Interception of the Sdc4 pathway enhances infarct expansion and hypertrophic remodelling during early infarct healing in ischaemic-reperfusion injury and permanent infarction mouse models and exerts net beneficial effects on LV function.
Epidemiological data indicate that intake of estrogens and isoflavones may be beneficial for the prevention of colorectal cancer (CRC). Based on this data, the aim of the study was to investigate estrogen receptor (ER) subtype-specific effects on intestinal homeostasis. Ovariectomized (OVX) female Wistar rats were either treated with 17β-estradiol (4 μg/kg body wt/day) (E2), an ERα-specific agonist (ALPHA) (10 μg/kg body wt/day), an ERβ-specific agonist (BETA) (100 μg/kg body wt/day) or genistein (GEN) (10 mg/kg body wt/day) for three weeks. Vehicle-treated OVX and SHAM animals and those cotreated with BETA and the pure antiestrogen Fulvestrant (ICI 182780) (100 μg/kg body wt/day and 3 mg/kg body wt/day) served as controls. GEN and BETA treatment but not E2 and ALPHA administration reduced proliferation in ileal and colonic mucosa cells. The rate of apoptosis in the small intestine and colon was increased by treatment with BETA and GEN, but not by E2. BETA induced antiproliferative and proapoptotic activity also in SHAM animals. The effects were antagonized by the pure antiestrogen Fulvestrant. Polymerase chain reaction gene array analysis revealed that BETA resulted in the downregulation of the oncogene transformation-related protein 63 (p63). Our data indicate that activation of the ERβ by specific ERβ agonists and GEN induces antiproliferative and proapoptotic effects in the intestinal tract. This observation can be taken as an indication that intake of GEN and specific ERβ agonists may protect the ileal and colonic epithelium from tumor development via modulation of tissue homeostasis.
Background:Inflammation is characterized by leukocyte recruitment. Macrophages and neutrophils contribute to tissue damage and organ dysfunction. Modulating leukocyte invasion can protect from these adverse effects. Leukocyte recruitment critically depends on the urokinase-type plasminogen activator receptor (u-PAR). We here use a novel technique to longitudinally quantify cell trafficking in inflammatory models in live animals. Methods: Near-infrared fluorophore-labeled leukocytes were adoptively transferred to mice with thioglycollate peritonitis to study leukocyte trafficking to sites of inflammation. Macrophage and neutrophil trafficking was followed with three-dimensional fluorescence-mediated-tomography. u-PARϪ/Ϫ and wild-type macrophage recruitment was studied by cross-over adoptive cell transfer to elucidate the role of leukocytic versus u-PAR expressed on other cells. Endotoxic shock-induced pulmonary inflammation was used to study u-PARs role for pulmonary neutrophil recruitment. Results: Mice experiencing peritonitis showed a significant increase in mean fluorescence intensity because of enhanced macrophage (315%, n ϭ 9-10), P Ͻ 0.05) or neutrophil (194%, n ϭ 6, P Ͻ 0.02) recruitment. Fluorescence-mediated-tomography uncovered a macrophage recruitment defect in the peritonitis model for u-PARϪ/Ϫ mice (147% of baseline) compared with control mice (335% of baseline, n ϭ 8-9, P Ͻ 0.05). When u-PARϪ/Ϫ-macrophages were transferred to wild-type mice fluorescence intensity increased to 145% while wild-type macrophage transfer into u-PARϪ/Ϫ resulted in 192% increase compared with baseline (n ϭ 6, P Ͻ 0.05). Reduced neutrophil recruitment in pulmonary inflammation in u-PARϪ/Ϫ mice was accompanied by improved pulmonary gas exchange. Conclusion: Using noninvasive in vivo fluorescence-mediated tomography to image leukocyte recruitment in inflammatory mouse models, we describe a novel macrophage recruitment defect in u-PARϪ/Ϫ mice. Targeting u-PAR for modulation of leukocyte recruitment is a promising therapeutic strategy to ameliorate leukocyte induced tissue damage.
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