurs association with perivascular infiltrates of T-cells and macrophages. The similarities in immunopathology suggest that these two diseases share common mechanisms of tissue destruction.

Prazosin treatment suppresses increased vascular permeability in both acute and passively transferred experimental autoimmune encephalomyelitis in the Lewis rat.

Prazosin, an antagonist of the alpha 1-adrenoceptor, has been found to suppress the clinical and histologic expression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. This effect appears to be specific for the alpha 1-receptor. To determine the effect of this drug on vascular permeability to serum proteins and inflammatory cells, leakage of serum proteins into the central nervous system (CNS) was measured with [125I]albumin, and quantitation of cellular inflammation was determined by an estimation of total DNA.

Prazosin treatment during the effector stage of disease suppresses experimental autoimmune encephalomyelitis in the Lewis rat.

As part of a study on the role of vasoactive amines in experimental autoimmune encephalomyelitis (EAE), we have found that treatment beginning 7 days post-inoculation (dpi) with the specific alpha 1-adrenoceptor antagonist prazosin can significantly suppress clinical signs of disease in the Lewis rat. In this paper we have addressed the effect of treatment with prazosin commencing at varying times in the disease process. The results show that treatment during the early inductive stage (1 to 6 dpi) has no effect on the clinical course of the disease, whereas treatment commencing at the time of onset of early clinical signs (10 to 16 dpi) still significantly suppresses EAE.

Astrocytic reactivity and intermediate filament metabolism in experimental autoimmune encephalomyelitis: the effect of suppression with prazosin.

In either actively or passively transferred experimental autoimmune encephalomyelitis (EAE), increased immunocytochemical staining of glial fibrillary acidic protein (GFAP) in astrocytes was detected early in the disease process in both the gray and white matter of the spinal cord. Staining was not restricted to areas of perivascular mononuclear infiltration, and was observed at all levels of the cord. This enhanced staining pattern was delayed in rats in which clinical signs of EAE had been suppressed by treatment with the alpha 1-adrenoceptor antagonist prazosin.

Prazosin, an alpha 1-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat.

Prazosin, an antagonist of alpha 1-adrenergic receptors, has been found to suppress the clinical and histological expression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Suppression was more significant in females than in males and was a dose-dependent phenomenon. Analysis of the effect of other adrenergic receptor antagonists supports the conclusion that the suppressive effect of prazosin is a consequence of blockade of the alpha 1-receptor since treatment with either the alpha 2-antagonist yohimbine or the beta-antagonist propranolol exacerbated the disease, whereas treatment with the long-acting mixed alpha 1/alpha 2-antagonist phenoxybenzamine had some suppressive activity.