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    Understanding the role of inflammatory cytokines in malaria and related diseases. Clark Ian A,Alleva Lisa M,Budd Alison C,Cowden William B Travel medicine and infectious disease It is now broadly accepted for infectious disease in general that it is not the invading organism, but the body's unbridled response to it--the "cytokine storm"--that causes illness and pathology. Nevertheless, many researchers still regard the harmful effects of falciparum malaria as being governed by oligaemic hypoxia arising from parasitised erythrocytes obstructing blood flow through vulnerable organs, particularly the brain, and we summarise why these notions are no longer tenable. In our view, this harmful sequestration is readily accommodated within the cytokine storm perspective as one of its secondary effects. We approach these issues by examining aspects of malaria, sepsis and influenza in parallel, and discuss the insights that comparisons of the literature can provide on the validity of possible anti-disease therapies. 10.1016/j.tmaid.2007.07.002
    Coagulopathy in malaria. Angchaisuksiri Pantep Thrombosis research Blood coagulation activation is frequently found in patients with malaria. Clinically apparent bleeding or disseminated intravascular coagulation (DIC) is associated with very severe disease and a high mortality. Protein C, protein S, and antithrombin levels were found to be low in P. falciparum, but were normal in P. vivax infection. Plasma levels of plasminogen activator inhibitor-1 were high in cases of P. falciparum infection whereas tissue plasminogen activator levels were low. Elevated plasma levels of von Willebrand factor (vWF) and vWF propeptide, thrombomodulin, endothelial microparticles have been reported in P. falciparum-infected patients. It has been demonstrated that severe P. falciparum infection is associated with acute endothelial cell (EC) activation, abnormal circulating ultralarge vWF multimers, and a significant reduction in plasma ADAMTS13 function. These changes may result in intravascular platelet aggregation, thrombocytopenia, and microvascular disease. It has also been shown that P. falciparum-parasitized red blood cells (pRBCs) induce tissue factor (TF) expression in microvascular ECs in vitro. Recently, loss of endothelial protein C receptor (EPCR) localized to sites of cytoadherent pRBCs in cerebral malaria has been demonstrated. Severe malaria is associated with parasite binding to EPCR. The cornerstone of the treatment of coagulopathy in malaria is the use of effective anti-malarial agents. DIC with spontaneous systemic bleeding should be treated with screened blood products. Study in Thailand has shown that for patients who presented with parasitemia >30% and severe systemic complications such as acute renal failure and ARDS, survival was superior in the group who received exchange transfusion. The use of heparin is generally restricted to patients with DIC and extensive deposition of fibrin, as occurs with purpura fulminans or acral ischemia. Antiplatelet agents interfere with the protective effect of platelets against malaria and should be avoided. 10.1016/j.thromres.2013.09.030
    Malaria inflammation by xanthine oxidase-produced reactive oxygen species. Ty Maureen C,Zuniga Marisol,Götz Anton,Kayal Sriti,Sahu Praveen K,Mohanty Akshaya,Mohanty Sanjib,Wassmer Samuel C,Rodriguez Ana EMBO molecular medicine Malaria is a highly inflammatory disease caused by Plasmodium infection of host erythrocytes. However, the parasite does not induce inflammatory cytokine responses in macrophages in vitro and the source of inflammation in patients remains unclear. Here, we identify oxidative stress, which is common in malaria, as an effective trigger of the inflammatory activation of macrophages. We observed that extracellular reactive oxygen species (ROS) produced by xanthine oxidase (XO), an enzyme upregulated during malaria, induce a strong inflammatory cytokine response in primary human monocyte-derived macrophages. In malaria patients, elevated plasma XO activity correlates with high levels of inflammatory cytokines and with the development of cerebral malaria. We found that incubation of macrophages with plasma from these patients can induce a XO-dependent inflammatory cytokine response, identifying a host factor as a trigger for inflammation in malaria. XO-produced ROS also increase the synthesis of pro-IL-1β, while the parasite activates caspase-1, providing the two necessary signals for the activation of the NLRP3 inflammasome. We propose that XO-produced ROS are a key factor for the trigger of inflammation during malaria. 10.15252/emmm.201809903