Salas, J.T. (January T.)

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    Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis
    (WB Saunders, 2008) Banales, J.M. (Jesús M.); Oude-Elferink, R.P.J. (Ronald P.J.); Salas, J.T. (January T.); Sarvide, S. (Sarai); Uriarte, I. (Iker); Medina, J.F. (Juan Francisco); Prieto, J. (Jesús); Ferrer, A. (Álex); Recalde, S. (Sergio)
    BACKGROUND & AIMS: Cl(-)/HCO(3)(-) anion exchanger 2 (AE2) is involved in intracellular pH (pH(i)) regulation and transepithelial acid-base transport, including secretin-stimulated biliary bicarbonate excretion. AE2 gene expression was found to be reduced in liver biopsy specimens and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic nonsuppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. In mice with widespread Ae2 gene disruption, we previously reported altered spermiogenesis and reduced gastric acid secretion. We now describe the hepatobiliary and immunologic changes observed in these Ae2(a.b)-deficient mice. METHODS: In this murine model, splenocyte pH(i) and T-cell populations were studied by flow cytometry. CD3-stimulated cytokine secretion was estimated using cytokine arrays. AMA were evaluated by immunoblotting and proteomics. Hepatobiliary changes were assessed by immunohistopathology, flow cytometry, and serum biochemistry. Cholangiocyte gene expression was analyzed by real-time polymerase chain reaction. RESULTS: Ae2(a,b)(-/-) mice exhibit splenomegaly, elevated pH(i) in splenocytes, increased production of interleukin-12p70 and interferon gamma, expanded CD8(+) T-cell population, and under represented CD4(+)FoxP3(+)/regulatory T cells. Most Ae2(a,b)(-/-) mice tested positively for AMA, showing increased serum levels of immunoglobulin M and G, and liver-specific alkaline phosphatase. About one third of Ae2(a,b)(-/-) mice had extensive portal inflammation with CD8(+) and CD4(+) T lymphocytes surrounding damaged bile ducts. Cholangiocytes isolated from Ae2(a,b)(-/-) mice showed gene expression changes compatible with oxidative stress and increased antigen presentation. CONCLUSIONS: Ae2 deficiency alters pH(i) homeostasis in immunocytes and gene expression profile in cholangiocytes, leading to immunologic and hepatobiliary changes that resemble PBC.
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    Inefficient chronic activation of parietal cells in Ae2a,b-/-
    (Elsevier, 2006-07-01) Oude-Elferink, R.P.J. (Ronald P.J.); Mardones, P. (Pablo); Salas, J.T. (January T.); Kunne, C. (Cindy); Medina, J.F. (Juan Francisco); Saez, E. (Elena); Burrell, M.A. (María Ángela); Prieto, J. (Jesús); Looije, N. (Norbert); Recalde, S. (Sergio); Martinez-Anso, E. (Eduardo)
    In parietal cells, basolateral Ae2 C1 /HCO3 exchanger (S1c4a2) appears to compensate for luminal H pumping while providing C1 for apical secretion. In mouse and rat, mRNA variants Ae2a, Ae2b1, Ae2b2, and Ae2c2 are all found in most tissues (altough the latter at very low levels), whereas Ae2c1 is restricted to the stomach. We studied the acid secretory function of gastric mucosa in mice with targeted disruption of Ae2a, Ae2b1, and Ae2b2 (but not Ae2c) isoforms. In the oxyntic mucosa of Ae2a,b−/− mice, total Ae2 protein was nearly undetectable, indicating low gastric expression of the Ae2c isoforms. In Ae2a,b−/− mice basal acid secretion was normal, whereas carbachol/histamine-stimulated acid secretion was impaired by 70%. These animals showed increased serum gastrin levels and hyperplasia of G cells. Immunohistochemistry and electron microscopy revealed baseline activation of parietal cells with fusion of intracellular H+/K+-ATPase-containing vesicles with the apical membrane and degenerative changes (but not substantial apoptosis) in a subpopulation of these cells. Increased expression of proliferating cell nuclear antigen in the oxyntic glands suggested enhanced Ae2a,b−/− parietal cell turnover. These data reveal a critical role of Ae2a-Ae2b1-Ae2b2 isoforms in stimulated gastric acid secretion whereas residual Ae2c isoforms could account to a limited extent for basal acid secretion.