Paradoxical rise of hemolytic complement in the blood of mice during zymosan- and liposome-induced CARPA: a pilot study

AbstractThe complement (C) activating effect of zymosan and liposomal drugs (AmBisome, Caelyx) leads to significant C consumption in rats, dogs, pigs and other species in vivo, as reflected by a fall in hemolytic complement activity (HCA) of their plasma. However, the acute C activating effect of zymosan and liposomal drugs is unclear in the mouse. Therefore, using sheep red blood cells, we assayed the HCA of plasma obtained from apolipoprotein E-deficient (ApoE) as well as from background C57BL/6 (BL6) mice. Intravenous (i.v.) administration of C activators led to a significant rise (up to 40%) in HCA of the plasma. The HCA steadily rose up to 30 min in ApoE mice, while it peaked at 3 min in BL6 mice, returning to baseline thereafter. The elevated HCA after IV injection of C activators is “paradoxical” in mice, since it implies an increase rather than a decrease in C levels in the blood. One possible explanation of the phenomenon is hemoconcentration due to anaphylatoxin-induced capillary leakage, resulting in an apparent rise of HCA. In conclusion, these preliminary observations highlight, for the first time, a species-dependent opposing impact of C activation and the resulting anaphylatoxin actions on hemolytic complement activity.

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Ex Vivo Microsphiltration Profile of Plasmodium Falciparum Infected Red Blood Cells in Patients with Malaria in Kéniéroba, Mali: Exploring the Spleen in Vivo Retention Function

10.21203/rs.3.rs-557105/v2 ◽

2021 ◽

Author(s):

Bourama KEITA ◽

Seidina Diakité ◽

Agnes Guindo ◽

Drissa Konaté ◽

Karim Traoré ◽

...

Keyword(s):

Pilot Study ◽

Red Blood Cells ◽

Blood Cells ◽

Ex Vivo ◽

Retention Rate ◽

Deep Inspiration ◽

Clinical Forms ◽

Filtering Function ◽

The Impact

Abstract Malaria pathophysiology is not still fully understood. The main mechanisms of malaria involve the synergistic interactions between host and parasite. Although, the role of the spleen has been mentioned in various clinical forms of malaria, a supportive clinical evidence is still needed. We conducted a pilot study to determine the impact of the spleen functional state in different clinical forms of malaria. Ex vivo microsphiltration was used to assess the splenic function in patients received during routine consultation with mild malaria at the Kéniéroba health center, a high malaria endemic area in Mali. A total of 25 patients were enrolled for ex vivo microsphiltration. Spleen was non-palpable (Hackett stage 0) in two patients, palpable with deep inspiration (Hackett stage 1) in 22 patients and without deep inspiration (Hackett stage 2) in one patient, parasitaemia ranged from 5360 trophozoites/µl to 342720 trophozoites/µl with a mean parasitemia of 50774 trophozoites/µl ± 65540 trophozoites/µl. The mean hemoglobin level was 11.2g/dl ± 1.2 [8.7-13.4]. The retention rate of the infected red blood cell ranged from 11.11% to 94.44% with 65.4% ± 23.7% on average. A higher ex vivo retention rate of infected red blood cells was observed in patients with Hackett stage other than 0 (p= 0.03). This pilot study proved that it was feasible to use the ex vivo microsphiltration to explore the spleen filtering function in malaria patients.

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Reduced CD36-dependent tissue sequestration of Plasmodium-infected erythrocytes is detrimental to malaria parasite growth in vivo

Journal of Experimental Medicine ◽

10.1084/jem.20110762 ◽

2011 ◽

Vol 209 (1) ◽

pp. 93-107 ◽

Cited By ~ 72

Author(s):

Jannik Fonager ◽

Erica M. Pasini ◽

Joanna A.M. Braks ◽

Onny Klop ◽

Jai Ramesar ◽

...

Keyword(s):

Vascular Endothelium ◽

Plasmodium Berghei ◽

Blood Cells ◽

Malaria Infection ◽

Plasmodium Falciparum Malaria ◽

Parasite Growth ◽

Plasmodium Berghei Anka ◽

Parasite Plasmodium ◽

First Time

Adherence of parasite-infected red blood cells (irbc) to the vascular endothelium of organs plays a key role in the pathogenesis of Plasmodium falciparum malaria. The prevailing hypothesis of why irbc adhere and sequester in tissues is that this acts as a mechanism of avoiding spleen-mediated clearance. Irbc of the rodent parasite Plasmodium berghei ANKA sequester in a fashion analogous to P. falciparum by adhering to the host receptor CD36. To experimentally determine the significance of sequestration for parasite growth, we generated a mutant P. berghei ANKA parasite with a reduced CD36-mediated adherence. Although the cognate parasite ligand binding to CD36 is unknown, we show that nonsequestering parasites have reduced growth and we provide evidence that in addition to avoiding spleen removal, other factors related to CD36-mediated sequestration are beneficial for parasite growth. These results reveal for the first time the importance of sequestration to a malaria infection, with implications for the development of strategies aimed at reducing pathology by inhibiting tissue sequestration.

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Metabolite Profiling of Dihydroartemisinin in Blood of Plasmodium-Infected and Healthy Mice Using UPLC-Q-TOF-MSE

Frontiers in Pharmacology ◽

10.3389/fphar.2020.614159 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yifan Zhao ◽

Peng Sun ◽

Yue Ma ◽

Xiaoqiang Chang ◽

Xingyu Chen ◽

...

Keyword(s):

Blood Plasma ◽

Red Blood Cells ◽

Metabolic Pathway ◽

Blood Cells ◽

Metabolite Profiling ◽

First Line ◽

First Time ◽

Insight Into ◽

Tof Ms

Dihydroartemisinin (DHA) and its’ derivatives have been employed as the most powerful first-line drugs for malarial treatment for several decades. The metabolism of DHA has not been studied clearly. Previous reports were focused on the pharmacokinetics procedure of DHA in healthy rats. The metabolites of DHA in red blood cells (RBC), especially in the RBC from Plasmodium-infected models, have rarely been studied. The Plasmodium species parasitize inside RBC, and these cells should be the final place where DHA performs its activity. In this study, the profile of DHA metabolites in biosample (blood, plasma, and RBC) of the infected and healthy mice was investigated with UPLC-Q-TOF-MS and UNIFI platform to gain insight into DHA metabolism. Results show that a total of 25 metabolites were successfully identified in infected (30 in healthy) blood, 27 in infected (27 in healthy) plasma, and 15 in infected (22 in healthy) RBC. Results show that hydroxylation, OH-dehydration, and glucuronidation reactions were important in the metabolic pathway in vivo. Significantly, DHA metabolites inside RBC were identified for the first time. 8-Hydroxy (8-OH) DHA, 4α-OH deoxy ART, and 6β-OH deoxy ART were identified in vivo for the first time.

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High-sensitivity determination of 2-chlorovinylarsonous acid in biomedical samples for retrospective detection of exposure to lewisite upon antidotal therapy

Spectroscopy An International Journal ◽

10.1155/2011/840141 ◽

2011 ◽

Vol 26 (1) ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

N. L. Koryagina ◽

E. S. Ukolova ◽

E. I. Savel’eva ◽

N. G. Voitenko ◽

O. I. Orlova ◽

...

Keyword(s):

Blood Cells ◽

Solid Phase Microextraction ◽

Solid Phase ◽

Single Injection ◽

High Sensitivity ◽

Rat Urine ◽

First Time ◽

Antidotal Therapy

A procedure for determination of the lewisite metabolite 2-chlorovinylarsonous acid (CVAA) in biomedical samples, involving derivatization of the latter with propane-1,3-dithiol and head-space solid-phase microextraction of the derivative on a 100-μm PDMS fiber followed by GC-MS, was applied for the first time to analysis ofin vivosamples. The detection limits of CVAA in urine, plasma and red blood cells were 0.1, 1.0 and 10 ng/ml, respectively. Upon exposure to lewisite at a dose of 1.6 mg/kg, CVAA could be detected in rat urine for about three months. Study of the effect of a single injection of the antidote unithiol on the CVAA excretion profile revealed more active CVAA excretion during the first two days after the injection, compared to that observed in the absence of antidotal therapy.

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Ex Vivo Microsphiltration Profile of Plasmodium Falciparum Infected Red Blood Cells in Patients with Malaria in Kéniéroba, Mali: Exploring the Spleen in Vivo Retention Function

10.21203/rs.3.rs-557105/v1 ◽

2021 ◽

Author(s):

Bourama KEITA ◽

Seidina A.S. Diakité ◽

Agnes M. Guindo ◽

Drissa S. Konaté ◽

Karim Traoré ◽

...

Keyword(s):

Pilot Study ◽

Red Blood Cells ◽

Blood Cells ◽

Ex Vivo ◽

Retention Rate ◽

Clinical Forms ◽

Filtering Function ◽

Stage 1 ◽

The Impact

Abstract Malaria pathophysiology is not still fully understood. The main mechanisms of malaria involve the synergistic interactions between host and parasite. Although, the role of the spleen has been mentioned in various clinical forms of malaria, a supportive clinical evidence is still needed. We conducted a pilot study to determine the impact of the spleen functional state in different clinical forms of malaria.Ex vivo microsphiltration was used to assess the splenic function in patients received during routine consultation with malaria at the Kéniéroba health center, a high malaria endemic area in Mali.A total of 25 patients were enrolled for microsphiltration. Two patients (8%) had a no palpable spleen (Hackett stage 0), 22 patients (88%) had a palpable spleen with at deep inspiration (Hackett stage 1) and only one patient (4%) presented a palpable spleen (Hackett stage 2). Parasitaemia ranged from 5360 trophozoites/µl to 342720 trophozoites/µl with a mean parasitemia of 50774 trophozoites/µl ± 65540 trophozoites/µl; the mean hemoglobin rate was 11.2 ± 1.2 g/dl with the extremes of 8.7 g/dl and 13.4 g/dl. The retention rate of the infected red blood cell ranged from 11.11% to 94.44% with an average of 65.4% ± 23.7%. A higher ex vivo retention rate of infected red blood cells was observed in patients with Hackett stages greater than or equal to 1 (p= 0.03). This pilot study proved the feasibility of the exploration of the spleen filtering function in malaria patients using the ex vivo microsphiltration.

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Complement is not involved in monocrotaline pyrrole-induced pulmonary injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.254.2.h258 ◽

1988 ◽

Vol 254 (2) ◽

pp. H258-H264

Author(s):

L. H. Bruner ◽

K. J. Johnson ◽

G. O. Till ◽

R. A. Roth

Keyword(s):

Lung Injury ◽

Complement Activation ◽

Pulmonary Injury ◽

Serum Complement ◽

Rat Serum ◽

Complement Activity ◽

Hemolytic Complement Activity ◽

Monocrotaline Pyrrole

Monocrotaline pyrrole (MCTP) causes pulmonary vascular injury, pulmonary hypertension, and right ventricular hypertrophy in rats. The mechanisms by which MCTP causes lung injury are not known. After treatment with a moderate dose of MCTP, several days pass before major lung injury is detected, thus suggesting that the damage is caused indirectly. Since activation of the complement system can cause lung injury, it was of interest to test whether complement activation may be important in lung injury due to MCTP. Accordingly, rats were given a single dose of MCTP (3.5 mg/kg iv), and serum hemolytic complement activity was measured at several times after rats were treated. Neutrophil aggregometry also was used to determine whether complement activation products could be detected in serum after MCTP was given in vivo. The effect of complement depletion on MCTP-induced pulmonary injury was tested by cotreating rats with purified cobra venom factor and MCTP. MCTP treatment did not cause detectable complement activation in vivo, and complement depletion did not protect rats from lung injury. The direct effect of MCTP on serum complement also was tested by exposing fresh rat serum to MCTP in vitro and measuring serum complement activity. MCTP decreased serum hemolytic complement activity in vitro, but it did not interfere with subsequent zymosan-induced activation of complement. These results suggest that complement does not play a role in the development of major lung injury that occurs several days after treatment of rats with MCTP.

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THE RELATIONSHIPS BETWEEN SERUM COMPLEMENT ACTIVITY AND THE DEVELOPMENT OF ALLERGIC LESIONS IN RABBITS

Journal of Experimental Medicine ◽

10.1084/jem.114.5.633 ◽

1961 ◽

Vol 114 (5) ◽

pp. 633-646 ◽

Cited By ~ 13

Author(s):

Marie Britt Rhyne ◽

Frederick G. Germuth

Keyword(s):

Hemolytic Activity ◽

Serum Sickness ◽

Total Serum ◽

Temporary Reduction ◽

Complement Activity ◽

Arterial Lesions ◽

Total Complement ◽

Hemolytic Complement Activity ◽

Antigen Antibody

Total serum hemolytic complement activity is consistently reduced in animals undergoing accelerated "serum sickness". The time of maximum reduction in complement titer invariably coincides with the time of complete antigen disappearance. This temporal relationship supports the belief that the reduction in complement titer is brought about by in vivo antigen-antibody combination. The intravenous administration of a single daily large dose of BGG-precipitated complexes produces a marked but temporary reduction in total complement hemolytic activity. On the other hand, multiple injections of soluble BGG immune complexes prepared in antigen excess failed to even temporarily alter complement titers. Animals undergoing the development of accelerated "serum sickness" treated by either type immune complex showed a significantly reduced incidence of arterial lesions. Apparently, this inhibiting effect on the development of arterial lesions was independent of variations in total complement hemolytic activity.

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Ultrastructural observations on the in vitro cytoadherence of Plasmodium falciparum infected red blood cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162132 ◽

1990 ◽

Vol 48 (3) ◽

pp. 914-915

Author(s):

D.J.P. Ferguson ◽

A.R. Berendt ◽

J. Tansey ◽

K. Marsh ◽

C.I. Newbold

Keyword(s):

Plasmodium Falciparum ◽

Red Blood Cells ◽

Blood Cells ◽

Umbilical Vein ◽

Cell Types ◽

Amelanotic Melanoma ◽

Cytoplasmic Process ◽

Umbilical Vein Endothelial Cells

In human malaria, the most serious clinical manifestation is cerebral malaria (CM) due to infection with Plasmodium falciparum. The pathology of CM is thought to relate to the fact that red blood cells containing mature forms of the parasite (PRBC) cytoadhere or sequester to post capillary venules of various tissues including the brain. This in vivo phenomenon has been studied in vitro by examining the cytoadherence of PRBCs to various cell types and purified proteins. To date, three Ijiost receptor molecules have been identified; CD36, ICAM-1 and thrombospondin. The specific changes in the PRBC membrane which mediate cytoadherence are less well understood, but they include the sub-membranous deposition of electron-dense material resulting in surface deformations called knobs. Knobs were thought to be essential for cytoadherence, lput recent work has shown that certain knob-negative (K-) lines can cytoadhere. In the present study, we have used electron microscopy to re-examine the interactions between K+ PRBCs and both C32 amelanotic melanoma cells and human umbilical vein endothelial cells (HUVEC).We confirm previous data demonstrating that C32 cells possess numerous microvilli which adhere to the PRBC, mainly via the knobs (Fig. 1). In contrast, the HUVEC were relatively smooth and the PRBCs appeared partially flattened onto the cell surface (Fig. 2). Furthermore, many of the PRBCs exhibited an invagination of the limiting membrane in the attachment zone, often containing a cytoplasmic process from the endothelial cell (Fig. 2).

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The Ullrastructure of Platelet Participation in Hemostasis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656288 ◽

1965 ◽

Vol 13 (01) ◽

pp. 065-083 ◽

Cited By ~ 7

Author(s):

Shirley A. Johnson ◽

Ronaldo S. Balboa ◽

Harlan J. Pederson ◽

Monica Buckley

Keyword(s):

Platelet Aggregation ◽

Red Blood Cells ◽

Blood Cells ◽

Guinea Pigs ◽

Platelet Factor ◽

Mesenteric Vessels ◽

Platelet Aggregates ◽

Electron Lucent

SummaryThe ultrastructure of platelet aggregation in vivo in response to bleeding brought about by transection of small mesenteric vessels in rats and guinea pigs has been studied. Platelets aggregate, degranulate and separating membranes disappear in parallel with fibrin appearance which is first seen at several loci after 30 seconds of bleeding. About 40 per cent of the electron opaque granules, some of which contain platelet factor 3 have disappeared after one minute of bleeding while the electron lucent granules increase by 70 per cent suggesting that some of them may be empty vesicles. Most of the platelet aggregates of the random type disappear leaving clumped red blood cells entrapped by a network of fibrin fibers which emanate from the remains of platelet aggregates of the rosette type to maintain hemostasis.

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