RESUMO
OBJECTIVE: Erythropoietin-producing hepatocellular (Eph)/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc). METHODS: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models of skin fibrosis. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from patients with SSc and healthy controls, which was followed by in vivo analysis of fibroblast-specific Ephb2-deficient mice. RESULTS: Expression of EphB2 is up-regulated in SSc skin tissue and explanted SSc dermal fibroblasts compared with healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-ß (TGF-ß) cytokines up-regulate EphB2 in dermal fibroblasts via noncanonical TGF-ß/mother against decapentaplegic signaling, and silencing EPHB2 in human dermal fibroblasts is sufficient to dampen TGF-ß-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge. CONCLUSION: Our data implicate TGF-ß regulation of EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.
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ABSTRACT D2-40/podoplanin (D2-40/PDPN) is a multifunctional protein that can be expressed in lymphatic endothelium and immune cells. D2-40/ PDPN expression in chronic villitis (CV) has not been studied. In 22 cases of CV, we analyzed both D2-40/PDPN expression as well as its coexpression with immune cells markers, and the relationship with stromal cells. In the non-inflamed villi, the D2-40/PDPN positive plexiform pattern has a lymphatic-like conductive network. In the inflamed villi, the D2-40/PDPN expression, predominantly restricted to stromal cells forming a cellular network, is likely related to a phase of the inflammatory response, such as reorganization of the damaged tissue.
RESUMO Podoplanina/D2-40 (PDPN/D2-40) é uma proteína multifuncional que pode ser expressa no endotélio linfático e nas células imunes. Na vilosite crônica (VC), a expressão de PDPN/D2-40 ainda não foi estudada. Em 22 casos de VC, analisamos tanto a expressão de PDPN/D2-40 como sua coexpressão com marcadores de células imunes, além da relação com células estromais. Nas vilosidades não inflamadas, o padrão plexiforme PDPN/D2-40 positivo tem aspecto de rede condutora linfática. Nas vilosidades inflamadas, a expressão de PDPN/D2-40, com predominância restrita às células estromais, formando rede densa está, possivelmente, relacionada com uma fase da resposta inflamatória, como a reorganização do tecido danificado.
RESUMO
Listeria monocytogenes is an endemic agent in the primate population at the California National Primate Research Center and has been associated with both sporadic cases and a general outbreak of pregnancy failures. The primary objective of this study was to verify the incidence of L. monocytogenes-associated abortion and fetal deaths in the Center's outdoor breeding colony. In addition, we sought to compare the group of female macaques that presented with Listeria-associated abortion with both those with nonlisteria-associated abortion and animals with successful pregnancy outcome. We calculated the incidence of L. monocytogenes-associated abortion and stillbirth by dividing the number of positive L. monocytogenes cultures from aborted fetuses by the number of pregnant female macaques from 1989 through 2009. To compare the pregnancy outcome of female macaques that have presented L. monocytogenes-associated abortion and stillbirth, we created 2 control groups: female macaques with successful pregnancy outcomes during the 1999 breeding season and animals with nonlisteria-associated pregnancy failure. These macaques were followed for 2 subsequent breeding seasons. The results showed a range in the incidence of L. monocytogenes-associated abortion and stillbirth from 0% to 8.39% throughout the 1989 to 2009 breeding seasons. In addition, the Listeria-associated abortion group did not present statistically significant differences in fertility and abortion rates when compared with the control groups. We conclude that although L. monocytogenes is an endemic agent at the Center's outdoor breeding colony, the agent's incidence varied in significance. Furthermore, an episode of L. monocytogenes-associated abortion did not affect subsequent pregnancies.
