BN.MES-Cyba(mes) Congenic Rats Manifest Focal Necrosis with Eosinophilic Infiltration in the Liver without Blood Eosinophilia

The Matsumoto Eosinophilia Shinshu (MES) rat strain develops hereditary blood eosinophilia and eosinophil-related inflammatory lesions in organs due to the mutant Cyba(mes) gene. We hypothesized that a new eosinophilia model with a different phenotype could be established by changing the genetic background of rats. We bred and characterized a congenic strain, in which the mutant Cybames gene was introduced into the background of a BN strain (BN.MES-Cyba(mes)). The congenic rats showed robust proliferation of eosinophils in the bone marrow. Nonetheless, blood eosinophil levels of the rats remained within the normal range. In addition, the rats manifested focal necrosis with eosinophilic infiltration in the liver, a phenotype rarely observed in the original MES rat strain. These results imply the presence of genetic polymorphisms between MES and BN strains which modulate the mobilization of eosinophils to the peripheral circulation and organs. The newly established BN.MES-Cyba(mes) congenic rat strain, together with the original MES strain, will provide useful models for elucidating the molecular genetic mechanisms involved in the development and trafficking of eosinophils.ArticleEXPERIMENTAL ANIMALS. 59(4):469-478 (2010)journal articl

BN.MES-Cybames Congenic Rats Manifest Focal Necrosis with Eosinophilic Infiltration in the Liver without Blood Eosinophilia

The Matsumoto Eosinophilia Shinshu (MES) rat strain develops hereditary blood eosinophilia and eosinophil-related inflammatory lesions in organs due to the mutant Cyba(mes) gene. We hypothesized that a new eosinophilia model with a different phenotype could be established by changing the genetic background of rats. We bred and characterized a congenic strain, in which the mutant Cybames gene was introduced into the background of a BN strain (BN.MES-Cyba(mes)). The congenic rats showed robust proliferation of eosinophils in the bone marrow. Nonetheless, blood eosinophil levels of the rats remained within the normal range. In addition, the rats manifested focal necrosis with eosinophilic infiltration in the liver, a phenotype rarely observed in the original MES rat strain. These results imply the presence of genetic polymorphisms between MES and BN strains which modulate the mobilization of eosinophils to the peripheral circulation and organs. The newly established BN.MES-Cyba(mes) congenic rat strain, together with the original MES strain, will provide useful models for elucidating the molecular genetic mechanisms involved in the development and trafficking of eosinophils.ArticleEXPERIMENTAL ANIMALS. 59(4):469-478 (2010)journal articl

The identification of an orally active, nonpeptide bradykinin B(2) receptor antagonist, FR173657

1. An orally active, nonpeptide bradykinin (BK) B(2) receptor antagonist, FR173657 (E)-3-(6-acetamido-3 - pyridyl) - N - [N - [2 - 4 -dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide) has been identified. 2. This compound displaced [(3)H]-BK binding to B(2) receptors present in guinea-pig ileum membranes with an IC(50) of 5.6×10(−10) M and in rat uterus with an IC(50) of 1.5×10(−9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [(3)H]-BK binding to B(2) receptors with an IC(50) of 2.9×10(−9) M and a K(i) of 3.6×10(−10) M, but did not reduce [(3)H]-des-Arg(10)-kallidin binding to B(1) receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC(50) of 7.9×10(−9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(−6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(−9) M and 3.2×10(−9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(−8) M. Analysis of the data yield a pA(2) of 9.2±0.2 (n=5) and a slope of 1.5±0.2 (n=5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED(50) of 0.075 mg kg(−1), but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg(−1). FR173657 also inhibited carrageenin-induced paw oedema with an ED(50) of 6.8 mg kg(−1) 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B(2) receptor antagonist