RESUMO
INTRODUCTION: The role of suppressor of cytokine signaling 2 (SOCS2) in Aggregatibacter actinomycetemcomitans (Aa)-induced alveolar bone loss is unknown; thus, it was investigated in this study. METHODS: Alveolar bone loss was induced by infecting C57BL/6 wild-type (WT) and Socs2-knockout (Socs2-/-) mice with Aa. Bone parameters, bone loss, bone cell counts, the expression of bone remodeling markers, and cytokine profile were evaluated by microtomography, histology, qPCR, and/or ELISA. Bone marrow cells (BMC) from WT and Socs2-/- mice were differentiated in osteoblasts or osteoclasts for analysis of the expression of specific markers. RESULTS: Socs2-/- mice intrinsically exhibited irregular phenotypes in the maxillary bone and an increased number of osteoclasts. Upon Aa infection, SOCS2 deficiency resulted in the increased alveolar bone loss, despite decreased proinflammatory cytokine production, in comparison to the WT mice. In vitro, SOCS2 deficiency resulted in the increased osteoclasts formation, decreased expression of bone remodeling markers, and proinflammatory cytokines after Aa-LPS stimulus. CONCLUSIONS: Collectively, data suggest that SOCS2 is a regulator of Aa-induced alveolar bone loss by controlling the differentiation and activity of bone cells, and proinflammatory cytokines availability in the periodontal microenvironment and an important target for new therapeutic strategies. Thus, it can be helpful in preventing alveolar bone loss in periodontal inflammatory conditions.
Assuntos
Perda do Osso Alveolar , Doenças Periodontais , Camundongos , Animais , Perda do Osso Alveolar/genética , Aggregatibacter actinomycetemcomitans/metabolismo , Camundongos Endogâmicos C57BL , Doenças Periodontais/metabolismo , Osteoclastos/metabolismo , Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Plasmodium berghei ANKA (PbA) infection in mice resembles several aspects of severe malaria in humans, such as cerebral malaria and acute respiratory distress syndrome. Herein, the effects of N-(coumarin-3-yl)cinnamamide (M220) against severe experimental malaria have been investigated. Treatment with M220 proved to protect cognitive abilities and lung function in PbA-infected mice, observed by an object recognition test and spirometry, respectively. In addition, treated mice demonstrated decreased levels of brain and lung inflammation. The production and accumulation of microglia, and immune cells that produce the inflammatory cytokines TNF and IFN-γ, decreased, while the production of the anti-inflammatory cytokine IL-10 by innate and adaptive immune cells was enhanced. Treatment with M220 promotes immunomodulatory, neuroprotective, and lung function-preserving effects during experimental severe malaria. Therefore, it may be an interesting therapeutic candidate to treat severe malaria effects.
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Rheumatoid arthritis(RA) is a debilitating chronic inflammatory disease. Suppressors of Cytokine Signaling(SOCS) proteins regulate homeostasis and pathogenesis in several diseases. The intersection between RA pathophysiology and SOCS2 is unclear. Herein, we investigated the roles of SOCS2 during the development of an experimental antigen-induced arthritis(AIA). In wild type mice, joint SOCS2 expression was reduced during AIA development. At the peak of inflammation, SOCS2-/- mice presented with reduced numbers of infiltrated cells in their joints. At the late phase of AIA, however, exhibited increased adhesion/infiltration of neutrophils, macrophages, CD4+-T cells, CD4+CD8+-T cells, and CD4-CD8--T cells associated with elevated IL-17 and IFN-γ levels, joint damage, proteoglycan loss, and nociception. SOCS2 deficiency resulted in lower numbers of apoptotic neutrophils and reduced efferocytosis. The present study demonstrated the vital role of SOCS2 during the development and resolution of an experimental RA model. Hence, this protein may be a novel therapeutic target for this disorder.
Assuntos
Artrite Experimental/etiologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Imunidade Adaptativa , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Adesão Celular , Progressão da Doença , Endocitose/imunologia , Imunidade Inata , Leucócitos/imunologia , Leucócitos/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/imunologia , Baço/patologia , Proteínas Supressoras da Sinalização de Citocina/deficiência , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.
Assuntos
Angiotensina I , Macrófagos , Monócitos , Fragmentos de Peptídeos , Fagocitose , Proto-Oncogene Mas/metabolismo , Angiotensina I/metabolismo , Angiotensina I/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Peritonite , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Fenótipo , Receptores CCR2/metabolismoRESUMO
Chagas disease has a complex pathogenesis wherein the host immune response is essential for controlling its development. Suppressor of cytokine signaling(SOCS)2 is a crucial protein that regulates cytokine production. In this study, SOCS2 deficiency resulted in an initial imbalance of IL12- and IL-10-producing neutrophils and dendritic cells (DCs), which caused a long-lasting impact reducing inflammatory neutrophils and DCs, and tolerogenic DCs at the peak of acute disease. A reduced number of inflammatory and pro-resolving macrophages, and IL17A-producing CD4+ T cells, and increased lymphocyte apoptosis was found in SOCS2-deficient mice. Electrocardiogram analysis of chimeric mice showed that WT mice that received SOCS2 KO bone marrow transplantation presented increased heart dysfunction. Taken together, the results demonstrated that SOCS2 is a crucial regulator of the immune response during Trypanosoma cruzi infection, and suggest that a SOCS2 genetic polymorphism, or failure of its expression, may increase the susceptibility of cardiomyopathy development in Chagasic patients.
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Cardiomiopatias/etiologia , Doença de Chagas/imunologia , Células Dendríticas/imunologia , Neutrófilos/imunologia , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Animais , Transplante de Medula Óssea , Doença de Chagas/complicações , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Proteínas Supressoras da Sinalização de Citocina/genética , Células Th17/imunologiaRESUMO
Chagas disease is an important disease of the heart. Lipoxins have important regulatory functions in host immune response (IR). Herein, we examined whether the receptor for lipoxin A4, the formyl peptide receptor (FPR) 2, had an effect on Trypanosoma cruzi infection. In vitro, FPR2 deficiency or inhibition improved the activity of macrophages against T. cruzi. In vivo, during the acute phase, the absence of FPR2 reduced parasitemia and increased type 2 macrophages, type 2 neutrophils, and IL-10-producing dendritic cells. Moreover, the acquired IR was characterized by greater proportions of Th1/Th2/Treg, and IFNγ-producing CD8+T cells, and reductions in Th17 and IL-17-producing CD8+T cells. However, during the chronic phase, FPR2 deficient mice presented and increased inflammatory profile regarding innate and acquired IR cells (Th1/IFN-γ-producing CD8+T cells). Notably, FPR2 deficiency resulted in increased myocarditis and impaired heart function. Collectively, our data suggested that FPR2 is important for the orchestration of IR and prevention of severe T. cruzi-induced disease.
Assuntos
Cardiomiopatia Chagásica/imunologia , Miocardite/imunologia , Receptores de Formil Peptídeo/imunologia , Animais , Cardiomiopatia Chagásica/complicações , Modelos Animais de Doenças , Feminino , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologiaRESUMO
The emergence of life-threatening zoonotic diseases caused by betacoronaviruses, including the ongoing coronavirus disease 19 (COVID-19) pandemic, has highlighted the need for developing preclinical models mirroring respiratory and systemic pathophysiological manifestations seen in infected humans. Here, we showed that C57BL/6J wild-type mice intranasally inoculated with the murine betacoronavirus murine hepatitis coronavirus 3 (MHV-3) develop a robust inflammatory response leading to acute lung injuries, including alveolar edema, hemorrhage, and fibrin thrombi. Although such histopathological changes seemed to resolve as the infection advanced, they efficiently impaired respiratory function, as the infected mice displayed restricted lung distention and increased respiratory frequency and ventilation. Following respiratory manifestation, the MHV-3 infection became systemic, and a high virus burden could be detected in multiple organs along with morphological changes. The systemic manifestation of MHV-3 infection was also marked by a sharp drop in the number of circulating platelets and lymphocytes, besides the augmented concentration of the proinflammatory cytokines interleukin 1 beta (IL-1ß), IL-6, IL-12, gamma interferon (IFN-γ), and tumor necrosis factor (TNF), thereby mirroring some clinical features observed in moderate and severe cases of COVID-19. Importantly, both respiratory and systemic changes triggered by MHV-3 infection were greatly prevented by blocking TNF signaling, either via genetic or pharmacologic approaches. In line with this, TNF blockage also diminished the infection-mediated release of proinflammatory cytokines and virus replication of human epithelial lung cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, results show that MHV-3 respiratory infection leads to a large range of clinical manifestations in mice and may constitute an attractive, lower-cost, biosafety level 2 (BSL2) in vivo platform for evaluating the respiratory and multiorgan involvement of betacoronavirus infections. IMPORTANCE Mouse models have long been used as valuable in vivo platforms to investigate the pathogenesis of viral infections and effective countermeasures. The natural resistance of mice to the novel betacoronavirus SARS-CoV-2, the causative agent of COVID-19, has launched a race toward the characterization of SARS-CoV-2 infection in other animals (e.g., hamsters, cats, ferrets, bats, and monkeys), as well as adaptation of the mouse model, by modifying either the host or the virus. In the present study, we utilized a natural pathogen of mice, MHV, as a prototype to model betacoronavirus-induced acute lung injure and multiorgan involvement under biosafety level 2 conditions. We showed that C57BL/6J mice intranasally inoculated with MHV-3 develops severe disease, which includes acute lung damage and respiratory distress that precede systemic inflammation and death. Accordingly, the proposed animal model may provide a useful tool for studies regarding betacoronavirus respiratory infection and related diseases.
Assuntos
Infecções por Coronavirus/patologia , Modelos Animais de Doenças , Pulmão/patologia , Vírus da Hepatite Murina/patogenicidade , Animais , Linhagem Celular , Contenção de Riscos Biológicos , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Inflamação , Fígado/patologia , Fígado/virologia , Pulmão/virologia , Camundongos , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/fisiologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Mice are widely used to assess the pathogenesis of diseases. An experimental model of gout consists of the injection of uric acid crystals into joints of mice, which reproduce inflammation and functional changes of the human disease. Uric acid crystals activate synoviocytes culminating in the release of IL-1ß and neutrophil recruitment, key inflammatory elements in gouty arthritis. Since MIF plays an important role in orchestrating gout inflammation, we detail valuable procedures to investigate uric acid crystal-induced joint inflammation in mice and give options for further understanding the functions of MIF in gouty arthritis in vivo and in vitro.
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Suscetibilidade a Doenças , Gota/etiologia , Gota/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Gota/patologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Sinoviócitos/metabolismoRESUMO
INTRODUCTION: Obesity is usually triggered by a nutrient overload that favors adipocyte hypertrophy and increases the number of pro-inflammatory cells and mediators into adipose tissue. These mediators may be regulated by suppressors of cytokine signaling (SOCS), such as SOCS2, which is involved in the regulation of the inflammatory response of many diseases, but its role in obesity is not yet known. We aimed to investigate the role of SOCS2 in metabolic and inflammatory dysfunction induced by a high-refined carbohydrate-containing diet (HC). MATERIAL AND METHODS: Male C57BL/6 wild type (WT) and SOCS2 deficient (SOCS2-/-) mice were fed chow or an HC diet for 8 weeks. RESULTS: In general, SOCS2 deficient mice, independent of the diet, showed higher adipose tissue mass compared with their WT counterparts that were associated with decreased lipogenesis rate in adipose tissue, lipolysis in adipocyte culture and energy expenditure. An anti-inflammatory profile was observed in adipose tissue of SOCS2-/- by reduced secretion of cytokines, such as TNF and IL-6, and increased M2-like macrophages and regulatory T cells compared with WT mice. Also, SOCS2 deficiency reduced the differentiation/expansion of pro-inflammatory cells in the spleen but increased Th2 and Treg cells compared with their WT counterparts. CONCLUSION: The SOCS2 protein is an important modulator of obesity that regulates the metabolic pathways related to adipocyte size. Additionally, SOCS2 is an inflammatory regulator that appears to be essential for controlling the release of cytokines and the differentiation/recruitment of cells into adipose tissue during the development of obesity.
Assuntos
Tecido Adiposo/metabolismo , Inflamação , Obesidade/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Glicemia/metabolismo , Citocinas/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Lipogênese , Lipólise , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Consumo de Oxigênio , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T Reguladores/citologia , Células Th2/citologiaRESUMO
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used animal model for the study of MS. The Suppressor of Cytokine Signaling (SOCS) 2 protein plays a critical role in regulating the immune responses. The role of SOCS2 during EAE has not been explored. EAE was induced in WT and SOCS2-/- mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Brain and spinal cord were examined during the peak (day 14) and recovery phase (day 28) of the disease. SOCS2 was upregulated in the brain of WT mice at the peak and recovery phase of EAE. The development of the acute phase was slower in onset in SOCS2-/- mice and was associated with reduced number of Th1 (CD3+CD4+IFN-γ +) cells in the spinal cord and brain. However, while in WT mice, maximal clinical EAE score was followed by a progressive recovery; the SOCS2-/- mice were unable to recover from locomotor impairment that occurred during the acute phase. There was a prolonged inflammatory response (increased Th1 and decreased Th2 and T regulatory cells) in the late phase of EAE in the CNS of SOCS2-/- mice. Transplantation of bone marrow cells from SOCS2-/- into irradiated WT mice resulted in higher lethality at the early phase of EAE. Altogether, these results suggest that SOCS2 plays a dual role in the immune response during EAE. It is necessary for damage during the acute phase damage but plays a beneficial role in the recovery stage of the disease.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Western Blotting , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Citometria de Fluxo , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Supressoras da Sinalização de Citocina/genética , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismoRESUMO
Acetaminophen (APAP) is usually safe when administrated in therapeutic doses; however, APAP overdose can lead to severe liver injury. APAP can cause direct hepatocyte damage, and stimulates an inflammatory response leading to oxidative stress. Supressor of Cytokine Signaling (SOCS) 2 modulates cytokine and growth factor signaling, and plays a role in the regulation of hepatic cellular processes. Our study evaluated the role of SOCS2 in APAP liver injury. The administration of a toxic dose (600 mg/kg) of APAP caused significant liver necrosis in WT mice. In SOCS2-/- mice, there was significantly more necrosis, neutrophil recruitment, and expression of the neutrophil-active chemokine CXCL-1. Expression of proinflammatory cytokines, such as TNF-α and IL-6, was elevated, while expression of anti-inflammatory cytokines, IL-10 and TGF-ß, was diminished. In vitro, SOCS2-/- hepatocytes expressed more p-NF-kB and produced more ROS than WT hepatocytes when exposed to APAP. SOCS2-/- hepatocytes were more sensitive to cell death in the presence of IL-6 and hydrogen peroxide. The administration of catalase in vitro and in vivo resulted in a pronounced reduction of cells/mice death and necrosis in the SOCS2-/- group. We have demonstrated that SOCS2 has a protective role in the liver by controlling pro-oxidative and inflammatory mechanisms induced by APAP.
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Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Imunidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Proteínas Supressoras da Sinalização de Citocina/genética , Acetaminofen/efeitos adversos , Animais , Biomarcadores , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment.
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Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/administração & dosagem , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Infecção por Zika virus/complicações , Infecção por Zika virus/patologia , Zika virus/crescimento & desenvolvimento , Animais , Modelos Animais de Doenças , Camundongos , Resultado do TratamentoRESUMO
BACKGROUND: Flaviviruses are a genre of closely related viral pathogens which emerged in the last decades in Brazil and in the world. Saint (St.) Louis encephalitis virus (SLEV) is a neglected flavivirus that can cause a severe neurological disease that may lead to death or sequelae. St. Louis encephalitis pathogenesis is poorly understood, which hinders the development of specific treatment or vaccine. METHODS: To address this problem, we developed a model of SLEV infection in mice to study mechanisms involved in the pathogenesis of severe disease. The model consists in the intracranial inoculation of the SLEV strain BeH 355964, a strain isolated from a symptomatic human patient in Brazil, in adult immunocompetent mice. RESULTS: Inoculated mice presented SLEV replication in the brain, accompanied by tissue damage, disease signs, and mortality approximately 7 days post infection. Infection was characterized by the production of proinflammatory cytokines and interferons and by leukocyte recruitment to the brain, composed mainly by neutrophils and lymphocytes. In vitro experiments indicated that SLEV is able to replicate in both neurons and glia and caused neuronal death and cytokine production, respectively. CONCLUSIONS: Altogether, intracranial SLEV infection leads to meningoencephalitis in mice, recapitulating several aspects of St. Louis encephalitis in humans. Our study indicates that the central nervous system (CNS) inflammation is a major component of SLEV-induced disease. This model may be useful to identify mechanisms of disease pathogenesis or resistance to SLEV infection.
Assuntos
Citocinas/metabolismo , Modelos Animais de Doenças , Vírus da Encefalite de St. Louis/fisiologia , Encefalite de St. Louis/patologia , Análise de Variância , Animais , Linhagem Celular Transformada , Encefalite de St. Louis/virologia , Peroxidase de Eosinófilo/metabolismo , Hexosaminidases/metabolismo , Leucócitos/metabolismo , Leucócitos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Fatores de Tempo , Carga ViralRESUMO
Current treatments for chronic Chagas cardiomyopathy, a disease with high mortality rates and caused by the protozoan Trypanosoma cruzi, are unsatisfactory. Myocardial inflammation, including endothelial activation, is responsible for the structural and functional damage seen in the chronic phase. The clinical efficacy of benznidazole could be improved by decreasing chronic inflammation. Statins, which have anti-inflammatory properties, may improve the action of benznidazole. Here, the action of simvastatin in a murine model of chronic Chagas cardiomyopathy and the link with the production of the proresolving eicosanoid 15-epi-lipoxin A4, produced by 5-lipoxygenase, are evaluated. Simvastatin decreased the expression of the adhesion molecules E-selectin, intracellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1) in T. cruzi-infected mice. However, when this drug was administered to 5-lipoxygenase-deficient mice, the anti-inflammatory effect was not observed unless exogenous 15-epi-lipoxin A4 was administered. Thus, in chronic Chagas disease, 5-epi-lipoxin A4 induced by simvastatin treatment could improve the pathophysiological condition of patients by increasing the trypanocidal action of benznidazole.