Nitric Oxide Donors with Therapeutic Strategic in Experimental Schistossomiasis Mansoni (original) (raw)
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The Hepatoprotective Effect of Nitric Oxide on Murine Schistosomiasis Mansoni
2014
MANSOURA MEDICAL JOURNAL ABSTRACT Background: Schistosomiasis is a major public health problem in developing countries. Currently, praziquantel (PZQ) is the drug of choice for human schistosomiasis. Isosorbide-5-mononitrate (IS-5-MN) is a nitro compound that is used as an antianginal remedy. It must be enzymatically metabolized to release nitric oxide (NO) to exert its pharmacologic activities. This study evaluates the vasodilator effect of the NO donor IS-5-MN on hepatic bilharzial lesions caused by Schistosoma mansoni, and determines whether the combined use of IS-5-MN and PZQ is synergistic or antagonistic. Methods: Swiss albino female mice (CD I strain) were divided into five groups: (i) non-infected; (ii) infected non-treated; (iii) infected and treated with PZQ, 6 weeks post infection (WPI) in a dose of 500 mg/ kg/day for two successive days; (iv) infected and treated with IS-5-MN from the fourth to the tength WPI 5 days/week in a dose of 10.08 mg/kg; (v) infected and treated ...
Nitric Oxide-biology and Chemistry, 1998
Over the past decade, nitric oxide has been intensely studied due to its relevance as a widespread intra- and intercellular messenger and as a cytotoxin released during several physiopathological events, including immunological reactions and inflammation. In the present paper, we investigate the effect of inhibition of NO synthesis, using an analogue ofl-arginine,Nω-nitro-l-arginine methyl ester (L-NAME), onin vitrogranulomatous formation of human peripheral blood mononuclear cells (PBMC) fromSchistosoma mansoni-infected individuals. The results demonstrated that human PBMC are capable ofin vitroNO production and that inhibition of its production through the addition of L-NAME is responsible for exacerbating granulomatous reaction. This L-NAME-induced granuloma enhancement (ranging from 30 to 65%) was measured using the granuloma index. Furthermore, we observed a general time-dependent increase in NO production during the period of cell culture (21 days) and an inverse relationship between nitrite detection and granuloma reactivity. Collectively, our results point to a possible regulatory role of NO on the development of granulomatous inflammation.
Infection and Immunity, 2002
Schistosoma mansoni-infected wild-type (WT) mice develop a Th2 response and chronic disease. In contrast, infected interleukin-4 double-deficient (IL-4 ؊/؊ ) mice develop a Th1-like response and an acute, lethal syndrome. Disease severity in these animals correlates with excessive and prolonged production of nitric oxide (NO) associated with enhanced antigen-driven gamma interferon (IFN-␥) production in the absence of IL-4. Strikingly, splenic lymphocytes from infected IL-4 ؊/؊ mice failed to proliferate as well as those from infected WT mice following stimulation in vitro with antigen or anti-CD3 antibody. Contrary to antigen-driven IFN-␥ responses, anti-CD3 antibody stimulation of splenocytes resulted in significantly less IFN-␥ being produced by CD8 cells from infected IL-4 ؊/؊ mice than by those from infected WT mice or normal mice. NO is largely responsible for the impaired T-cell functions in infected IL-4 ؊/؊ mice, as inhibition of iNOS significantly enhanced proliferation and IFN-␥ production.
Nitric Oxide, 1999
Nitric oxide (NO) has been implicated, both and paradoxically, as a pro-and anti-inflammatory agent in a wide range of circumstances. It is of common concern that NO can be either up-or downregulated by different inflammatory cytokines. Attempting to assess the contribution of NO to the granulomatous response, we used the in vitro granuloma (IVG) model which consists on a reaction of mononuclear cells around polyacrylamide beads conjugated to antigens. Our assays employed Schistosoma mansoni antigens and human peripheral blood mononuclear cells (PBMC) from schistosomiasis patients. Recently, we have described evidence for a regulatory role of NO, with the aid of an inhibitor of NO synthesis, L-NAME. The addition of L-NAME to IVG cultures elicited an increase on the granuloma formation index. Based on these data we decided to investigate the mechanisms involved in the effects of L-NAME-enhanced granuloma formation. Cytokines and chemokines are involved in inflammatory responses by, particularly the latter, inducing migration and adhesion of leukocytes, which led us on this search for their interactions with NO on granulomatous reaction. We evaluated the cytokine/chemokine-secreting profile of PBMC (treated and not treated with L-NAME) on the IVG reaction in order to investigate how NO could interfere on the release of these soluble mediators. Comparison of cell culture releasing amounts of IL-2, IL-10, TNF␣, IFN␥, MIP-1␣, MCP-1, and RANTES demonstrated that MIP-1␣ had increased levels when NO production was blocked with L-NAME, whereas IL-10 secretion decreased in presence of L-NAME. The other tested cytokines (IL-2, TNF␣, and IFN␥) and chemokines (MCP-1 and RANTES) showed no significant differences between the presence or absence of L-NAME. Results obtained in this work suggest that inhibition of NO production could upregulate the IVG reaction on human schistosomiasis through changes in the cytokine/chemokine profile released by PBMC. The mechanisms involved may lead to a MIP-1␣increased and IL-10-decreased secretion under our experimental conditions, which could partly account for the previously ascribed IVG-exacerbating action of NO inhibition.
Memórias do Instituto …, 1998
Nitric oxide (NO) is an important effector molecule involved in immune regulation and defense. NO produced by cytokine-activated macrophages was reported to be cytotoxic against the helminth Schistosoma mansoni. Identification and characterization of S. mansoni antigens that can provide protective immunity is crucial for understanding the complex immunoregulatory events that modulate the immune response in schistosomiasis. It is, then, essential to have available defined, purified parasite antigens. Previous work by our laboratory identified a fraction of S. mansoni soluble adult worm antigenic preparation (SWAP), named PIII, able to elicit significant in vitro cell proliferation and at the same time lower in vitro and in vivo granuloma formation when compared either to SEA (soluble egg antigen) or to SWAP. In the present work we report the effect of different in vivo trials with mice on their spleen cells ability to produce NO. We demonstrate that PIII-immunization is able to significantly increase NO production by spleen cells after in vitro stimulation with LPS. These data suggest a possible role for NO on the protective immunity induced by PIII.
Human Immunology, 1999
Identification and characterization of Schistosoma mansoni antigens that can provide protective immunity, as well as an investigation of their role in host-parasite interaction, is crucial for understanding the complex immunoregulatory events that modulate granuloma formation in schistosomiasis. Previous work by our laboratory identified a fraction of S. mansoni soluble adult worm antigenic preparation (SWAP), named PIII, obtained by anionic chromatography on fast protein liquid chromatography (FPLC). This fraction was able to elicit significant in vitro cell proliferation and at the same time lower in vitro and in vivo granuloma formation when compared either to SWAP or to soluble egg antigens (SEA). In the present work, we investigate some biological activities of PIII, such as the stimulation of nitric oxide (NO) and cytokine production. Our data demonstrated that SEA, SWAP and specially PIII were able to induce a time-dependent increased NO production during in vitro granuloma reaction. Besides that, PIII evoked increased IL-10 production, but not IL-2 or IFNγ. Collectively, our results indicate the possibility that the modulation role of PIII on in vitro granuloma might be mediated in part by its ability to induce the higher production, initially of IL-10, and lately of NO.
Proceedings of the National Academy of Sciences, 1994
Like many pathogens that undergo an intravascular stage of development, larvae of the helminth parasite Schistosoma mansoni migrate through the blood vessels, where they are in close contact with endothelial cells. In vito exposure of murine endothelial cells to various cytokines (interferon y, tumor necrosis factor a, and interleukin la or 113) resulted in their activation to kill schistosomula through an argininedependent mechanism involving production of nitric oxide (NO). Cytokine-treated endothelial cells showed increased expression of mRNA for the inducible form of the NO synthase, and both NO production and larval killing were suppressed by treatment with competitive inhibitors. The effector function of cytokine-treated endothelial cells was similar to that of activated inflammatory tissue macrophages, although activation appeared to be differentially regulated in these two cell types. Activated endothelial cells killed older (18-day) forms of the parasite, such as those currently thought to be a primary target of immune elimination in the lungs of mice previously vaccinated with radiation-attenuated cercariae, as well as newly transformed larvae. In C57BL/6 mice, which become resistant
Nitric oxide-dependent changes in Schistosoma mansoni gene expression
Molecular and Biochemical Parasitology, 2006
Nitric oxide (NO)-related pathways potentially play at least two critical roles in schistosomes, the causative agents of schistosomiasis. First, these pathways may represent essential signaling cascades required for normal parasite physiology and survival. Second, NO-related pathways may also play an important role in parasite-host interactions. Several reports have demonstrated that platyhelminths have nitric oxide synthase (NOS) activity and that NO is likely acting as a signaling molecule in these organisms [1-4]. Furthermore, the host NO pathway may be involved in host defense against schistosome infection, though its precise role in vivo is not clear [5-7]. Here we examine changes in parasite gene expression in response to exposure to exogenous NO in vitro. Prior studies have provided evidence of NO-related pathways in adult schistosomes [1,2,8]. However, the physiological role and downstream targets of NO have not been elucidated in adult worms. To assay NO-dependent changes in gene expression, we have used Long-SAGE (serial analysis of gene expression) [9], which provides both the identity of expressed genes and the relative levels of their expression. In Long-SAGE, a short 21 bp sequence tag from the most polyA proximal NlaIII restriction site of an mRNA molecule is used to uniquely identify the source gene from within the genome. Short sequence tags are sampled from all NlaIII-positive transcripts in a mRNA sample and are linked together to form long concatenated molecules that are cloned and sequenced. Quantification of all tags provides a relative measure of gene expression (i.e., mRNA abundance). Using SAGE, we have identified genes which respond to NO by changing expression levels, and we also show by RT-PCR that RNA encoding extracellular superoxide dismutase (EC-SOD, also referred to as signal peptide-SOD [10-11]) is upregulated in response to exposure to an NO donor. These results provide insights into NO
Brazilian Journal of Medical and Biological Research, 1999
Nitric oxide (NO) is an extremely important and versatile messenger in biological systems. It has been identified as a cytotoxic factor in the immune system, presenting anti-or pro-inflammatory properties under different circumstances. In murine monocytes and macrophages, stimuli by cytokines or lipopolysaccharide (LPS) are necessary for inducing the immunologic isoform of the enzyme responsible for the high-output production of NO, nitric oxide synthase (iNOS). With respect to human cells, however, LPS seems not to stimulate NO production in the same way. Addressing this issue, we demonstrate here that peripheral blood mononuclear cells (PBMC) obtained from schistosomiasis-infected patients and cultivated with parasite antigens in the in vitro granuloma (IVG) reaction produced more nitrite in the absence of LPS. Thus, LPS-induced nitrite levels are easily detectable, although lower than those detected only with antigenic stimulation. Concomitant addition of LPS and L-N-arginine methyl ester (L-NAME) restored the ability to produce detectable levels of nitrite, which had been lost with L-NAME treatment. In addition, LPS caused a mild decrease of the IVG reaction and its association with L-NAME was responsible for reversal of the L-NAME-exacerbating effect on the IVG reaction. These results show that LPS alone is not as good an NO inducer in human cells as it is in rodent cells or cell lines. Moreover, they provide evidence for interactions between LPS and NO inhibitors that require further investigation. Correspondence A.M. Goes
Nitric oxide blocks the development of the human parasiteSchistosoma japonicum
Proceedings of the National Academy of Sciences
Human schistosomiasis, caused bySchistosomaspecies, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant toSchistosoma japonicuminfection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS−/−) Sprague–Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development inS. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by...