Hyalinosis and Ym1/Ym2 Gene Expression in the Stomach and Respiratory Tract of 129S4/SvJae and Wild-Type and CYP1A2-Null B6,129 Mice

Abstract

The C57BL/6, 129, and B6,129 mouse strains or stocks have been commonly used to generate targeted mutant mice. The pathology of these mice is not well characterized. In studies of these aging mice, we found high incidences of hyalinosis (eosinophilic cytoplasmic change) in the glandular stomach, respiratory tract, bile duct, and gall bladder of B6,129 CYP1A2-null and wild-type mice as well as in both sexes of the background 129S4/SvJae strain. The gastric lesions of the glandular stomach were found in 95.7% of female CYP1A2-null mice as well as in 45.7% of female 129S4/SvJae animals. The eosinophilic protein isolated from characteristic hyaline gastric lesions was identified as Ym2, a member of the chitinase family. Immunohistochemistry, using rabbit polyclonal antibodies to oligopeptides derived from the Ym1 sequence, detected focal to diffuse reactivity within both normal and abnormal nasal olfactory and respiratory epithelium, pulmonary alveolar macrophages, bone marrow myeloid cells, and the squamous epithelium of the forestomach and epithelium of the glandular stomach. Alveolar macrophages in acidophilic pneumonia, a major cause of death of aging 129 mice, and in mice with the me mutation also were highly immunoreactive. CYP1A2 carries out oxidation and N-hydroxylation of arylamine carcinogens and heterocyclic amine food mutagens which, when followed by O-esterification by acetate or sulfate transferases, results in unstable electrophilic derivatives that can cause cell toxicity, cell death, or cell transformation. 1-3 CYP1A2 catalyzes caffeine 3-demethylation and metabolically activates aflatoxin B 1 to its ultimate carcinogenic intermediate 4 and paradoxically catalyzing the hydroxylation of aflatoxin B 1 to aflatoxin M 1 in a detoxification pathway. 5 In addition, CYP1A2 was found to be involved in both hamster and human catechol estrogen metabolism. 6 Although CYP1A2 is constitutively expressed in the liver of mice, rats, and humans and is inducible by ligands of the aryl hydrocarbon receptor (Ahr) in all mammalian species analyzed, no expression has been demonstrated in the stomach, even after treating animals with known inducers of this enzyme. 7 However, the mechanisms involved in CYP1A2 gene regulation are less well established than CYP1A1 because it is difficult to induce expression in vitro and the sensitivities of current methodologies may simply be too low under normal in vivo conditions. The mammalian conservation of the CYP1A subfamily argues for an essential function in metabolism not limited to activation and detoxification of exogenous chemicals and toxins. As with most of the cytochromes P-450, determination of function has primarily been a consequence of exposures to man-made compounds, but it must be remembered that their evolution predates industrialization. The genes of the two recognized members of the CYP1A subfamily,

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“…Tumors were always multiple, with early, well-differentiated lesions, and more advanced malignant lesions coexisting within the same animal, suggesting an asynchronous tumor development. Acidophilic macrophage pneumonia was observed in some animals; this unusual pneumonia was occasionally reported in some mouse strains, including the 129sv strain (29). To validate the MRI data, a high resolution histologic slice of the whole lung was reconstructed for five samples and count of lesions was compared with the in vivo imaging data.…”

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IL-13 induces the expression of the alternative activation marker Ym1 in a subset of testicular macrophages

“…The cells were then washed in 1ml of Perm/Wash solution and blocked with 10% goat serum (Zymed, San Francisco, CA) and 20% FBS in Perm/Wash solution for 30 min at room temperature. After blocking, the cells were washed again with 1ml Perm/Wash solution and resuspended in 100μl Perm/Wash solution containing rabbit polyclonal anti-Ym1 Ab, kindly provided by Dr. Shioko Kimura (National Cancer Institute, Bethesda, MD), which recognizes both Ym1 and Ym2 proteins (Ward et al, 2001) or rabbit serum as a control (Sigma-Aldrich, St. Louis, MO). After 1.5 h incubation at room temperature, cells were washed with 1ml Perm/Wash solution and then incubated in 100μl Perm/Wash solution containing biotinylated anti-rabbit IgG (Jackson Immuno Research, West Grove, PA) for 20 min at room temperature.…”