RESUMO
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures. It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause PAH, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human endogenous retrovirus K(HERV-K), and human immunodeficiency virus (HIV), in part due to acute and chronic inflammation. In this review, we discuss the connections between HERV-K, HIV, SARS-CoV-2, and PAH, to stimulate research regarding new therapeutic options and provide new targets for the treatment of the disease.
Assuntos
COVID-19 , Retrovirus Endógenos , Infecções por HIV , Hipertensão Arterial Pulmonar , Humanos , HIV , SARS-CoV-2 , Hipertensão Pulmonar Primária Familiar , InflamaçãoRESUMO
People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.
Assuntos
Infecções por HIV , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Infecções por HIV/complicações , Humanos , Hipertensão Pulmonar/etiologia , Hipóxia/patologia , Sistema Imunitário/patologia , Inflamação/complicações , CamundongosRESUMO
Proapoptotic and monocyte chemotactic endothelial monocyte-activating protein 2 (EMAPII) is released extracellularly during cigarette smoke (CS) exposure. We have previously demonstrated that, when administered intratracheally during chronic CS exposures, neutralizing rat antibodies to EMAPII inhibited endothelial cell apoptosis and lung inflammation and reduced airspace enlargement in mice (DBA/2J strain). Here we report further preclinical evaluation of EMAPII targeting using rat anti-EMAPII antibodies via either nebulization or subcutaneous injection. Both treatment modalities efficiently ameliorated emphysema-like disease in two different strains of CS-exposed mice, DBA/2J and C57BL/6. Of relevance for clinical applicability, this treatment showed therapeutic and even curative potential when administered either during or following CS-induced emphysema development, respectively. In addition, a fully humanized neutralizing anti-EMAPII antibody administered subcutaneously to mice during CS exposure retained anti-apoptotic and anti-inflammatory effects similar to that of the parent rat antibody. Furthermore, humanized anti-EMAPII antibody treatment attenuated CS-induced autophagy and restored mammalian target of rapamycin signaling in the lungs of mice, despite ongoing CS exposure. Together, our results demonstrate that EMAPII secretion is involved in CS-induced lung inflammation and cell injury, including apoptosis and autophagy, and that a humanized EMAPII neutralizing antibody may have therapeutic potential in emphysema.
Assuntos
Anticorpos Neutralizantes/farmacologia , Lesão Pulmonar/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Fumar/efeitos adversos , Animais , Autofagia/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Lesão Pulmonar/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteínas de Neoplasias/efeitos dos fármacos , Pneumonia/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/metabolismo , Proteínas de Ligação a RNA/efeitos dos fármacosRESUMO
Diabetic retinopathy (DR) is the leading cause of vision loss among working-age adults. The interplay between hyperglycemia and endothelial activation in inducing endoplasmic reticulum (ER) stress pathways and visual deficits in DR is not fully understood. To address this, we used a mouse model of chronic vascular activation using endothelial-specific tumor necrosis factor-α (TNF-α)-expressing (tie2-TNF) mice to induce diabetes with streptozotocin. At 4 weeks post streptozotocin, a significant 2-fold to 10-fold increase in retinal neurovascular inflammatory gene transcript response in tie2-TNF mice was further increased in diabetic tie2-TNF mice. A decrease in visual acuity and scotopic b-wave amplitude in tie2-TNF mice was further accentuated in diabetic tie2-TNF mice and these changes correlated with a multi-fold increase in retinal ER stress markers and a reduction in adherens junctions. Cultured retinal endothelial cells showed a significant decrease in trans-endothelial resistance as well as VE-cadherin expression under TNF-α and high glucose stress. These changes were partly rescued by tauroursodeoxycholic acid, a potent ER stress inhibitor. Taken together, constant endothelial activation induced by TNF-α further exacerbated by hyperglycemia results in activation of ER stress and chronic proinflammation in a feed forward loop ultimately resulting in endothelial junction protein alterations leading to visual deficits in the retina. Inhibition of ER stress and endothelial activation may prove to be a novel therapeutic target in DR.
Assuntos
Retinopatia Diabética/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Células Endoteliais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Análise de Variância , Animais , Linhagem Celular , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Eletrorretinografia , Expressão Gênica , Humanos , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor TIE-2/genética , Retina/patologia , Estreptozocina , Acuidade Visual/fisiologiaAssuntos
Acetilcisteína/uso terapêutico , Antivirais/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , F2-Isoprostanos/sangue , Sequestradores de Radicais Livres/uso terapêutico , Infecções por HIV/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Idoso , Antivirais/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Endotélio Vascular/fisiologia , Sequestradores de Radicais Livres/administração & dosagem , Infecções por HIV/metabolismo , Humanos , Malondialdeído/sangue , Pessoa de Meia-Idade , Projetos Piloto , Estudos ProspectivosRESUMO
BACKGROUND: Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy. METHODS: We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed. RESULTS: The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [-1.06 (1.45)%] and PTX [-1.93 (3.03)%] groups was not significant (Pâ=â0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; Pâ=â0.03]. PTX was generally well-tolerated. CONCLUSIONS: PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00796822.
Assuntos
Endotélio Vascular/metabolismo , Infecções por HIV/complicações , Pentoxifilina/uso terapêutico , Vasculite/tratamento farmacológico , Vasculite/etiologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Biomarcadores , Endotélio Vascular/efeitos dos fármacos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pentoxifilina/efeitos adversos , Pentoxifilina/farmacologia , Fatores Sexuais , Resultado do Tratamento , Adulto JovemRESUMO
Although the roles of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in pathologic neovascularization have been well characterized in certain tissues, their particular functions and expression patterns in choroidal neovascularization (CNV) have not been clearly established. After localized laser trauma to Bruch's membrane to induce CNV development, the temporal changes in mRNA and protein expression of these 3 cytokines were documented and compared histologically to areas of immunofluorescence, the proliferation of endothelial cells, neovascular development, and temporal changes in vascular permeability. Changes in mRNA and protein levels of bFGF and HGF occurred quickly and reached peak expression within hours. This activity corresponded in time to intense and localized immunofluorescence for these cytokines within the choriocapillaris within laser lesion sites. During this same initial time period, mRNA upregulation of VEGF occurred, primarily within the neural retina and this expression corresponded to intense immunolabeling of Müller cells immediately adjacent to the lesion sites. By 3 days after lasering, increased VEGF(164) protein expression was measurable, whereas early neovascular development histologically corresponded to HGF and bFGF mRNA expansion into the developing choroidal neovascular membrane (CNVM). At 7 days, CNV expansion, maturation, and increased vascular permeability corresponded to peak VEGF mRNA and protein expression and to immunofluorescence of the CNVM. Differences also occurred in the expression of precursor and activated isoforms of these cytokines in the retinal pigment epithelium/choroid as compared to those in the retina. These molecular and immunocytochemical results suggest that bFGF and HGF may be important as initial regulators neovascularization in this CNV model; whereas VEGF may be important during later phases of angiogenesis and neovascular hyperpermeability.
Assuntos
Neovascularização de Coroide/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Animais , Western Blotting/métodos , Permeabilidade Capilar , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/patologia , Neovascularização de Coroide/fisiopatologia , Progressão da Doença , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fotocoagulação a Laser , Masculino , Microscopia de Fluorescência/métodos , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos BN , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
AIMS: Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro. Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo. METHODS AND RESULTS: In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI). After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment. CONCLUSION: These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.
Assuntos
Citocinas/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas de Ligação a RNA/fisiologia , Sirolimo/farmacologia , Túnica Íntima/patologia , Angioplastia Coronária com Balão , Animais , Apoptose , Células Cultivadas , Reestenose Coronária/prevenção & controle , Vasos Coronários/patologia , Regulação para Baixo , Inflamação/etiologia , Macrófagos/fisiologia , Camundongos , Sirolimo/antagonistas & inibidoresRESUMO
Neointima formation, the leading cause of restenosis, is caused by proliferation of coronary artery smooth muscle cells (CASMCs) and is associated with infiltration by monocytes. Rapamycin inhibits neointima formation after stent implantation in humans. It reduces proliferation by its effects on mammalian target of rapamycin (mTOR) kinase. In this study, we investigated the expression of mTOR in human neointima and the effect of rapamycin on global transcriptional events controlling CASMC phenotype. In neointimal CASMCs, mTOR exhibited increased phosphorylation and was translocated to the nucleus compared with control. Comparative gene expression analysis of CASMCs treated with rapamycin (100 ng/ml) revealed down-regulation of the transcription factor E2F-1, a key regulator of G(1)/S-phase entry, and of various retinoblastoma protein/E2F-1-regulated genes. In addition, we found changes in the expression of genes associated with replication, apoptosis, and extracellular matrix formation. Furthermore, rapamycin decreased the gene expression of endothelial monocyte-activating polypeptide-II (EMAP-II). This decrease of EMAP-II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells. Addition of EMAP-II counteracted the antiadhesive effect of rapamycin. Therefore, EMAP-II may comprise a mechanism of rapamycin-mediated reduction of the proinflammatory activation of CASMCs. The effects reported here of rapamycin on the down-regulation of genes involved in cell cycle progression, apoptosis, proliferation, and extracellular matrix formation in CASMCs provide an explanation of how rapamycin reduces CASMC proliferation. In addition, rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC, a mechanism suggested to be mediated by the production and release of EMAP II.