Polymorphonuclear leucocyte elastase in Plasmodium falciparum malaria

Pukrittayakamee, Sasithon; Clemens, Ralf; Pramoolsinsap, Chutima; Karges, H E; Vanijanonta, S; Bunnag, D; White, Nicholas J.

doi:10.1016/0035-9203(92)90143-z

Cited by 22 publications

(21 citation statements)

References 16 publications

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“…This suggests that the neutrophil-related response represents an increase in cell activity as well as in cell count. Neutrophilia has been linked with acute malaria [23], but the role of neutrophil activation in the host response to malaria has been relatively underinvestigated [24,25]. The expression data also confirmed that lymphocyte activity is important in host response to malaria; we observed significantly increased expression of T cellrelated genes (TRG@, GZMA, GZMB, GNLY, NK4, and CTSW) in patients with acute malaria, compared with that in patients with bacterial infection.…”

Section: Discussionsupporting

confidence: 88%

Genomewide Analysis of the Host Response to Malaria in Kenyan Children

et al. 2005

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Malaria is a global problem, and there is a critical need for further understanding of the disease process. When malarial parasites invade and develop within the bloodstream, they stimulate a profound host response whose main clinical sign is fever. To explore this response, we measured host gene expression in whole blood from Kenyan children hospitalized with either acute malaria or other febrile illnesses. Genomewide analysis of expression identified 2 principal gene-expression profiles related to neutrophil and erythroid activity. In addition to these general acute responses, a third gene-expression profile was associated with host parasitemia; mediators of erythrophagocytosis and cellular stress were notable components of this response. The delineation of subjects on the basis of patterns of gene expression provides a molecular perspective of the host response to malaria and further functional insight into the underlying processes of pathogenesis.

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Section: Discussionsupporting

confidence: 88%

Genomewide Analysis of the Host Response to Malaria in Kenyan Children

et al. 2005

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“…The antiapoptotic strategy derived from our in vitro model may be relevant for P. falciparum malaria, since this disease is associated with both elevated levels of human neutrophil elastase in plasma (23,26,40) and a decreased serum antioxidative status with abnormally low levels of ascorbic acid (9). Thus, antioxidants and protease inhibitors may offer clinical benefit by preventing organ complications due to endothelial apoptosis even though they may not accelerate parasite clearance or defervescence.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparumMalaria: Reduction of Endothelial Cell Apoptosis In Vitro

Hemmer

Lehr²,

Westphal

et al. 2005

Infect Immun

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Organ failure in Plasmodium falciparum malaria is associated with neutrophil activation and endothelial damage. This study investigates whether neutrophil-induced endothelial damage involves apoptosis and whether it can be prevented by neutralization of neutrophil secretory products. Endothelial cells from human umbilical veins were coincubated with neutrophils from healthy donors and with sera from eight patients with P. falciparum malaria, three patients with P. vivax malaria, and three healthy controls. Endothelial apoptosis was demonstrated by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and annexin V staining. The rate of apoptosis of cells was markedly increased after incubation with patient serum compared to that with control serum. Apoptosis was most pronounced after incubation with sera from two patients with fatal cases of P. falciparum malaria, followed by sera of survivors with severe P. falciparum malaria and, finally, by sera of patients with mild P. falciparum and P. vivax malaria. Ascorbic acid, tocopherol, and ulinastatin reduced the apoptosis rate, but gabexate mesilate and pentoxifylline did not. Furthermore, in fatal P. falciparum malaria, apoptotic endothelial cells were identified in renal and pulmonary tissue by TUNEL staining. These findings show that apoptosis caused by neutrophil secretory products plays a major role in endothelial cell damage in malaria. The antioxidants ascorbic acid and tocopherol and the protease inhibitor ulinastatin can reduce malaria-associated endothelial apoptosis in vitro.

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“…hemozoin, glycosylphosphatidylinositol anchor, and oxidized heme) are potentially proinflammatory and may participate in disease pathogenesis 43 -45. Microparticle production 21 which reportedly display TF and PS 46, and host responses such as activation of the contact pathway, complement system, and neutrophils-known to produce radical oxygen species (ROS) and to release procoagulant elastase (reviewed in ref 20)-may also play an important pro-inflammatory role in P. falciparum infection 15,18,19 . Finally, the plasma or local levels of anticoagulants (e.g.…”

Section: The Tissue Factor Model For Malaria Pathogenesismentioning

confidence: 99%

“…The main argument that supports this notion is the fact that the vast majority, perhaps all patients with mild and severe malaria, present elevated levels of D-dimers20, a specific marker of plasmin-mediated fibrin proteolysis in vivo 23 . Finally, it has been reported that hemostatic alterations correlate with parasitemia, thrombocytopenia, and/or severity of P. falciparum infection in a number of studies; in addition, antiparasitic treatment halts the coagulation disorder and improves clinical outcome [12][13][14][15][16][17][18][19][20] .Therefore, it is plausible that hemostatic alterations play a role in the disease progression and organ failure observed in malaria 16,20 .More recently, it has been demonstrated that P. falciparum-parasitized RBC (pRBC) induce tissue factor (TF) expression in the microvascular EC in vitro, and support the assembly of multimolecular coagulation complexes 10 . TF is the clotting initiator 24-26 and a structural member of the cytokine receptor family, which signifies the expansion of the adaptive immune system in vertebrates, indicating a close connection of the coagulation pathways with the host response to infection 27 .…”

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confidence: 99%

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Francischetti

2008

Trends in Parasitology

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Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor (TF) in the brain endothelium of patients who died from cerebral malaria casts new light in our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells (pRBC) support assembly of multimolecular coagulation complexes. In this article, the role of TF expression by the endothelium and amplification of the coagulation cascade by pRBC and/or activated platelets-particularly at sequestration sitesis discussed as crucial events in mounting and sustaining a coagulation-inflammation cycle that contributes to organ dysfunction and coma in P. falciparum malaria. Blood coagulation and malariaMalaria caused by P. falciparum remains a highly endemic disease; it has been estimated that at least one million deaths occur every year. Children are at high risk, and often severe malaria (severe anemia or cerebral malaria [CM]) is the cause of death in this population 1-4. P. falciparum infection is associated with sequestration 5 -8 , endothelial cell (EC) activation 8-10, increase in inflammatory cytokines 3 , 11, and activation of the coagulation cascade 12 -20. Despite several papers devoted to the coagulation disorder in malaria-many of them published during the 1970s and 1980s (reviewed in Ref. 20)-the mechanism that triggers and propagates the coagulation activation in P. falciparum infection has remained elusive. These studies, however, demonstrated that bleeding and/or hemorrhage are typically not present, although laboratory tests indicate a certain degree of in vivo blood coagulation activation 12 -20 . Accordingly, prothrombin time (PT) and partial thromboplastin time (PTT) are close to normal values or prolonged, whereas thrombin-antithrombin complex (TAT) (which indicates in vivo thrombin formation) and D-dimers (which are a marker of in vivo fibrinolysis) are often elevated, and thrombocytopenia is a usual finding 12 -21 . This laboratory profile is compatible with disseminated intravascular coagulation (DIC), which is diagnosed according to a score defined by the International Society of Thrombosis and Haemostasis (ISTH) 22 . The scoring system takes into account i) platelet count, ii) elevated fibrin related markers, iii) prolonged prothrombin time, and iv) fibrinogen level 22 23 . Depending on the score punctuation, levels < 5 are suggestive of non-overt (compensated) DIC while scores > or = 5 are compatible with overt (decompensated) DIC. Bleeding is more common in overt DIC, but it is not needed for the formal diagnosis 22 23. In other words, absence of bleeding in P. falciparum-infected patients does not exclude the presence of DIC in this same population; actually, most of these patients meet the criteria for DIC as defined above 22 . Unfortunately, absence of bleeding is often mistakenly regarded as the reason why DIC is supposedly not present in malaria. Further, some reports do not support the view that coa...

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Polymorphonuclear leucocyte elastase in Plasmodium falciparum malaria

Cited by 22 publications

References 16 publications

Genomewide Analysis of the Host Response to Malaria in Kenyan Children

Genomewide Analysis of the Host Response to Malaria in Kenyan Children

Plasmodium falciparumMalaria: Reduction of Endothelial Cell Apoptosis In Vitro

Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

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