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1.
Hamostaseologie ; 41(5): 387-396, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34695855

RESUMO

Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2-mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.


Assuntos
COVID-19/complicações , SARS-CoV-2 , Pele/irrigação sanguínea , Enzima de Conversão de Angiotensina 2/fisiologia , Anticorpos Antifosfolipídeos/sangue , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/patologia , COVID-19/patologia , COVID-19/fisiopatologia , Ativação do Complemento , Citocinas/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Microvasos/imunologia , Microvasos/patologia , Microvasos/fisiopatologia , Pandemias , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Pele/imunologia , Vasculite/etiologia , Vasculite/patologia , Vasculite/fisiopatologia , Internalização do Vírus
2.
Pharmacol Res ; 168: 105581, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33781873

RESUMO

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.


Assuntos
Encefalopatias/terapia , Encéfalo/efeitos dos fármacos , COVID-19/terapia , Cardiopatias/terapia , Coração/efeitos dos fármacos , Corticosteroides/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Antivirais/administração & dosagem , Encéfalo/imunologia , Encéfalo/metabolismo , Encefalopatias/imunologia , Encefalopatias/metabolismo , COVID-19/imunologia , COVID-19/metabolismo , Cuidados Críticos/métodos , Estado Terminal/terapia , Suplementos Nutricionais , Alimento Funcional , Cardiopatias/imunologia , Cardiopatias/metabolismo , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Microvasos/metabolismo , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/terapia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo
3.
Scand J Immunol ; 93(6): e13024, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33523532

RESUMO

Early airway responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are of interest since they could decide whether coronavirus disease-19 (COVID-19) will proceed to life-threatening pulmonary disease stages. Here I discuss endothelial-epithelial co-operative in vivo responses producing first-line, humoral innate defence opportunities in human airways. The pseudostratified epithelium of human nasal and tracheobronchial airways are prime sites of exposure and infection by SARS-CoV-2. Just beneath the epithelium runs a profuse systemic microcirculation. Its post-capillary venules respond conspicuously to mucosal challenges with autacoids, allergens and microbes, and to mere loss of epithelium. By active venular endothelial gap formation, followed by transient yielding of epithelial junctions, non-sieved plasma macromolecules move from the microcirculation to the mucosal surface. Hence, plasma-derived protein cascade systems and antimicrobial peptides would have opportunity to operate jointly on an unperturbed mucosal lining. Similarly, a plasma-derived, dynamic gel protects sites of epithelial sloughing-regeneration. Precision for this indiscriminate humoral molecular response lies in restricted location and well-regulated duration of plasma exudation. Importantly, the endothelial responsiveness of the airway microcirculation differs distinctly from the relatively non-responsive, low-pressure pulmonary microcirculation that non-specifically, almost irreversibly, leaks plasma in life-threatening COVID-19. Observations in humans of infections with rhinovirus, coronavirus 229E, and influenza A and B support a general but individually variable early occurrence of plasma exudation in human infected nasal and tracheobronchial airways. Investigations are warranted to elucidate roles of host- and drug-induced airway plasma exudation in restriction of viral infection and, specifically, whether it contributes to variable disease responses following exposure to SARS-CoV-2.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Humoral , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Biomarcadores/sangue , Proteínas Sanguíneas , COVID-19/diagnóstico , COVID-19/metabolismo , Permeabilidade Capilar/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Exsudatos e Transudatos , Humanos , Imunidade Inata , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Microvasos/imunologia , Microvasos/metabolismo , Mucosa Respiratória/metabolismo
4.
Clin Exp Immunol ; 203(1): 96-104, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32681658

RESUMO

Involvement of the alternative complement pathway (AP) in microvascular endothelial cell (MVEC) injury characteristic of a thrombotic microangiopathy (TMA) is well documented. However, the role of the lectin pathway (LP) of complement has not been explored. We examined mannose-binding lectin associated serine protease (MASP2), the effector enzyme of the LP, in thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome and post-allogeneic hematopoietic stem cell transplantation (alloHSCT) TMAs. Plasma MASP2 and terminal complement component sC5b-9 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Human MVEC were exposed to patient plasmas, and the effect of the anti-MASP2 human monoclonal antibody narsoplimab on plasma-induced MVEC activation was assessed by caspase 8 activity. MASP2 levels were highly elevated in all TMA patients versus controls. The relatively lower MASP2 levels in alloHSCT patients with TMAs compared to levels in alloHSCT patients who did not develop a TMA, and a significant decrease in variance of MASP2 levels in the former, may reflect MASP2 consumption at sites of disease activity. Plasmas from 14 of the 22 TMA patients tested (64%) induced significant MVEC caspase 8 activation. This was suppressed by clinically relevant levels of narsoplimab (1·2 µg/ml) for all 14 patients, with a mean 65·7% inhibition (36.8-99.4%; P < 0·0001). In conclusion, the LP of complement is activated in TMAs of diverse etiology. Inhibition of MASP2 reduces TMA plasma-mediated MVEC injury in vitro. LP inhibition therefore may be of therapeutic benefit in these disorders.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Células Endoteliais , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Serina Proteases Associadas a Proteína de Ligação a Manose , Microvasos , Microangiopatias Trombóticas , Adulto , Aloenxertos , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/antagonistas & inibidores , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Microvasos/imunologia , Microvasos/metabolismo , Microangiopatias Trombóticas/sangue , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/imunologia
5.
Fluids Barriers CNS ; 17(1): 55, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912226

RESUMO

Human coronaviruses are highly pathogenic viruses that pose a serious threat to human health. Examples include the severe acute respiratory syndrome outbreak of 2003 (SARS-CoV-1), the Middle East Respiratory Syndrome (MERS-CoV) outbreak of 2012, and the current SARS-CoV-2 (COVID-19) pandemic. Herein, we review the neurological manifestations of coronaviruses and discuss the potential pathogenic role of blood-brain barrier dysfunction. We present the hypothesis that pre-existing vascular damage (due to aging, cardiovascular disease, diabetes, hypertension or other conditions) facilitates infiltration of the virus into the central nervous system (CNS), increasing neuro-inflammation and the likelihood of neurological symptoms. We also discuss the role of a neuroinflammatory cytokine profile in both blood-brain barrier dysfunction and macrovascular disease (e.g. ischemic stroke and thromboembolism). Future studies are needed to better understand the involvement of the microvasculature in coronavirus neuropathology, and to test the diagnostic potential of minimally-invasive screening tools (e.g. serum biomarkers, fluorescein retinal angiography and dynamic-contrast MRI).


Assuntos
Barreira Hematoencefálica/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Inflamação/fisiopatologia , Microvasos/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Pneumonia Viral/fisiopatologia , Betacoronavirus , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , COVID-19 , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Diabetes Mellitus/fisiopatologia , Encefalite/imunologia , Encefalite/fisiopatologia , Humanos , Inflamação/imunologia , Microvasos/imunologia , Doenças do Sistema Nervoso/imunologia , Pandemias , Pneumonia Viral/imunologia , SARS-CoV-2 , Convulsões/imunologia , Convulsões/fisiopatologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Tromboembolia/imunologia , Tromboembolia/fisiopatologia
6.
ACS Chem Neurosci ; 11(14): 2048-2050, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32614178

RESUMO

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipotensão/fisiopatologia , Pulmão/irrigação sanguínea , Microvasos/fisiopatologia , Pneumonia Viral/fisiopatologia , Edema Pulmonar/fisiopatologia , Núcleo Solitário/fisiopatologia , Trombose/fisiopatologia , Betacoronavirus , COVID-19 , Permeabilidade Capilar/fisiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Nervo Facial , Nervo Glossofaríngeo , Humanos , Inflamação , Pulmão/imunologia , Microvasos/imunologia , Pandemias , Sistema Nervoso Parassimpático/fisiopatologia , Pneumonia Viral/imunologia , Edema Pulmonar/imunologia , SARS-CoV-2 , Núcleo Solitário/imunologia , Nervo Vago , Vasoconstrição
8.
BMC Cancer ; 20(1): 359, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345237

RESUMO

BACKGROUND: Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. Trastuzumab, a monoclonal antibody that targets HER2, has been shown pre-clinically to induce vascular changes that can increase delivery of chemotherapy. To quantify the role of immune modulation in treatment-induced vascular changes, this study identifies temporal changes in myeloid cell infiltration with corresponding vascular alterations in a preclinical model of HER2+ breast cancer following trastuzumab treatment. METHODS: HER2+ tumor-bearing mice (N = 46) were treated with trastuzumab or saline. After extraction, half of each tumor was analyzed by immunophenotyping using flow cytometry. The other half was quantified by immunohistochemistry to characterize macrophage infiltration (F4/80), vascularity (CD31 and α-SMA), proliferation (Ki67) and cellularity (H&E). Additional mice (N = 10) were used to quantify differences in tumor cytokines between control and treated groups. RESULTS: Immunophenotyping showed an increase in macrophage infiltration 24 h after trastuzumab treatment (P ≤ 0.05). With continued trastuzumab treatment, the M1 macrophage population increased (P = 0.02). Increases in vessel maturation index (i.e., the ratio of α-SMA to CD31) positively correlated with increases in tumor infiltrating M1 macrophages (R = 0.33, P = 0.04). Decreases in VEGF-A and increases in inflammatory cytokines (TNF-α, IL-1ß, CCL21, CCL7, and CXCL10) were observed with continued trastuzumab treatment (P ≤ 0.05). CONCLUSIONS: Preliminary results from this study in a murine model of HER2+ breast cancer show correlations between immune modulation and vascular changes, and reveals the potential for anti-HER2 therapy to reprogram immunosuppressive components of the tumor microenvironment. The quantification of immune modulation in HER2+ breast cancer, as well as the mechanistic insight of vascular alterations after anti-HER2 treatment, represent novel contributions and warrant further assessment for potential clinical translation.


Assuntos
Neoplasias da Mama/patologia , Modelos Animais de Doenças , Microvasos/imunologia , Células Mieloides/imunologia , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/farmacologia , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Nus , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Chim Acta ; 507: 167-173, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32348783

RESUMO

Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.


Assuntos
Aldosterona/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Microvasos/imunologia , Pneumonia Viral/imunologia , Sistema Renina-Angiotensina/imunologia , Trombofilia/imunologia , Trombose/imunologia , COVID-19 , Infecções por Coronavirus/fisiopatologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/virologia , Microvasos/fisiopatologia , Microvasos/virologia , Pandemias , Pneumonia Viral/fisiopatologia , SARS-CoV-2 , Trombofilia/fisiopatologia , Trombofilia/virologia , Trombose/fisiopatologia , Trombose/virologia
10.
Lancet Diabetes Endocrinol ; 8(3): 206-215, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32032540

RESUMO

BACKGROUND: Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status. METHODS: We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. FINDINGS: Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p<0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbA1c seen in adults with latent autoimmune diabetes than in those with type 2 diabetes explained entirely their subsequent increased risk for the composite microvascular outcome (adjusted HR 0·99 [95% CI 0·80-1·23], p=0·93). INTERPRETATION: At diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes. FUNDING: European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).


Assuntos
Autoanticorpos/sangue , Biomarcadores/análise , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Microvasos/patologia , Adolescente , Adulto , Idoso , Autoanticorpos/imunologia , Glicemia/análise , Estudos de Casos e Controles , Criança , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/epidemiologia , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Incidência , Masculino , Microvasos/imunologia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Tempo , Reino Unido/epidemiologia , Adulto Jovem
11.
Am J Physiol Lung Cell Mol Physiol ; 318(4): L813-L830, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32073879

RESUMO

Our understanding of mesenchymal cell subsets and their function in human lung affected by aging and in certain disease settings remains poorly described. We use a combination of flow cytometry, prospective cell-sorting strategies, confocal imaging, and modeling of microvessel formation using advanced microfluidic chip technology to characterize mesenchymal cell subtypes in human postnatal and adult lung. Tissue was obtained from patients undergoing elective surgery for congenital pulmonary airway malformations (CPAM) and other airway abnormalities including chronic obstructive pulmonary disease (COPD). In microscopically normal postnatal human lung, there was a fivefold higher mesenchymal compared with epithelial (EpCAM+) fraction, which diminished with age. The mesenchymal fraction composed of CD90+ and CD90+CD73+ cells was enriched in CXCL12 and platelet-derived growth factor receptor-α (PDGFRα) and located in close proximity to EpCAM+ cells in the alveolar region. Surprisingly, alveolar organoids generated from EpCAM+ cells supported by CD90+ subset were immature and displayed dysplastic features. In congenital lung lesions, cystic air spaces and dysplastic alveolar regions were marked with an underlying thick interstitium composed of CD90+ and CD90+PDGFRα+ cells. In postnatal lung, a subset of CD90+ cells coexpresses the pericyte marker CD146 and supports self-assembly of perfusable microvessels. CD90+CD146+ cells from COPD patients fail to support microvessel formation due to fibrinolysis. Targeting the plasmin-plasminogen system during microvessel self-assembly prevented fibrin gel degradation, but microvessels were narrower and excessive contraction blocked perfusion. These data provide important new information regarding the immunophenotypic identity of key mesenchymal lineages and their change in a diverse setting of congenital lung lesions and COPD.


Assuntos
Imunomodulação/imunologia , Células-Tronco Mesenquimais/metabolismo , Antígenos Thy-1/imunologia , Antígenos Thy-1/metabolismo , Adolescente , Biomarcadores/metabolismo , Antígeno CD146/imunologia , Antígeno CD146/metabolismo , Separação Celular/métodos , Criança , Pré-Escolar , Molécula de Adesão da Célula Epitelial/imunologia , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Lactente , Recém-Nascido , Masculino , Células-Tronco Mesenquimais/imunologia , Microvasos/imunologia , Microvasos/metabolismo , Pericitos/imunologia , Pericitos/metabolismo , Estudos Prospectivos
12.
J Clin Invest ; 130(5): 2301-2318, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31971917

RESUMO

Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability-enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.


Assuntos
Permeabilidade Capilar/imunologia , Microvasos/imunologia , Ativação de Neutrófilo , Neutrófilos/imunologia , Migração Transendotelial e Transepitelial/imunologia , Animais , Permeabilidade Capilar/genética , Masculino , Camundongos , Camundongos Transgênicos , Microvasos/patologia , Neutrófilos/patologia , Migração Transendotelial e Transepitelial/genética
13.
Cancer Res ; 80(1): 91-101, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31662326

RESUMO

Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell-independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell-dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro, and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. SIGNIFICANCE: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.


Assuntos
Anticorpos Biespecíficos/efeitos adversos , Adesão Celular/efeitos dos fármacos , Células Endoteliais/imunologia , Síndromes Neurotóxicas/imunologia , Linfócitos T/imunologia , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/patologia , Adesão Celular/imunologia , Linhagem Celular , Criança , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Feminino , Humanos , Incidência , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/imunologia , Masculino , Microvasos/citologia , Microvasos/imunologia , Microvasos/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Linfócitos T/efeitos dos fármacos
14.
Ren Fail ; 42(1): 19-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31858861

RESUMO

Renal microvascular lesions, common in lupus nephritis (LN), are associated with long-term poor outcomes. There are mainly five pathological types of renal microvascular lesions in LN: (1) vascular immune complex deposits (ICD), (2) arteriosclerosis (AS), (3) thrombotic microangiopathy (TMA), (4) non-inflammatory necrotizing vasculopathy (NNV), and (5) true renal vasculitis (TRV). The pathogenesis of renal microvascular lesions in LN remains to be elucidated. The activation and dysfunction of endothelial cells, in addition to the contribution of immune system dysfunction, especially the immune complex-induced vascular inflammation and antiphospholipid antibody-associated thrombotic events, are key mechanisms in the development of vascular lesions in LN that need to be further investigated. Alteration of the microvascular environment produces an acute immunological response that recruits immune cells, such as T cells, monocytes, and macrophages, which induces platelet aggregation with microthrombus formation. There is also increased cytotoxicity caused by cytokines produced by immune cells in the kidney. Identifying the mechanism underlying the pathogenesis of renal microvascular lesions in LN might provide potential targets for the development of novel therapies.


Assuntos
Rim/irrigação sanguínea , Nefrite Lúpica/complicações , Doenças Vasculares/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Rim/imunologia , Nefrite Lúpica/imunologia , Microvasos/imunologia , Microvasos/patologia , Literatura de Revisão como Assunto , Doenças Vasculares/patologia
15.
Int Immunopharmacol ; 78: 106060, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31841757

RESUMO

Overwhelming inflammation and extensive alveolar-endothelial injury are characteristic pathological features of acute respiratory distress syndrome (ARDS)). MicroRNAs are involved in the regulation of a variety of cellular processes including endothelial damage and inflammatory responses. However, little is known about their function and the molecules regulating lung microvascular endothelial injury. Here, we determined the levels of microRNA-92a (miR-92a) in lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cells (HPMECs). We found that miR-92a expression was greater in HPMECs treated with LPS than in control cells. Inhibition of miR-92a through transfection with a miR-92a inhibitor significantly increased HPMECs migration, enhanced tube formation, and improved endothelial cell barrier dysfunction. Inhibition of miR-92a ameliorated the inflammatory response by decreasing the release of the proinflammatory factors IL-6 and TNF-α. In addition, integrin α5 (ITGA5) was found to be a target gene of miR-92a in LPS-induced endothelial barrier dysfunction. Western blot analysis showed that inhibition of miR-92a may ameliorate endothelial barrier dysfunction by activating the PI3K/Akt signaling pathway. Together, these results reveal an important role of miR-92a in LPS-induced endothelial barrier dysfunction, and suggest that miR-92a may have potential as a prognostic indicator and a future target for the treatment of acute lung injury (ALI)/ARDS.


Assuntos
Endotélio Vascular/imunologia , Integrinas/genética , MicroRNAs/metabolismo , Síndrome do Desconforto Respiratório/genética , Transdução de Sinais/genética , Biomarcadores/metabolismo , Linhagem Celular , Células Endoteliais , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Regulação da Expressão Gênica/imunologia , Humanos , Integrinas/imunologia , Lipopolissacarídeos/imunologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Microvasos/citologia , Microvasos/imunologia , Microvasos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia , Transdução de Sinais/imunologia , Transfecção
16.
Front Immunol ; 11: 604470, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33679695

RESUMO

Microvascular dysfunction plays a fundamental role in the pathogenesis of salivary gland disorders. Restoring and preserving microvascular integrity might therefore represent a promising strategy for the treatment of these pathologies. The mechanisms underlying microvascular dysfunction in salivary glands, however, are still obscure, partly due to the unavailability of adequate in vivo models. Here, we present a novel experimental approach that allows comprehensive in vivo analyses of the salivary gland microvasculature in mice. For this purpose, we employed different microscopy techniques including multi-photon in vivo microscopy to quantitatively analyze interactions of distinct immune cell subsets in the submandibular gland microvasculature required for their infiltration into the surrounding parenchyma and their effects on microvascular function. Confocal microscopy and multi-channel flow cytometry in tissue sections/homogenates complemented these real-time analyses by determining the molecular phenotype of the participating cells. To this end, we identified key adhesion and signaling molecules that regulate the subset- and tissue-specific trafficking of leukocytes into inflamed glands and control the associated microvascular leakage. Hence, we established an experimental approach that allows in vivo analyses of microvascular processes in healthy and diseased salivary glands. This enables us to delineate distinct pathogenetic factors as novel therapeutic targets in salivary gland diseases.


Assuntos
Permeabilidade Capilar , Moléculas de Adesão Celular/metabolismo , Quimiotaxia de Leucócito , Inflamação/metabolismo , Migração e Rolagem de Leucócitos , Leucócitos/metabolismo , Microvasos/metabolismo , Glândula Submandibular/irrigação sanguínea , Animais , Anticorpos/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Citometria de Fluxo , Inflamação/imunologia , Inflamação/patologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia de Fluorescência por Excitação Multifotônica , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Microvasos/patologia , Fenótipo , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia
17.
Nat Commun ; 10(1): 5779, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852955

RESUMO

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.


Assuntos
Sistema Nervoso Central/irrigação sanguínea , Endotélio Vascular/patologia , Microvasos/patologia , Síndrome de Susac/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Feminino , Humanos , Integrina alfa4/antagonistas & inibidores , Integrina alfa4/metabolismo , Masculino , Camundongos Transgênicos , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Pessoa de Meia-Idade , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Síndrome de Susac/sangue , Síndrome de Susac/tratamento farmacológico , Adulto Jovem
18.
JCI Insight ; 4(20)2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31527312

RESUMO

Tissue engineering may address organ shortages currently limiting clinical transplantation. Off-the-shelf engineered vascularized organs will likely use allogeneic endothelial cells (ECs) to construct microvessels required for graft perfusion. Vasculogenic ECs can be differentiated from committed progenitors (human endothelial colony-forming cells or HECFCs) without risk of mutation or teratoma formation associated with reprogrammed stem cells. Like other ECs, these cells can express both class I and class II major histocompatibility complex (MHC) molecules, bind donor-specific antibody (DSA), activate alloreactive T effector memory cells, and initiate rejection in the absence of donor leukocytes. CRISPR/Cas9-mediated dual ablation of ß2-microglobulin and class II transactivator (CIITA) in HECFC-derived ECs eliminates both class I and II MHC expression while retaining EC functions and vasculogenic potential. Importantly, dually ablated ECs no longer bind human DSA or activate allogeneic CD4+ effector memory T cells and are resistant to killing by CD8+ alloreactive cytotoxic T lymphocytes in vitro and in vivo. Despite absent class I MHC molecules, these ECs do not activate or elicit cytotoxic activity from allogeneic natural killer cells. These data suggest that HECFC-derived ECs lacking MHC molecule expression can be utilized for engineering vascularized grafts that evade allorejection.


Assuntos
Aloenxertos/imunologia , Células Endoteliais/imunologia , Rejeição de Enxerto/prevenção & controle , Proteínas Nucleares/genética , Engenharia Tecidual/métodos , Transativadores/genética , Microglobulina beta-2/genética , Aloenxertos/irrigação sanguínea , Aloenxertos/provisão & distribuição , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Progenitoras Endoteliais , Feminino , Sangue Fetal/citologia , Técnicas de Inativação de Genes , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Voluntários Saudáveis , Humanos , Isoanticorpos/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/genética , Camundongos , Microvasos/citologia , Microvasos/imunologia , Microvasos/transplante , Proteínas Nucleares/imunologia , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Cultura Primária de Células , Transativadores/imunologia , Microglobulina beta-2/imunologia
19.
PLoS One ; 14(8): e0220776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437163

RESUMO

Cell-to-cell communication is a key element of microvascular blood flow control, including rapidly carrying signals through the vascular endothelium in response to local stimuli. This cell-to-cell communication is negatively impacted during inflammation through the disruption of junctional integrity. Such disruption is associated with promoting the onset of cardiovascular diseases as a result of altered microvascular blood flow regulation. Therefore, understanding the mechanisms how inflammation drives microvascular dysfunction and compounds that mitigate such inflammation and dysfunction are of great interest for development. As such we aimed to investigate extracts of mushrooms as potential novel compounds. Using intravital microscopy, the medicinal mushroom, Inonotus obliquus was observed, to attenuate histamine-induced inflammation conducted vasodilation in second-order arterioles in the gluteus maximus muscle of C57BL/6 mice. Mast cell activation by C48/80 similarly disrupted endothelial junctions and conducted vasodilation but only histamine was blocked by the histamine antagonist, pyrilamine not C48/80 suggesting the importance of mast cell activation. Data presented here supports that histamine induced inflammation is a major disruptor of junctional integrity, and highlights the important anti-inflammatory properties of Inonotus obliquus focusing future assessment of mast cells as putative target for Inonotus obliquus.


Assuntos
Basidiomycota/isolamento & purificação , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Agaricales/isolamento & purificação , Agaricales/metabolismo , Animais , Arteríolas/efeitos dos fármacos , Basidiomycota/metabolismo , Endotélio Vascular/efeitos dos fármacos , Histamina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Pirilamina/farmacologia , Vasodilatação/efeitos dos fármacos
20.
Kidney Int ; 96(3): 689-698, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31307777

RESUMO

Development of donor-specific antibodies is associated with reduced allograft survival in renal transplantation. Recent clinical studies highlight the prevalence of human leukocyte antigen (HLA)-DQ antibodies amongst de novo donor-specific antibodies (DSAs), yet the specific contribution of these DSAs to rejection has not been examined. Antibody-mediated rejection primarily targets the microvasculature, so this study explored how patient HLA-DQ alloantibodies can modulate endothelial activation and so immunoregulation. HLA-DQ antibodies phosphorylated Akt and S6 kinase in microvascular endothelial cells. This activation prior to culture with alloreactive lymphocytes increased IL-6 and RANTES secretion. The antibody-mediated upregulation of IL-6 was indeed Akt-dependent. The binding of HLA-DQ antibodies to endothelial cells selectively reduced T cell alloproliferation and FoxP3high Treg differentiation. In clinical studies, detection of HLA-DQ DSAs with other DSAs is associated with worse graft survival than either alone. Endothelial cells stimulated with HLA-DR and HLA-DQ antibodies showed a synergistic increase in pro-inflammatory cytokine secretion and a decrease in Treg expansion. HLA-DQ antibodies strongly promote pro-inflammatory responses in isolation and in combination with other HLA antibodies. Thus, our data give new insights into the pathogenicity of HLA-DQ DSAs.


Assuntos
Endotélio Vascular/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA-DQ/imunologia , Isoanticorpos/imunologia , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Técnicas de Cultura de Células , Diferenciação Celular/imunologia , Linhagem Celular , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/sangue , Rejeição de Enxerto/patologia , Humanos , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Microvasos/citologia , Microvasos/imunologia , Linfócitos T Reguladores/metabolismo
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