RESUMO
Pulmonary arterial hypertension (PAH) is characterized by cardiac remodelling. Glutaminolysis plays a crucial role in PAH-induced remodelling. The metabotropic glutamate receptor 5 (mGluR5) may mediate this process. This study investigated whether or not the blockade of mGluR5 may attenuate PAH-induced pathological cardiac remodelling. Pulmonary arterial hypertension was induced by intraperitoneally injecting male Sprague-Dawley (SD) rats with 60 mg/kg of monocrotaline (MCT). 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) (10 mg/kg intraperitoneally) was used as a therapeutic intervention to block mGluR5. Cardiac functions were assessed with right heart catheterization and electrocardiography. Alterations in protein expressions and inflammatory markers were investigated using western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Increased right ventricular systolic pressure (RSVP), elevated protein expressions of mGluR5, collagen types I and III and cartilage intermediate layer protein 1 (CILP1), enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and p38 mitogen-activated protein kinase (P38MAPK), increased angiopoietin 2 (Ang 2) and vascular endothelial growth factor-α (VEGF) protein expressions and elevated serum levels of interleukin 6 (IL-6) and tumour necrotic factor α (TNF-α) were observed in MCT-induced PAH rats. MTEP improved hemodynamics and right ventricular hypertrophy. MTEP also attenuated MCT-induced elevations in the protein expressions of mGluR5, collagen types I and III, CILP1, Ang 2 and VEGF and decreased PI3K, AKT and P38MAPK phosphorylations and inflammatory cytokine levels. Metabotropic glutamate receptor 5 blockade using MTEP ameliorates PAH-induced pathological right cardiac remodelling via inhibiting the signalling cascade involving PI3K/AKT, P38MAPK, Ang 2 and VEGF.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Modelos Animais de Doenças , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Masculino , Monocrotalina , Fosfatidilinositol 3-Quinases/metabolismo , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Fator A de Crescimento do Endotélio Vascular , Remodelação VentricularRESUMO
Fatty acid metabolism contributes to energy supply and plays an important role in regulating immunity. Free fatty acids (FFAs) bind to free fatty acid receptors (FFARs) on the cell surface and mediate effects through the intra-cellular FFAR signaling pathways. FFAR4, also known as G-protein coupled receptor 120 (GPR120), has been identified as the primary receptor of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). FFAR4 is a promising target for treating metabolic and inflammatory disorders due to its immune regulatory functions and the discovery of highly selective and efficient agonists. This review summarizes the reported immune regulatory functions of ω-3 PUFAs and FFAR4 in immune cells and immune-related diseases. We also speculate possible involvements of ω-3 PUFAs and FFAR4 in other types of inflammatory disorders.
Assuntos
Ácidos Graxos Insaturados , Receptores Acoplados a Proteínas G , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , HumanosRESUMO
T-cells mediated immunopathology is crucial for pathogenesis of chronic graft-versus-host disease (cGVHD), a common complication following allogeneic hematopoietic cell transplantation. Programmed death-1 (PD-1) regulates long-term survival and functional exhaustion of T-cell which might play a role in regulating cGVHD. We examined PD-1 expression on T cells of cGVHD mice and tested the impact of a PD-1 antibody on severity of cGVHD in murine allotransplant models. We also used a murine graft-versus-tumor (GVT) model to explore how tumor cell-derived PD-L1 affect the GVT effect and occurrence of cGVHD. PD-1 fluorescence intensity on CD4+ T-cells increased in mice developing cGVHD. PD-1High T cells expressed higher levels of IFNγ and IL-17, comparing with PD-1Low T cells. Giving the PD-1 antibody increased proportions of Th1, Th17 and Tc1 cells, but decreased proportion of Treg cells in allotransplant mice. The PD-1 antibody decreased survival of recipients and induced severe lung cGVHD. In the GVT model, knockdown of PD-L1 in A20 tumor cells enhanced GVT effect but increased cGVHD. In vitro study showed knockdown of PD-L1 in tumor cells increased cytotoxicity of T cells and reduced apoptosis of T cells. Knockdown of PD-L1 in tumor cells increased protein levels of phosphorylated AKT, Bcl-2 and Mcl-1, but decreased protein levels of Bak and Bax in co-cultured allogeneic T cells. In conclusion, expression of PD-1 on T cells increased in mice undergoing cGVHD. Intervention of the PD-1/PD-L1 pathway showed a significant impact on occurrence of cGVHD and GVT effect.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Antígeno B7-H1 , Doença Crônica , Camundongos , Receptor de Morte Celular Programada 1 , Linfócitos T Reguladores , Células Th17RESUMO
The immune system's ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus's development, factors causing thymic injury, and the strategies for improving thymus regeneration.
Assuntos
Regeneração/fisiologia , Timo/fisiologia , Animais , HumanosRESUMO
AIMS: Interleukin-22 (IL-22) promotes thymus recovery and improves T-cell recovery in preclinical allogeneic hematopoietic cell transplant models. However, the correlation between IL-22 and thymus recovery is unknown in human transplant. MATERIALS AND METHODS: In this study, plasma IL-22 levels of transplanted humans were analyzed peri-transplant. Thymic output was assessed by detecting blood signal joint T-cell receptor excision circles (TRECs). Flow cytometry was applied to measure T-cell subsets. KEY FINDINGS: Plasma IL-22 level positively correlated with blood TRECs level at days 14 and 28 posttransplant. Multiple linear regression analysis showed plasma IL-22 level, occurrence of acute graft-versus-host disease (aGVHD) and age were significantly associated with blood TRECs level at day 28 after allotransplant. An increase of plasma IL-22 level during day 14 and day 28 correlated with faster recovery of blood TRECs and naïve T-cell levels in allotransplant recipients. Recipients with high TRECs levels at day 28 had lower incidence of aGVHD comparing with those who with low TRECs levels according to a median split of their TRECs levels, an effect also seen in the high IL-22 level and low IL-22 level cohorts. Other factors such as age and infection had impacts on plasma IL-22 level in allotransplants. SIGNIFICANCE: Our findings suggest that dynamic change of plasma IL-22 level is an indicator of thymic output and occurrence of aGVHD. Monitoring plasma IL-22 level might help to assess recovery of thymus function in human allotransplants.
Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Interleucinas/sangue , Timo/metabolismo , Adulto , Citometria de Fluxo , Humanos , Incidência , Subpopulações de Linfócitos T/imunologia , Fatores de Tempo , Transplante Homólogo , Adulto Jovem , Interleucina 22RESUMO
Pulmonary arterial hypertension (PAH) is a decimating ailment described by chronic precapillary pulmonary hypertension, an elevated mean pulmonary arterial pressure with a normal pulmonary capillary wedge pressure, and a raised pulmonary vascular resistance resulting in increased right ventricular afterload culminating in heart failure and death. Current PAH treatments regulate the vasodilatory/vasoconstrictory balance of pulmonary vessels. However, these treatment options are unable to stop the progression of, or reverse, an already established disease. Recent studies have advanced a metabolic dysregulation, featuring increased glutamine metabolism, as a mechanism driving PAH progression. Metabolic dysregulation in PAH leads to increased glutaminolysis to produce substrate to meet the high-energy requirement by hyperproliferative and apoptosis-resistant pulmonary vascular cells. This article explores the role of glutamate metabolism in PAH and how it could be targeted as an anti-remodeling therapeutic strategy.