Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 365
Filtrar
1.
Theranostics ; 11(1): 316-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391477

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , /imunologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
2.
J Surg Res ; 257: 468-476, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32896815

RESUMO

BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Obtenção de Tecidos e Órgãos , Animais , Morte , Avaliação Pré-Clínica de Medicamentos , Coração/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Masculino , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/metabolismo , Distribuição Aleatória
3.
Biomed Pharmacother ; 134: 111171, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383312

RESUMO

Periodontitis is a multifactorial chronic infectious disease leading to a host immune response involving inflammatory cytokines, especially IL-1ß, which is the main reason for further developing this disease. IL-1 receptor antagonist (IL-1ra) binds IL-1 receptor, inhibiting IL-1ß signaling and reducing the levels of other cytokines closely related to periodontitis, such as IL-6 and TNF-α. Therefore, the use of IL-1ra to inhibit periodontitis development in a system, ensuring its sustained release, might be an effective way to combat this disease. Hence, in this study, a novel IL-1ra-loaded dextran/PLGA microsphere was developed to allow the sustained release of IL-1ra and enhance the anti-inflammatory properties. Therefore, this study's purposes were to develop a novel periodontal treatment for inhibition and treatment of periodontitis and evaluate the sustained-release effect and anti-inflammatory properties of IL-1ra-loaded dextran/PLGA microspheres in vitro by cell experiments and in vivo by animal experiments. The results showed that IL-1ra-loaded dextran/PLGA microspheres were non-toxic both in vitro and in vivo and could be used as a safe and effective treatment. In addition, these microspheres could significantly prolong the half-life of IL-1ra drug, exerting a useful anti-inflammatory effect in macrophages stimulated with P. gingivalis lipopolysaccharide and in rats with periodontitis. In conclusion, IL-1ra-loaded dextran/PLGA microsphere might be a useful tool to combat periodontal disease.


Assuntos
Anti-Inflamatórios/farmacologia , Dextranos/química , Portadores de Fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Periodontite/prevenção & controle , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/química , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Proteína Antagonista do Receptor de Interleucina 1/química , Lipopolissacarídeos/isolamento & purificação , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Microesferas , Periodontite/imunologia , Periodontite/metabolismo , Porphyromonas gingivalis/química , Células RAW 264.7 , Ratos Sprague-Dawley
4.
Front Immunol ; 11: 1518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655582

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1ß. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/metabolismo , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imunidade Inata , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Camundongos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , /etiologia , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/uso terapêutico , Sulfonas/farmacologia , Sulfonas/uso terapêutico
5.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L137-L147, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159969

RESUMO

Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro. Cytokines were measured in the apical supernatant by Luminex, and the effect on the HBE transcriptome was assessed by RNA sequencing. NETs consistently stimulated IL-8, TNF-α, and IL-1α secretion by HBEs from multiple donors, with variable effects on other cytokines (IL-6, G-CSF, and GM-CSF). Expression of HBE RNAs encoding IL-1 family cytokines, particularly IL-36 subfamily members, was increased in response to NETs. NET exposure in the presence of anakinra [recombinant human IL-1 receptor antagonist (rhIL-1RA)] dampened NET-induced changes in IL-8 and TNF-α proteins as well as IL-36α RNA. rhIL-36RA limited the increase in expression of proinflammatory cytokine RNAs in HBEs exposed to NETs. NETs selectively upregulate an IL-1 family cytokine response in HBEs, which enhances IL-8 production and is limited by rhIL-1RA. The present findings describe a unique mechanism by which NETs may contribute to inflammation in human lung disease in vivo. NET-driven IL-1 signaling may represent a novel target for modulating inflammation in diseases characterized by a substantial NET burden.


Assuntos
Brônquios/citologia , Células Epiteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-1/metabolismo , Interleucina-8/metabolismo , Adulto , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Elastase de Leucócito/metabolismo , Peroxidase/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
6.
Sci Adv ; 6(10): eaax6346, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181339

RESUMO

Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model. The reduction in birth weight in babies from infected mothers is paralleled by increased placental expression of AIM2 and NLRP3 inflammasomes. Using genetic dissection, we reveal that inflammasome activation pathways are involved in the production and detrimental action of interleukin-1ß (IL-1ß) in the infected placenta. The IL-1R pharmacological antagonist Anakinra improved pregnancy outcomes by restoring fetal growth and reducing resorption in an experimental model. These findings unveil that IL-1ß-mediated signaling is a determinant of PM pathogenesis, suggesting that IL-1R antagonists can improve clinical outcomes of malaria infection in pregnancy.


Assuntos
Inflamassomos/efeitos dos fármacos , Interleucina-1beta/imunologia , Malária Falciparum/imunologia , Malária/imunologia , Plasmodium falciparum/patogenicidade , Complicações Parasitárias na Gravidez/imunologia , Transdução de Sinais/efeitos dos fármacos , Animais , Caspase 1/genética , Caspase 1/imunologia , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Fatores Imunológicos/farmacologia , Inflamassomos/genética , Inflamassomos/imunologia , Interferon gama/genética , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Malária/tratamento farmacológico , Malária/genética , Malária/parasitologia , Malária Falciparum/genética , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Plasmodium berghei/imunologia , Plasmodium berghei/patogenicidade , Plasmodium falciparum/imunologia , Gravidez , Complicações Parasitárias na Gravidez/genética , Complicações Parasitárias na Gravidez/parasitologia , Complicações Parasitárias na Gravidez/prevenção & controle , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Células THP-1 , Trofoblastos/efeitos dos fármacos , Trofoblastos/imunologia , Trofoblastos/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
Curr Atheroscler Rep ; 22(1): 4, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932973

RESUMO

PURPOSE OF REVIEW: Despite major advances in terms of prevention, diagnosis, risk-stratification, management and rehabilitation, atherosclerosis and atherothrombosis continue to have major morbidity and mortality implications worldwide. Since the unraveling of the pivotal role of inflammation in atherothrombosis pathophysiology, several focused treatments have been proposed with the ultimate goal of preventing or treating myocardial infarction, stroke, and peripheral artery disease. In particular, given the centrality of interleukin-1 (IL-1), targeted anti-IL-1 agents have attracted substantial attention and efforts. Yet, uncertainty persists on the real risk-benefit and cost-benefit balance of anti-IL-1 agents in patients with or at risk of atherothrombosis. RECENT FINDINGS: Several trials have been recently completed on atherothrombosis prevention and treatment with anti-IL-1 agents, ranging, for instance, from the large Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial to the series of translational studies conducted within the Virginia Commonwealth University-Anakinra Remodeling Trial (VCU-ART) platform. In light of the present scoping umbrella review, it appears evident that anti-IL-1 agents can reduce systemic inflammation and improve surrogate markers of cardiac and vascular function, with potential benefits on the risk of new/worsening heart failure. One trial suggested an increased risk of major adverse events with anti-interleukin-1 agents, possibly due to a rebound phenomenon, but this was based on a post-hoc analysis of a small number of events, and it was not supported by all other pertinent trials. The CANTOS study showed a potential hazard due to an increased risk of fatal infections, but the effect size was rather small. In addition, cost issues limit the foreseeable scope of these treatment strategies in unselected patients, calling instead for more refined prescribing. The evidence base on the risk-benefit and cost-benefit profile of anti-IL-1 agents for atherothrombosis prevention and treatment has expanded substantially in the last decade. While largely dominated by the landmark CANTOS trial, effect estimates also including the VCU-ART trials suggest complex short- and long-term effects which may prove favorable in carefully selected patients with acute or chronically sustained inflammation. Conversely, more liberal use appears less promising, and further studies with currently available agents or novel ones are eagerly needed to better define their role in the era of precision molecular medicine.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Trombose/tratamento farmacológico , Trombose/prevenção & controle , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Biomarcadores , Humanos , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Infarto do Miocárdio/prevenção & controle , Medição de Risco , Acidente Vascular Cerebral/prevenção & controle
8.
Arterioscler Thromb Vasc Biol ; 40(3): 802-818, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996019

RESUMO

OBJECTIVE: Kawasaki disease (KD) is the leading cause of acute vasculitis and acquired heart disease in children in developed countries. Notably, KD is more prevalent in males than females. We previously established a key role for IL (interleukin)-1 signaling in KD pathogenesis, but whether this pathway underlies the sex-based difference in susceptibility is unknown. Approach and Results: The role of IL-1 signaling was investigated in the Lactobacillus casei cell wall extract-induced experimental mouse model of KD vasculitis. Five-week-old male and female mice were injected intraperitoneally with PBS, Lactobacillus caseicell wall extract, or a combination of Lactobacillus caseicell wall extract and the IL-1 receptor antagonist Anakinra. Aortitis, coronary arteritis inflammation score and abdominal aorta dilatation, and aneurysm development were assessed. mRNA-seq (messenger RNA sequencing) analysis was performed on abdominal aorta tissue. Publicly available human transcriptomics data from patients with KD was analyzed to identify sex differences and disease-associated genes. Male mice displayed enhanced aortitis and coronary arteritis as well as increased incidence and severity of abdominal aorta dilatation and aneurysm, recapitulating the increased incidence in males that is observed in human KD. Gene expression data from patients with KD and abdominal aorta tissue of Lactobacillus caseicell wall extract-injected mice showed enhanced Il1b expression and IL-1 signaling genes in males. Although the more severe IL-1ß-mediated disease phenotype observed in male mice was ameliorated by Anakinra treatment, the milder disease phenotype in female mice failed to respond. CONCLUSIONS: IL-1ß may play a central role in mediating sex-based differences in KD, with important implications for the use of anti-IL-1ß therapies to treat male and female patients with KD.


Assuntos
Aorta Abdominal/metabolismo , Interleucina-1beta/metabolismo , Síndrome de Linfonodos Mucocutâneos/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Aorta Abdominal/imunologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Resistência a Medicamentos , Feminino , Disparidades nos Níveis de Saúde , Humanos , Incidência , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/genética , Lactobacillus casei , Masculino , Camundongos Endogâmicos C57BL , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/microbiologia , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais
9.
Arthritis Rheumatol ; 72(3): 499-505, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31599092

RESUMO

OBJECTIVE: To analyze the reported association of IL1RN polymorphisms with response to interleukin-1 (IL-1) blockade in a German cohort of patients with systemic juvenile idiopathic arthritis (JIA), and to assess the impact of other factors on treatment response. METHODS: Sixty-one patients with systemic JIA who had received IL-1 blockade were identified within the German Autoinflammatory Disease registry DNA biobank. Response to IL-1 blockade was assessed according to 1) the clinical response (initially at least a transient response or good response compared to a poor response), 2) switch (or no switch) to anti-IL-6 receptor therapy following IL-1 blockade, 3) achievement of clinically inactive disease within 6 months of IL-1 blockade, 4) improvement in disease activity measured using the modified Juvenile Arthritis Disease Activity Score, and 5) achievement of a glucocorticoid-free state. In addition, basic demographic data, key features of the disease course, laboratory data, and IL1RN single-nucleotide polymorphisms (SNPs) were assessed. RESULTS: Six of 7 IL1RN SNPs reported to be associated with response to anakinra therapy were analyzed. These 6 IL1RN SNPs were inherited as haplotypes. An association of IL1RN haplotypes and SNPs with response to IL-1 blockade could not be confirmed in this cohort of patients with systemic JIA. Patients who received tocilizumab following IL-1 blockade had a longer duration from disease onset to diagnosis than those who did not receive tocilizumab (median 0.27 years versus 0.08 years). CONCLUSION: The results of this study could not confirm an impact of IL1RN SNPs on response to IL-1 blockade therapy with either anakinra or canakinumab in a cohort of patients with systemic JIA. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response, thereby supporting the "window of opportunity" hypothesis that suggests improved long-term treatment response with shorter time from disease onset to diagnosis (and treatment).


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Artrite Juvenil/genética , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Adolescente , Artrite Juvenil/tratamento farmacológico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Alemanha , Haplótipos , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/antagonistas & inibidores , Masculino , Sistema de Registros , Resultado do Tratamento
10.
Inflammation ; 43(1): 168-178, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31664694

RESUMO

Periodontitis is a chronic infectious disease, the course and progression of which are determined by the interaction between microorganisms and the host. Interleukin 1ß plays an important role in the destruction of periodontal tissues. Interleukin 1 receptor antagonist (IL-1ra) can inhibit the biological activity of IL-1ß without triggering any intracellular signaling. This study aimed to prepare IL-1ra-loaded dextran/PLGA microspheres and evaluate the physical and chemical characteristics and anti-inflammatory properties. Results suggested that the microspheres can be easily prepared into a drug carrier with good biocompatibility and can effectively inhibit the gene expression of pro-inflammatory factors induced by IL-1ß in human gingival fibroblasts. Hence, the microspheres are excellent candidate for periodontitis treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Dextranos/química , Portadores de Fármacos , Fibroblastos/efeitos dos fármacos , Gengiva/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Periodontite/prevenção & controle , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Adolescente , Adulto , Anti-Inflamatórios/química , Criança , Composição de Medicamentos , Liberação Controlada de Fármacos , Fibroblastos/metabolismo , Gengiva/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/química , Cinética , Microesferas , Tamanho da Partícula , Periodontite/metabolismo , Adulto Jovem
11.
Am J Respir Crit Care Med ; 201(5): 526-539, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710506

RESUMO

Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/ß signaling. JAK/STAT inhibition or IFNß neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFNα/ß. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.Conclusions: Our data indicate that IL-18 (but not IL-1ß) production from human monocytes requires cooperative Toll-like receptor and IFNα/ß signaling. Interference with IFNα/ß expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.


Assuntos
Tolerância Imunológica/imunologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Receptores Toll-Like/imunologia , Adulto , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Modelos Animais de Doenças , Endotoxinas , Expressão Gênica , Humanos , Técnicas In Vitro , Interferon-alfa/efeitos dos fármacos , Interferon beta/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Inibidores de Janus Quinases/farmacologia , Lipopolissacarídeos/farmacologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/metabolismo , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Inibidores do Fator de Necrose Tumoral/farmacologia
12.
Clin Exp Immunol ; 199(3): 303-313, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31758701

RESUMO

Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40-80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. LCWE-injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE-injected mice developed cardiac ganglion inflammation, that may affect the impulse-conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE-injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)-1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1-/- mice and in wild-type mice treated with anakinra. Thus, similar to clinical KD, the LCWE-induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL-1 signaling. These data support the acceleration of anti-IL-1 therapy trials to benefit KD patients.


Assuntos
Modelos Animais de Doenças , Interleucina-1/metabolismo , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Vasculite/fisiopatologia , Animais , Antirreumáticos/farmacologia , Produtos Biológicos/toxicidade , Parede Celular/química , Criança , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1/genética , Lactobacillus casei/química , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Linfonodos Mucocutâneos/induzido quimicamente , Síndrome de Linfonodos Mucocutâneos/terapia , Fator de Crescimento Neural/sangue , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasculite/induzido quimicamente , Vasculite/terapia
14.
Front Immunol ; 10: 2277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616439

RESUMO

Aristolochic acid nephropathy (AAN), as a rapidly progressive interstitial nephropathy due to excessive ingestion of aristolochia herbal medications, has recently raised considerable concerns among clinicians and researchers as its underlying pathogenic mechanisms are largely unclear. In the current study, we identified NLRP3 inflammasome activation as a novel pathological mechanism of AAN. We found that NLRP3 inflammasome was aberrantly activated both in vivo and in vitro after AA exposure. Blockade of IL-1ß and NLRP3 inflammasome activation by IL-1Ra significantly attenuated renal tubular injury and function loss in AA-induced nephropathy. Moreover, NLRP3 or Caspase-1 deficiency protected against renal injury in the mouse model of acute AAN, suggesting that the NLRP3 signaling pathway was probably involved in the pathogenesis of AAN. We also found that administration of IL-22 could markedly attenuate renal tubular injury in AAN. Notably, IL-22 intervention significantly alleviated renal fibrosis and dysfunction in AA-induced nephropathy. Furthermore, IL-22 largely inhibited renal activation of NLRP3 inflammasome in AA-induced nephropathy. These results indicated that IL-22 ameliorated renal tubular injury in AAN through suppression of NLRP3 inflammasome activation. In summary, this study identified renal activation of NLRP3 inflammasome as a novel mechanism underlying the pathogenesis of AAN, thus providing a potential therapeutic strategy for AAN based on suppression of NLRP3 inflammasome activation.


Assuntos
Inflamassomos/efeitos dos fármacos , Interleucinas/farmacologia , Nefropatias/prevenção & controle , Túbulos Renais/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Ácidos Aristolóquicos , Modelos Animais de Doenças , Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucinas/administração & dosagem , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia
15.
Front Immunol ; 10: 2088, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552036

RESUMO

Cancer patients are at increased risk of developing thrombosis, comorbidity that has been associated with increased neutrophil counts and the formation of neutrophil extracellular traps (NETs). Interleukin-1ß (IL-1ß) modulates the expression of granulocyte colony-stimulating factor (G-CSF), a cytokine that promotes cancer-associated neutrophilia and NET generation. Herein, we combined a murine breast cancer model with a flow-restriction thrombosis model to evaluate whether the IL-1ß blockade could interfere with cancer-associated thrombosis. Mice bearing metastatic 4T1 tumors exhibited high neutrophil counts as well as elevated expression of G-CSF and IL-1ß in their tumors. On the other hand, mice bearing non-metastatic 67NR tumors showed no elevation in neutrophil counts and displayed low expression levels of G-CSF and IL-1ß in their tumors. 4T1 tumor-bearing mice but not 67NR tumor-bearing mice exhibited a NET-dependent prothrombotic state. Pharmacological blockade of IL-1 receptor (IL-1R) decreased the primary growth of 4T1 tumors and reduced the systemic levels of myeloperoxidase, cell-free DNA (cfDNA) and G-CSF, without interfering with the neutrophil counts. Most remarkably, the blockade of IL-1R abolished the prothrombotic state observed in 4T1 tumor-bearing mice. Overall, our results demonstrate that IL-1ß might be a feasible target to attenuate cancer-associated thrombosis, particularly in cancer types that rely on increased G-CSF production and involvement of NET formation.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/antagonistas & inibidores , Neoplasias Mamárias Experimentais/complicações , Receptores de Interleucina-1/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Armadilhas Extracelulares/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Contagem de Leucócitos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Peroxidase/metabolismo , Receptores de Interleucina-1/metabolismo , Trombose/complicações , Trombose/metabolismo , Carga Tumoral/efeitos dos fármacos
16.
FASEB J ; 33(11): 12135-12145, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373847

RESUMO

The protection of constantly proliferating gut epithelia and hematopoietic tissues from cytotoxicity could improve conventional chemotherapy efficacy and widen its therapeutic window. Previously, we reported that, in mouse models, pretreatment of recombinant human IL-1 receptor antagonist (rhIL-1Ra) protected both types of vulnerable tissues from chemotherapeutics. Here, we showed that rhIL-1Ra treatment up-regulated the protein levels of phosphorylated p38, p53, and p21 and induced transient hematopoietic stem/progenitor cell (HS/PC) quiescence. Knockout of IL-1 receptor I (IL-1RI), p53, or p21 alleles and pharmacological inactivation of p38 mapped the rhIL-1Ra pathway in the induction of HS/PC quiescence. Therefore, rhIL-1Ra administration before but not after chemotherapy alleviated 5-fluorouracil-induced neutropenia. In addition, in vivo and in vitro cell proliferation assays revealed that the rhIL-1Ra treatment did not affect cancer cell proliferation or chemosensitivity. Lastly, we propose an IL-1/IL-1Ra pathway (IL-1RI → p38 → p53 → p21), which regulates HS/PC quiescence. The rhIL-1Ra may provide a new route for p53-based cyclotherapy, which spares normal cells but kills cancer cells during chemotherapy.-Ye, H., Qian, L., Zhu, S., Deng, S., Wang, X., Zhu, J., Chan, G. L., Yu, Y., Han, W. IL-1Ra protects hematopoietic cells from chemotoxicity through p53-induced quiescence.


Assuntos
Fluoruracila/toxicidade , Células-Tronco Hematopoéticas/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/análise , Hematopoese , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Proteína Supressora de Tumor p53/análise , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Med Hypotheses ; 130: 109269, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383341

RESUMO

Colchicine is the first choice of the treatment in familial Mediterranean fever (FMF). However, in FMF patients with amyloidosis, especially during creatinine level >1.5 mg/dL and nephrotic range proteinuria, colchicine may be ineffective. Interleukin-1 (IL-1) blockers could be used in colchicine resistant cases. However, starting IL-1 blocker treatment after colchicine failure may lose opportunity for effective treatment. Therefore, administering IL-1 blocker together with colchicine as first line therapy may increase the chance for suppressing the disease.


Assuntos
Amiloidose/tratamento farmacológico , Colchicina/administração & dosagem , Febre Familiar do Mediterrâneo/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1/antagonistas & inibidores , Amiloidose/complicações , Colchicina/farmacologia , Creatinina/farmacologia , Febre Familiar do Mediterrâneo/complicações , Humanos , Proteinúria/complicações , Recidiva , Resultado do Tratamento
18.
Front Immunol ; 10: 1480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354700

RESUMO

Pulmonary hypertension secondary to bronchopulmonary dysplasia (BPD-PH) represents a major complication of BPD in extremely preterm infants for which there are currently no safe and effective interventions. The abundance of interleukin-1 (IL-1) is strongly correlated with the severity and long-term outcome of BPD infants and we have previously shown that IL-1 receptor antagonist (IL-1Ra) protects against murine BPD; therefore, we hypothesized that IL-1Ra may also be effective against BPD-PH. We employed daily injections of IL-1Ra in a murine model in which BPD/BPD-PH was induced by antenatal LPS and postnatal hyperoxia of 65% O2. Pups reared in hyperoxia for 28 days exhibited a BPD-PH-like disease accompanied by significant changes in pulmonary vascular morphology: micro-CT revealed an 84% reduction in small vessels (4-5 µm diameter) compared to room air controls; this change was prevented by IL-1Ra. Pulmonary vascular resistance, assessed at day 28 of life by echocardiography using the inversely-related surrogate marker time-to-peak-velocity/right ventricular ejection time (TPV/RVET), increased in hyperoxic mice (0.27 compared to 0.32 in air controls), and fell significantly with daily IL-1Ra treatment (0.31). Importantly, in vivo cine-angiography revealed that this protection afforded by IL-1Ra treatment for 28 days is maintained at day 60 of life. Despite an increased abundance of mediators of pulmonary angiogenesis in day 5 lung lysates, namely vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1), no difference was detected in ex vivo pulmonary vascular reactivity between air and hyperoxia mice as measured in precision cut lung slices, or by immunohistochemistry in alpha-smooth muscle actin (α-SMA) and endothelin receptor type-A (ETA) at day 28. Further, on day 28 of life we observed cardiac fibrosis by Sirius Red staining, which was accompanied by an increase in mRNA expression of galectin-3 and CCL2 (chemokine (C-C motif) ligand 2) in whole hearts of hyperoxic pups, which improved with IL-1Ra. In summary, our findings suggest that daily administration of the anti-inflammatory IL-1Ra prevents the increase in pulmonary vascular resistance and the pulmonary dysangiogenesis of murine BPD-PH, thus pointing to IL-1Ra as a promising candidate for the treatment of both BPD and BPD-PH.


Assuntos
Anti-Inflamatórios/farmacologia , Displasia Broncopulmonar/prevenção & controle , Hipertensão Pulmonar/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Resistência Vascular/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Endotelina-1/metabolismo , Hiperóxia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Eur J Immunol ; 49(11): 2063-2073, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31350760

RESUMO

The role of redox regulation in immune-mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte-derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL-1 family cytokines along with other cytokines relevant to ILC functions and development in serum-induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)-deficient Ncf1-/- mice. We found more severe serum-induced joint inflammation and increased NCR+ ILC3s in inflamed joints of Ncf1-/- mice. Furthermore, in vitro stimulation with IL-1ß on Tbet+ ILC1s from joints facilitated their differentiation into ROR-γt+ ILC3s. Moreover, treatment with IL-1 antagonists effectively lowered the proportions of NCR+ ILC3s and IL-17A producing ILC3s in Ncf1-/- arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential regulator of ILC transdifferentiation and may mediate this process in a redox-dependent manner through IL-1ß production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell-mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints.


Assuntos
Interleucina-1beta/imunologia , Linfócitos/imunologia , NADPH Oxidase 2/deficiência , Espécies Reativas de Oxigênio/imunologia , Tarso Animal/imunologia , Animais , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , NADPH Oxidase 2/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Oxirredução/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Fagócitos/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Soro/imunologia , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Tarso Animal/efeitos dos fármacos , Tarso Animal/patologia
20.
Eur Respir J ; 54(3)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31320452

RESUMO

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1ß in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1ß were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg-1·day-1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitroFra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1ß was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.


Assuntos
Inflamação/metabolismo , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Escleroderma Sistêmico/metabolismo , Células Th2/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Miócitos de Músculo Liso/metabolismo , Fibrose Pulmonar/patologia , Testes de Função Respiratória , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...