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Biomedical subjects

I A Clark

Publications and source records attributed to I A Clark.

At least 55 records · Page 3Linked to original sources
PubMed1990

The inhibition of Plasmodium falciparum growth in vitro by sera from mice infected with malaria or treated with TNF.

Despite some years of enquiry, the mechanism that leads to intra-erythrocytic death of malarial parasites during the host's response to infection has not been elucidated. We report here that serum from mice undergoing a successful immune response to Plasmodium chabaudi does not inhibit Plasmodium falciparum unless the Pl. chabaudi is virulent enough to rise to at least 50% parasitaemia and to cause illness. This appears to be true of the 556 KA and DS strains of Pl. chabaudi, and also other murine malaria parasites. In mice infected with Pl. chabaudi 556 KA inhibitory activity coincided with the presence of TNF in their serum. Exogenous TNF generated inhibitory activity in the serum of mice only if the animals were pretreated with Proprionobacterium acnes, implying a role for activated macrophages downstream from TNF in this process. The difference in inhibitory activity against Pl. falciparum in serum from mice infected with Pl. chabaudi of more or less virulence may be one of degree. Alternatively two distinct mechanisms may operate, the second coming into operation only in ill mice, with higher parasite burdens.

Animals↗
PubMed1989

Reactive oxygen species facilitate the in vitro and in vivo lipopolysaccharide-induced release of tumor necrosis factor.

Secretion of TNF from mouse peritoneal macrophages exposed to LPS in vitro was enhanced in the presence of H2O2 or sodium periodate. Neither of these agents induced release of TNF in the absence of LPS. Both iron chelators and free radical scavengers inhibited this enhanced secretion of TNF, implying the involvement of free radicals via a Fenton-type reaction. Oxidant stress, in the form of alloxan or divicine, also enhanced serum levels of TNF in mice made sensitive to LPS by low-level infection with malaria, and then given i.v. LPS. Pretreatment with the iron chelator, desferal, or the free radical scavenger, BHA, inhibited TNF release in these animals. Less TNF was also detected in mice given desferal before LPS in the absence of exogenous radical generator. These results could have implications for understanding the details of the MLR, the adherence of neutrophils to the walls of pulmonary vessels in free radical-induced lung pathology, and the side effects of bleomycin.

Animals↗
PubMed1989

Tumor necrosis factor inhibits the development of viral meningitis or induces rapid death depending on the severity of inflammation at time of administration.

Administration of human rTNF to both male and female mice with severe, but clinically inapparent, lymphocytic choriomeningitis caused death within 2 to 3 h. The development of fatal symptoms was accompanied by a two- to threefold reduction in the number of cells present in the cerebrospinal fluid, with this effect being more apparent in female mice. Giving the same dose of rTNF earlier in the course of the disease was not fatal and reduced the level of subsequent meningitis. In addition, prior exposure to rTNF protected against the acute development of lethal disease when a second dose of the cytokine was given later. The extent of this "tolerance" to rTNF was directly related to the degree of reduction of the inflammatory process resulting from the primary exposure to the cytokine.

Animals↗
PubMed1989

Immunopathophysiology of babesial infections.

Humans infected with Plasmodium falciparum and bovines infected with Babesia bovis display severe haemolysis, alterations in red cell deformability and rigidity, and endothelial cell damage leading to pulmonary oedema and cerebral dysfunction. Much of the pathology associated with these infections is not easily attributable to the relatively small numbers of parasites present. This paper considers the possible roles of soluble mediators released from macrophages, and chemical and physical changes in the infected red cell membrane, in the pathogenesis of babesial infections, and also discusses the effects of prior immunization with various immunogens.

Animals↗
PubMed1989

Some roles of free radicals in malaria.

Malaria parasites are very vulnerable to oxidant stress during the part of their life cycle when they inhabit erythrocytes. As the infection progresses they also activate macrophages, one consequence of which is extracellular release of reactive oxygen species. For these reasons free radicals are frequently discussed in the literature on antimalarial drugs, malarial immunity, and disease pathogenesis. They are also central to arguments explaining how the genetic mutations that lead to sickle cell disease, thalassemia and glucose-6-phosphate dehydrogenase have become so common in tropical regions. This review summarizes how these links between free radicals and this disease came to be understood, and the present state of the field.

Anemia, Sickle Cell↗
PubMed1989

Antioxidants can prevent cerebral malaria in Plasmodium berghei-infected mice.

A/J and CBA/H mice infected with Plasmodium berghei ANKA, a murine model of cerebral malaria, were used to see whether antioxidants influenced the outcome of this disease. Untreated, infected mice died 7 to 9 days after infection, often with cerebral symptoms. Haemorrhages, mononuclear infiltration and oedema were present in the central nervous system (CNS). Feeding a diet containing 0.75% (w/w) butylated hydroxyanisole (BHA) greatly altered the course of this disease. Death was delayed by up to 2 weeks and mice appeared healthy at parasitaemias that would have caused cerebral symptoms and death had they been on a conventional diet. BHA-fed mice showed few or no cerebral symptoms at a time at which control mice were clearly affected, and greatly reduced haemorrhages, mononuclear infiltration and oedema when the CNS was examined. Similar, but more consistent, protective effects were seen after administration of BHA by repeated injections or in osmotic pumps. The combination of superoxide dismutase and catalase, coupled to polyethylene glycol, when administered intravenously also protected mice against death from cerebral complications. Permeability of the blood-brain barrier was monitored by the use of 125I-labelled bovine serum albumin, 51Cr-labelled erythrocytes and the dye Evans blue, all of which are normally excluded from the CNS. Infected mice on control diet showed an increase in Evans blue staining and 125I and 51Cr retention in the CNS tissue itself. Feeding the diet containing BHA reduced these indices of increased blood-brain barrier permeability. In view of the potent radical scavenging activity of BHA in many other systems it is likely, but unproven, that this is its main role here. The protective effect of superoxide dismutase and catalase lends support to the idea that reactive oxygen species are involved in the pathology of experimental cerebral malaria.

Animals↗
PubMed1988

Detection of short-chain carbonyl products of lipid peroxidation from malaria-parasite (Plasmodium vinckei)-infected red blood cells exposed to oxidative stress.

Reversed-phase h.p.l.c. was used to detect 2,4-dinitrophenylhydrazine-reactive carbonyl products, which excludes malonaldehyde, in malaria-parasite (Plasmodium vinckei)-infected murine red blood cells (RBCs). A number of alkanals, 4-hydroxyalk-2-enals and alka-2,4-dienals were tentatively identified by comparison with authentic standards. The formation of 4-hydroxynon-2-enal, deca-2,4-dienal and hexanal was greater in P. vinckei-infected RBCs than in their uninfected counterparts and was increased by the presence of t-butyl hydroperoxide. Several of these aldehydes have previously been shown to be toxic to various types of cells, including P. falciparum, in vitro. The iron chelator desferrioxamine and the free-radical scavenger butylated hydroxyanisole inhibited the formation of these aldehydes. These experiments demonstrate that products of lipid peroxidation other than malonaldehyde are formed during the exposure of malaria-infected RBCs in vitro to drugs that generate reactive oxygen species and have anti-parasitic activity. The formation of products of this type during the natural course of malaria infection may have implications for the mechanisms underlying intra-RBC parasite death and the tissue damage associated with the disease.

Aldehydes↗
PubMed1988

Antioxidants inhibit proliferation and cell surface expression of receptors for interleukin-2 and transferrin in T lymphocytes stimulated with phorbol myristate acetate and ionomycin.

We have previously shown that several antioxidant compounds inhibit the proliferation of T lymphocytes stimulated with alloantigen (Chaudhri, G., Clark, I. A., Hunt, N. H., Cowden, W. B., and Ceredig, R., J. Immunol. 136, 2646, 1986). We concluded from these studies that free oxygen radicals are positive mediators in T-lymphocyte activation and proliferation. In order to extend these studies we examined the effects of antioxidants on T cells stimulated with a combination of phorbol myristate acetate (PMA) and ionomycin. The following antioxidants were used: ferricyanide, an inhibitor of superoxide production; iron chelators, which block hydroxyl radical formation; and butylated hydroxyanisole, a free radical scavenger. Responder cells included purified peripheral T cells (Lyt-2+ or L3T4+ cells) and immature (Lyt-2-/L3T4-) thymocytes. All agents, in the micromolar range, caused a dose-dependent inhibition of proliferation of each T-cell subset studied. Flow microfluorometric analysis of T cells stimulated for 48 hr showed that the expression of interleukin-2 (IL-2) receptors and transferrin receptors was inhibited by all the antioxidants tested but not by hydroxyurea (HU), an inhibitor of the enzyme ribonucleotide reductase. In contrast, the expression of a third activation marker, phagocytic glycoprotein-1 (Pgp-1 or Lyt-24), was not affected by any of the agents. Furthermore, while both the antioxidants and HU inhibited T-cell cycling, analysis of a light-scattering parameter related to cell size indicated that the antioxidant-treated cells remained small while the HU-treated and control cells were larger and blast-like. Therefore, the mechanism of action of the three classes of antioxidants is similar, but quite distinct from the inhibition of proliferation caused by HU. Taken together, these results suggest that free radicals are involved in specific early events in T-cell activation.

Animals↗
PubMed1988

Immunopathophysiology of Babesia bovis and Plasmodium falciparum infections.

Babesia bovis and Plasmodium falciparum are both vector-borne parasites primarily infecting the erythrocytes of their respective hosts. They have obvious differences, yet the diseases caused by these parasites share many common features. Both have generated a considerable body of research but, perhaps because of the classical distinction between veterinary and medical parasitology, many of the similarities between the two have been neglected. As this review shows however, many of the pathophysiological changes in B. bovis infections are poorly described for P. falciparum - and vice versa. Examples are the roles of lipid peroxidation, neutrophil adhesion and production of tumour necrosis factor (TNF) in malaria, which have been largely unstudied in babesiosis, or conversely the roles of fibronectin, immune complexes, cryofibrinogen and the complement cascade in babesiosis, which have been little studied (partly for ethical reasons) in human malaria. To clarify such questions, it may be that each of these diseases may serve as a partial model for the other.

Journal Article↗
PubMed1988

Breakdown of the blood-brain barrier in murine cerebral malaria.

Cerebral malaria in A/J and CBA/H mice infected with Plasmodium berghei ANKA is accompanied by mononuclear cell infiltration, haemorrhage and cerebral endothelial cell damage. This damage is presumably one of the causes of the breakdown of the blood-brain barrier which was detected by measuring the movement of the dye Evans blue and radioisotope labelled albumin and erythrocytes. The density of brain tissue, measured by a Percoll gradient technique, was significantly reduced in mice exhibiting cerebral symptoms, suggesting the occurrence of cerebral oedema.

Animals↗
PubMed1988

Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis.

Among the unexplained changes caused by malaria in several host species, including man and mouse, are erythrophagocytosis and dyserythropoiesis. In order to see whether tumour necrosis factor (TNF) could contribute to these changes we injected recombinant human TNF intravenously into mice made very susceptible to this monokine by low density infection with a mouse malaria (Plasmodium vinckei) or prior injection of an extract of Coxiella burneti. Appreciable erythrophagocytosis, involving nucleated erythroblasts as well as mature red cells, was observed in bone marrow preparations from TNF-treated mice and those with severe illness due to P. vinckei, but in no other group. Dyserythropoiesis, involving irregularly-shaped nuclei and karyorrhexis, had the same distribution. TNF at concentrations up to 8 ng/ml was detected in the serum of all mice with severe malaria, but not uninfected animals or those with light infections. These findings are consistent with TNF making an important contribution to erythrophagocytosis and dyserythropoiesis, and thus to anaemia, in malaria and other conditions.

Anemia↗
PubMed1988

Tumor necrosis factor in malaria-induced abortion.

The cause of fetal loss in malaria is not known. We report that a small (1.5-5.0 micrograms) intravenous dose of recombinant human tumor necrosis factor (TNF) caused fetal death and abortion in 16 day pregnant mice that were carrying low densities of Plasmodium vinckei. In contrast, 50 micrograms human TNF did not cause fetal death or abortion in uninfected 16 day pregnant mice. Endogenous TNF, which was not detectable in plasma of low parasitemia animals, pregnant or not, was present (1.6 +/- 0.9 ng/ml) in samples from malarial pregnant mice when, on day 17, parasitemia was high and the first signs of impending abortion were evident. No TNF was detectable in the plasma of uninfected mice at day 17 of pregnancy. A small dose of TNF also caused fetal death in 16 day pregnant mice that had received an intravenous injection of Coxiella burneti extract 9-10 days earlier. Thus, TNF-induced abortion may occur in a range of infections in which systemic macrophage activation occurs and a trigger for TNF release is present.

Abortion, Spontaneous↗
PubMed1988

Proliferation in vitro of Lyt2-,L3T4- thymocytes shows responsiveness to interleukin 1.

The responsiveness of adult mouse thymocytes to interleukin 1 (IL-1) was investigated. When stimulated with suboptimal concentrations of ionomycin and phorbol myristate acetate (PMA), the immature subpopulation of Lyt2-,L3T4- (2-4-) thymocytes responded to exogenous, purified IL-1 in a dose-dependent manner. In contrast, mature lymph node (LN) T cells were unresponsive to exogenous IL-1 under similar conditions. The proliferation of 2-4- thymocytes, which comprise 2-3% of cells in the adult mouse thymus, was independent of exogenous IL-2 and accounted for essentially all the 3H-thymidine incorporation by unfractionated thymocytes in response to IL-1. Optimally stimulated 2-4- cells did not show responsiveness to exogenous IL-1, and 48 h supernatants from these cultures were found to contain IL-1 like activity. Taken together, the data point to a role for IL-1 in the proliferation of immature 2-4- cells in the thymus.

Animals↗
PubMed1987

Inhibition of murine malaria (Plasmodium chabaudi) in vivo by recombinant interferon-gamma or tumor necrosis factor, and its enhancement by butylated hydroxyanisole.

Cell-mediated immunity to malaria may involve macrophages, the monokines that mediate endotoxicity, and reactive oxygen species. Since interferon-gamma activates macrophages to release reactive oxygen species, and tumor necrosis factor-alpha (TNF-alpha) helps both to mediate endotoxicity and to induce leukocytes to secrete reactive oxygen, we monitored the effects of administering recombinant forms of these cytokines on Plasmodium chabaudi adami infections in mice. We also fed infected mice a diet containing 0.75% butylated hydroxyanisole, a scavenger of free radicals. Infections were suppressed by daily i.p. injections of 5 x 10(4) U of recombinant mouse interferon-gamma from day -1 or by recombinant human TNF released from i.p. osmotic pumps at the rate of 6 x 10(3) U/hr. Degenerate intraerythrocytic parasites (crisis forms) were evident much sooner in the course of the suppressed infections, and parasitemias fell correspondingly earlier. The butylated hydroxyanisole diet, in contrast, enhanced the infections. In these mice crisis forms were seen later, and at higher parasitemias, than they normally occur. These observations are consistent with the concept that T cell-dependent, macrophage-derived mediators are central to the type of malarial immunity that kills parasites inside circulating red cells. They also suggest, but do not prove, that both TNF and reactive oxygen species are involved, and that the role of TNF may be more indirect, although no less important, than that of reactive forms of oxygen.

Administration, Oral↗
PubMed1987

Toxicity of certain products of lipid peroxidation to the human malaria parasite Plasmodium falciparum.

Aldehydes generated during radical-induced lipid peroxidation, in particular 4-hydroxynonenal, are known to inhibit growth of certain cells. To extend our arguments that free radicals might be involved in the host response against malaria parasites we tested 26 carbonyls (n-alkanals, C6-C11; 2-alkenals, C3-C9; 2,4-alkadienals, C7, C9, C10; 4-OH-2-alkenals, C6, C8, C9; 2-alkanones, C3-C9; and malonyldialdehyde) against Plasmodium falciparum in vitro. We had previously detected many of these substances in oxidant-stressed, malaria-infected erythrocytes. Three 2,4-alkadienals (C7, C9 and C10) and three 4-OH-2-alkenals (C6, C8 and C9), at 20-100 microM concentrations, markedly inhibited incorporation of [3H]-hypoxanthine by P. falciparum. Acrolein had low effect, and none of the other compounds (12 aldehydes and 7 ketones) were active at concentrations up to 100 microM. Malonyldialdehyde was without effect at concentrations up to 450 microM. The aldehydes found to be inhibitory against P. falciparum could contribute to both the non-antibody host responses against this parasite and the antimalarial effects of radical-generating compounds such as t-butyl hydroperoxide, hydrogen peroxide, alloxan, isouramil, divicine and primaquine.

Animals↗