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e conducted a study focus on clarifying the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria model, validating results in appropriate in vitro methods. We believe that our study will provide a basis for development of novel therapies targeting biological signaling molecules associated with development of fatal malaria. The potential novel therapeutic targets identified in this study will supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Results Infection of C57BL/6 with P.berghei ANKA causes brain, lung and kidney damage C57BL/6 mice were intraperitoneally inoculated with 16106 P.berghei parasitized RBC, an inoculum which ” leads to cerebral malaria in the majority of “8549627 infected mice. During infection, parasitemia and anemia status were monitored through mice tail blood analysis daily for eight consecutive days. P.berghei parasitemias was observed in both wild type and CXCL102/2 mice although below 15% in CXCL102/2 mice. Hemoglobin levels was lower in infected wild type mice when compared to CXCL102/2 mice as shown in infection). In addition, parenchymal microhaemorrhages were common in white and grey matters in ECM mice. Adherence of pRBC and leucocytes to brain 221244-14-0 web vessels and vascular plugging were present in all sections of ECM mice analyzed. Histopathological examination also showed necrotic tissues in grey matter in PBAinfected C57BL/6 mice. No histological lesions were detected in non-infected controls of brain tissues. No obvious pathological lesions were detected in CXCL10 gene deficient mice infected with PBA compared to corresponding controls. The lung tissues in C57BL/6 mice after the onset of ECM were characterized by a discrete presence of leucocytes and alveolar edema without marked thickening of the alveolar septum by HE staining compared to normal control. No obvious pathological lesions were detected in CXCL102/2 mice infected with PBA as well as non-infected controls. Apoptotic cells were recognized by a TUNEL assay in the lung tissue of WT mice. To determine whether the apoptotic cells are endothelial cells, staining with the endothelial specific anti-vWF antibody was used. The lowpower images show strong vWF immunoreactivity in STAT3 Activation in Severe Malaria pulmonary tissues and blood vessels. Co-localization of vWFpositive and TUNEL-positive cells in lung tissues confirm the presence of apoptotic pulmonary endothelial cells. Heme/HO-1, CXCL10 and STAT3 are involved in P. berghei ANKA infected ECM Plasma levels of Heme and HO-1 are increased in P. berghei ANKA infected ECM mice. Plasma levels of Heme significantly increased in infected wild type C57 BL/6 mice than those of non-infected controls, indicating that plasma Heme is associated with PBA infection in mice. Additionally, HO-1 plasma levels were significantly higher in the infected wild type C57 BL/6 mice compared to the control mice, suggesting HO-1 could be a protective factor against Heme. CXCL102/2 infected mice showed the same pattern as CXCL102/2 non-infected mice regarding plasma concentration of Heme and HO-1. When infected with PBA, CXCL102/2 mice do not present the same increase in the levels of Heme or HO-1 as WT mice do during infection. High expression levels of HO-1 and tyrosinephosphorylated STAT3 occur in kidney, brain and lung tissues of mice infected with P. berghei ANKA. down-regulated HO-1 in bot

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Author: Cholesterol Absorption Inhibitors