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Biomedical subjects

I A Clark

Publications and source records attributed to I A Clark.

At least 91 records · Page 5Linked to original sources
PubMed1984

Activity of divicine in Plasmodium vinckei-infected mice has implications for treatment of favism and epidemiology of G-6-PD deficiency.

Intravenous injection of divicine into mice infected with Plasmodium vinckei rapidly killed the parasites and caused haemolysis. Degenerating parasites were observed frequently inside intact circulating erythrocytes, implying that parasite death was not a passive consequence of haemolysis. Both parasite death and haemolysis were prevented by the iron chelator desferrioxamine. In vitro, divicine caused the accumulation of malonyldialdehyde and the depletion of reduced glutathione in normal mouse erythrocytes. Desferrioxamine inhibited the former event, but not the latter. These observations support the hypothesis advanced by Huheey & Martin (Experientia, 31, 1145, 1975) to explain the patchy geographical distribution of glucose-6-phosphate dehydrogenase deficiency in historic malarial areas and also suggest that desferrioxamine, a drug already in clinical use, is a potential treatment for favism and other examples of oxidative haemolysis.

Animals↗
PubMed1984

Macrophages from Babesia and malaria infected mice are primed for monokine release.

Serum from mice infected with Babesia microti or Plasmodium vinckei petteri and given lipopolysaccharide (LPS) contained appreciable amounts of tumour necrosis factor (TNF) and lymphocyte-activating factor (LAF; Interleukin I) activity. These monokines were not noted in serum from uninfected mice given the same dose of LPS. This pattern was repeated when adherent peritoneal cells from normal or infected mice were exposed to LPS in vitro and the supernatants assayed for LAF. This indicates that the hyper-reactivity of malaria and Babesia-infected mice to LPS resides in their macrophages, and that infection with these haemoprotozoa provides the host's macrophages with the same priming stimulus for subsequent triggering of monokine release as does an injection of Bacillus Calmette Guerin.

Animals↗
PubMed1984

Production of luminol-reactive oxygen radicals during Plasmodium vinckei infection.

We tested the ability of whole blood and enriched fractions of peripheral blood polymorphonuclear leukocytes obtained from mice during the course of infection with Plasmodium vinckei to produce luminol-mediated chemiluminescence in response to phagocytic and nonphagocytic stimuli. The chemiluminescence response of whole blood to all stimuli increased dramatically and nonlinearly as the infection progressed, and there was a concomitant increase (80%) and decrease (70%) in the total numbers of leukocytes and erythrocytes, respectively. The proportion of polymorphonuclear leukocytes in the total leukocyte population increased threefold. On a per cell basis and at a constant hematocrit, the chemiluminescence response of peripheral leukocytes from infected animals to phorbol myristate acetate or opsonized zymosan was only slightly greater than that of cells from uninfected animals. Polymorphonuclear leukocytes isolated from the blood of infected animals also showed no large increase per cell in chemiluminescence responsiveness. Thus, although leukocyte numbers increase during a murine malarial infection, there appears to be no major change in the capacity of individual peripheral blood leukocytes to produce activated species of oxygen. However, the physiological reduction in the total concentration of hemoglobin at high parasitemia, due to hemolysis and hemoglobin digestion by the parasites, increases the possibility of oxygen radical-mediated damage to tissues and intraerythrocytic parasites as a result of decreased antioxidant protection.

Animals↗
PubMed1984

Radical-mediated damage to parasites and erythrocytes in Plasmodium vinckei infected mice after injection of t-butyl hydroperoxide.

Intravenous injection of t-butyl hydroperoxide rapidly killed Plasmodium vinckei in mice, and caused haemolysis. The same dose seemed harmless to unparasitized mice. Many parasites disintegrated inside circulating erythrocytes, so parasite death was not simply a passive consequence of haemolysis. Injection of desferrioxamine, which removes the traces of free iron that promote the dissociation of t-butyl hydroperoxide into radical species, prevented both parasite death and haemolysis. Lipid peroxidation, as measured by accumulation of malonyldialdehyde over 2 h in vitro, occurred in erythrocytes exposed to t-butyl hydroperoxide, and was particularly marked in erythrocytes from parasitized mice. These erythrocytes accumulated appreciable malonyldialdehyde even without exposure to t-butyl hydroperoxide. Desferrioxamine inhibited the accumulation of malonyldialdehyde, but did not prevent depletion of reduced glutathione by t-butyl hydroperoxide. This suggests that t-butyl hydroperoxide damaged parasites and erythrocytes by dissociating into radical species, rather than by decreasing intraerythrocyte anti-oxidant capacity. In earlier experiments we suggested that intraerythrocytic parasite death and haemolysis caused by alloxan were mediated by radical species, and these experiments with t-butyl hydroperoxide add weight to this interpretation. We regard both of these systems as models for macrophage-induced parasite death and host pathology in acute malaria.

Animals↗
PubMed1983

Evidence for reactive oxygen intermediates causing hemolysis and parasite death in malaria.

A rapid reduction in parasitemia associated with damage to intraerythrocytic parasites was observed in Plasmodium vinckei-infected mice after they had received a single intravenous injection of alloxan. This was not prevented by prior injection of glucose, but was prevented by desferrioxamine or diethyldithiocarbamate. Prior injection of propanol partially blocked the phenomenon. A transient hemolysis was observed in malaria-infected mice, but not in controls, after injection of alloxan. This was also blocked by desferrioxamine, but not by glucose. Both the fall in parasitemia and hemolysis occurred, but less dramatically, when phenylhydrazine or hydrogen peroxide was injected into parasitized mice. Again, the hemolysis was blocked by desferrioxamine. These observations are consistent with the parasite death and hemolysis being mediated by reactive oxygen species, possibly hydroxyl radicals, and have implications for our understanding of hemolysis, endothelial damage, and parasite suppression in acute malaria. Our evidence that malaria parasites are susceptible to free oxygen radicals supports the view that high intraerythrocytic oxidative stress may contribute to the high frequencies in malarial areas of genes for certain erythrocyte-related traits and suggests that some antimalarial drugs may suppress parasites partly through oxidative damage.

Alloxan↗
PubMed1983

Production of lymphocyte activating factor in vivo.

Mice injected with Propionibacterium acnes, when challenged with lipopolysaccharide release a range of soluble mediators into their serum. Included among these is lymphocyte activating factor (LAF, interleukin-1). The release of LAF in vivo was detected only when serum samples were assayed at high dilution because inhibitors of its activity in vitro were also present. The kinetics of release of LAF in vivo after injection of P. acnes was dependent on the mouse strain used. LAF was also detected in serum collected from nude mice, implying that the LAF activity measured in vitro was not due to contamination with T cell products, such as interleukin 2.

Animals↗
PubMed1982

Correlation between susceptibility to malaria and babesia parasites and to endotoxicity.

Adult (185g) rats are about twice as sensitive to the harmful effects of injected endotoxin as are younger (65g) rats. This relationship correlates with an earlier report on the densities of Plasmodium berghei at which deaths occur in rats of these two age groups. Similarly lizards, which withstand very high parasitaemias of malaria parasites, are refractory to very large doses of endotoxin. This correlation appears to hold for malaria and babesiosis in all host species for which information is available, with man, for instance, very sensitive to these infections and to injected endotoxin. It is now realized that endotoxicity is not caused by the direct effects of endotoxin, but is the consequence of the release of a range of harmful soluble mediators, mainly from macrophages. Since the susceptibility of a host species to endotoxicity and to malaria and babesiosis correlate, and the illness produced in each case is very similar, these harmful mediators which cause endotoxicity are likely candidates for the origins of much of the pathology of malaria and babesiosis. This concept may also explain the relationship between parasite density and illness in these infections in man.

Age Factors↗
PubMed1982

Apparent irrelevance of NK cells to resolution of infections with Babesia microti and Plasmodium vinckei petteri in mice.

Increased natural killer (NK) cell activity was found in the spleen and peritoneal cavity of mice infected with Babesia microti or Plasmodium vinckei petteri. This increased activity appeared not to be associated with the effectiveness of the host response against these parasites, since it reached its maximum when the parasitaemia was still low, and had decreased by the time the parasites reached peak densities. In addition mice pretreated with 89Strontium of 17 beta-oestradiol experienced the same pattern of infection as did control mice, yet the infections induced much lower levels of NK activity in the pretreated mice. The course of infection with B. microti was also unaltered in beige mice, which are genetically deficient in NK cells. Thus we consider it unlikely that NK cells are of primary importance in non-specific immunity to these haemoprotozoan infections.

Animals↗
PubMed1982

Genetic control of Propionibacterium acnes-induced protection of mice against Babesia microti.

Using various strains of inbred mice, we found that Propionibacterium acnes-induced protection against the hemoprotozoan parasite Babesia microti was controlled by a dominant gene(s) not linked to the major histocompatibility gene (H2) complex of mice. P. acnes-induced resistance to infection was not merely an amplification of the normal immune response to B. microti, since innate resistance to infection was controlled by different genes. Expression of the nonspecific protection induced by P. acnes was found to be transferable with cells of bone marrow origin, and it did not necessarily accompany the induction of hepatosplenomegaly. The implication of these results for the understanding of the mechanism of P. acnes-induced protection is discussed.

Animals↗
PubMed1982

Failure of bacterial lipopolysaccharide to elicit a cytostatic effect on Plasmodium vinckei petteri in C3H/HeJ mice.

Malarial parasites, Plasmodium vinckei petteri, taken from lipopolysaccharide (LPS) high-responder (C3H/HeJGiFWeHi) mice which had been injected 7 to 8 h previously with either Escherichia coli LPS B or LPS W incorporated the purine nucleotide precursor hypoxanthine more slowly in an in vitro assay than parasites taken from saline-injected controls. In contrast, malarial parasites taken from LPS low-responder C3H/HeJ mice after injection of either LPS B or LPS W did not show reduced levels of hypoxanthine incorporation. These differing results with LPS high- and low-responder mouse strains demonstrated that the cytostatic effect on the parasites seen in the high-responder strain was not due to the direct action of LPS and implied that the cytostasis was mediated via host lymphoreticular cells. Furthermore, the failure of LPS B, a lipid A-associated protein-containing LPS preparation, to elicit a cytostatic effect on P. vinckei petteri in C3H/HeJ mice suggested that the LPS-induced effector mechanisms acting against malarial parasites may be similar to those reported against bacteria and tumors.

Animals↗
PubMed1981

Thromboxane may be important in the organ damage and hypotension of malaria.

Generalized circulatory changes, manifesting as pulmonary oedema, acute renal failure, liver damage and severe hypotension, are well recognized aspects of acute falciparum malaria. The organ pathology is thought to be associated with a restricted local blood flow. These aspects of falciparum malaria are strikingly analogous to the shock syndrome which follows trauma, the injection of indotoxin, or some bacterial infections. Two of the cyclooxygenase products of arachidonic acid, thromboxane A2 and prostacyclin, acting through their opposing effects on vasoactivity and platelet aggregation, are emerging as the major controlling influences of vascular homeostasis. The effects of thromboxane, which constricts blood vessels and aggregates platelets, appear to dominate during traumatic or endotoxic shock. Thus thromboxane is potentially one of the main mediators of endotoxicity, and as such, from our previously published model, is likely to be important in the pathogenesis of the circulatory disturbances seen in acute malaria. This suggestion is consistent with earlier evidence that the autonomic nerve supply and bradykinin may have an important role in the pathogenesis of the haemodynamic changes in this disease. It also implies that pharmacological antagonists of thromboxane may provide useful specific therapy for the main life-threatening aspects of acute falciparum malaria.

Bradykinin↗
PubMed1981

Possible importance of macrophage-derived mediators in acute malaria.

Tumor necrosis factor, lymphocyte-activating factor, and enhanced levels of type I interferon were found in serum samples taken 2 h after mice infected with Plasmodium vinckei subsp. petteri received a small intravenous injection of endotoxin. These three mediators are among those released when mice receive an endotoxin injection 2 weeks after Mycobacterium bovis BCG or Corynebacterium parvum have been administered. There is indirect evidence that this wider range of mediators is also released in P. vinckei subsp. petteri-infected mice given parenteral endotoxin. A recent report that endotoxin is detectable in the plasma of malaria-infected mice and children implies that these mediators may also be released in the acute phase of the natural infection. We propose that these macrophage-derived mediators may be important in the glucocorticoid antagonism, bone marrow depression, fever, hypergammaglobulinemia, splenomegaly, elevation of serum amyloid A, consumptive coagulopathy, and shock syndrome with associated organ damage which can accompany malaria. The intraerythrocytic parasite death seen at crisis in some malarias, as well as the subsequent development of specific protective immunity, may also depend on these mediators.

Animals↗
PubMed1981

Demonstration of a lipopolysaccharide-induced cytostatic effect on malarial parasites.

In an in vitro assay, malarial parasites (Plasmodium vinckei petteri) taken from mice 7 to 8 h after the injection of bacterial lipopolysaccharide (LPS) incorporated significantly less hypoxanthine into nucleic acid than did parasites from saline-treated controls. In contrast, incorporation was normal in parasites taken from mice within minutes of the injection of LPS and in parasites cultured with LPS. These results implied that the injection of LPS induced the release of mediators with a cytostatic effect on the parasite. This suggested an explanation for the protective action of LPS in malarial infections as well as for the "crisis forms" seen both in naturally resolving infections and in animals pretreated with such agents as BCG.

Animals↗
PubMed1980

Effects of endotoxin on the histology of intact and athymic mice infected with Plasmodium vinckei petteri.

Apparently healthy intact and athymic mice with low to moderate parasitaemias of P. vinckei petteri are very susceptible to the harmful effects of Endotoxin (LPS). The histological changes seen in such mice after injection of a small dose of LPS closely resemble those seen in mice terminally infected with this parasite. Thus the onset of pathology could be hastened by giving a little LPS. Both groups of intact mice showed foci of hepatic necrosis, severe necrosis in the thymus, and light to moderate necrosis in the germinal centres of the splenic white pulp and Peyer's patches. In contrast liver necrosis was seen in very few of the terminally ill athymic mice and in none of the athymic mice given LPS. Our results imply that the lesions produced by LPS in the liver and lymphoid organs of apparently healthy mice with low to moderate parasitaemias would have eventually developed, without the help of extrinsic LPS, as the parasitaemia rose further and the infection ran its normal fatal course. This would be consistent with an intrinsic LPS-like activity in these terminally infected mice. One possible contributor to the liver necrosis seen in this infection is a T-dependent mediator reported to block enzyme induction. Any proposal for the mechanism of this damage must explain its rarity in athymic mice, its induction by LPS in intact but not athymic mice, and host differences in parasite density at which it occurs.

Animals↗