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We explored post-pulmonary embolism (post-PE) follow-up at a large Australian regional city hospital health service. Over a 12-month period, we identified 195 (49% male) patients with a median age of 62 years. Post-PE follow-up was not organised for 23 patients and delayed for seven patients. Post-PE complication occurred in 21% of all patients reviewed in the clinic after discharge. Follow-up imaging was arranged in 28% of patients. To deliver high-quality care, we recommend implementing a local post-PE follow-up pathway, which balances individual physician preference with available resources and expert recommendations.
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Embolia Pulmonar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Aguda , Austrália , Alta do Paciente , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnósticoRESUMO
Obstructive sleep apnoea (OSA) is a prevalent disorder that causes repetitive, temporary collapses of the upper airways during sleep, resulting in intermittent hypoxaemia and sleep fragmentation. Given those with OSA also exhibit decreased blood fluidity, this clinical population is at heightened risk for cardiovascular disease (CVD) development. Continuous positive airway pressure (CPAP) remains a primary therapy in OSA, which improves sleep quality and limits sleep fragmentation. While CPAP effectively ameliorates nocturnal hypoxic events and associated arousals, it remains unclear whether CVD risk factors are positively impacted. The aim of the present study was thus to assess the effects of an acute CPAP therapy on sleep quality and the physical properties of blood that determine blood fluidity. Sixteen participants with suspected OSA were recruited into the current study. Participants attended the sleep laboratory for two visits: an initial diagnostic visit that included confirmation of OSA severity and comprehensive assessments of blood parameters, followed by a subsequent visit where participants were administered an individualised, acute CPAP therapy session and had their blood assessments repeated. Holistic appraisal of blood rheological properties included assessment of blood and plasma viscosity, red blood cell (RBC) aggregation, deformability, and osmotic gradient ektacytometry. Acute CPAP treatment significantly improved sleep quality parameters, which were associated with decreased nocturnal arousals and improved blood oxygen saturation. Whole blood viscosity was significantly decreased following acute CPAP treatment, which might be explained by the improved RBC aggregation during this visit. Although an acute increase in plasma viscosity was observed, it appears that the alterations in RBC properties that mediate cell-cell aggregation, and thus blood viscosity, overcame the increased plasma viscosity. While deformability of RBC was unaltered, CPAP therapy had mild effects on the osmotic tolerance of RBC. Collectively, novel observations demonstrate that a single CPAP treatment session acutely improved sleep quality, which was accompanied by improved rheological properties.
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Pressão Positiva Contínua nas Vias Aéreas , Apneia Obstrutiva do Sono , Apneia Obstrutiva do Sono/patologia , Apneia Obstrutiva do Sono/terapia , Humanos , Qualidade do Sono , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , HemorreologiaRESUMO
Activation and degranulation of mast cells (MCs) is an essential aspect of innate and adaptive immunity. Skin MCs, the most exposed to the external environment, are at risk of quickly degranulating with potentially severe consequences. Here, we define how MCs assume a tolerant phenotype via crosstalk with dermal fibroblasts (dFBs) and how this phenotype reduces unnecessary inflammation when in contact with beneficial commensal bacteria. We explore the interaction of human MCs (HMCs) and dFBs in the human skin microenvironment and test how this interaction controls MC inflammatory response by inhibiting the nuclear factor κB (NF-κB) pathway. We show that the extracellular matrix hyaluronic acid, as the activator of the regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor α-induced protein 3 (TNFAIP3), is responsible for the reduced HMC response to commensal bacteria. The role of hyaluronic acid as an anti-inflammatory ligand on MCs opens new avenues for the potential treatment of inflammatory and allergic disorders.
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Ácido Hialurônico , Mastócitos , Humanos , Mastócitos/metabolismo , Ácido Hialurônico/metabolismo , Pele/microbiologia , Bactérias , Fibroblastos/metabolismoRESUMO
BACKGROUND: Obstructive sleep apnea (OSA), characterised by recurrent episodes of upper airway collapse, intermittent hypoxia (IH) and sleep fragmentation (SF), has been associated with carcinogenesis in pre-clinical models. The relationship between OSA and colorectal cancer (CRC) in clinical studies is controversial. AIM: The objective of this meta-analysis was to assess the association between OSA and CRC. METHODS: Two independent investigators searched studies indexed in CINAHL, MEDLINE, EMBASE, the Cochrane Database and clinicaltrials.gov that were randomised controlled trials (RCT) or observational studies evaluating the relationship between OSA and CRC. Studies were included if they had available odds ratios (OR) and relative risks (RR) or if hazard ratios (HR) with 95% confidence intervals (CI) were available and a reference group composed of participants who did not have OSA. OR and 95% CI were calculated using a random-effect, generic inverse variance method. RESULTS: We included four observational studies out of 85 records, comprising a combined cohort of 5,651,662 identified patients in the data analysis. Three studies used polysomnography to identify OSA. The pooled OR of CRC in patients with OSA was 1.49 (95% CI, 0.75 to 2.97). The statistical heterogeneity was high with I2 of 95%. CONCLUSIONS: Our study is unable to conclusively point towards OSA being a risk factor in the development of CRC, despite the plausible biological mechanisms for this. Further well-designed prospective RCT assessing the risk of CRC in patients with OSA and the impact of OSA treatments on the incidence and prognosis of CRC are needed.
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Neoplasias Colorretais , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Polissonografia , Fatores de Risco , Incidência , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/complicaçõesRESUMO
A major limitation of time-lapse microscopy combined with fluorescent biosensors, a powerful tool for quantifying spatiotemporal dynamics of signaling in single living cells, is low-experimental throughput. To overcome this limitation, we created a highly customizable, MATLAB-based platform: flexible automated liquid-handling combined microscope (FALCOscope) that coordinates an OpenTrons liquid handler and a fluorescence microscope to automate drug treatments, fluorescence imaging, and single-cell analysis. To test the feasibility of the FALCOscope, we quantified G protein-coupled receptor (GPCR)-stimulated Protein Kinase A activity and cAMP responses to GPCR agonists and antagonists. We also characterized cAMP dynamics induced by GPR68/OGR1, a proton-sensing GPCR, in response to variable extracellular pH values. GPR68-induced cAMP responses were more transient in acidic than neutral pH values, suggesting a pH-dependence for signal attenuation. Ogerin, a GPR68 positive allosteric modulator, enhanced cAMP response most strongly at pH 7.0 and sustained cAMP response for acidic pH values, thereby demonstrating the capability of the FALCOscope to capture allosteric modulation. At a high concentration, ogerin increased cAMP signaling independent of GPR68, likely via phosphodiesterase inhibition. The FALCOscope system thus enables enhanced throughput single-cell dynamic measurements and is a versatile system for interrogating spatiotemporal regulation of signaling molecules in living cells and for drug profiling and screening.
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Álcoois Benzílicos , Transdução de Sinais , Álcoois Benzílicos/farmacologia , Microscopia de Fluorescência , Triazinas , Receptores Acoplados a Proteínas G/metabolismoRESUMO
OBJECTIVES: Currently, there are limited data available about patients who are diagnosed with lung cancer following an emergency department (ED) visit. This study sought to define the demographics, symptoms profile, staging, and prognosis of this cohort of patients. METHODS: We conducted a retrospective study of patients diagnosed with a primary lung malignancy at a lung cancer multidisciplinary meeting between January 2018 and January 2020. Medical records were reviewed to collect data around demographics, presenting symptoms, investigations, admission, cancer stage, and mortality. RESULTS: During the study period, 890 patients were diagnosed with a primary lung malignancy of which 209 (23.5%) presented to ED prompting diagnostic work-up. Of these 209 patients, 89% were hospitalized for a median duration of 6 days. Also, 104 (50%) were female and the average age of the cohort was 70 years. Dyspnea (38%) was the most common presenting symptom. Radiological staging and tissue biopsy were performed as an outpatient procedure in 46% and 41% of patients, respectively. A total of 188 patients had non-small cell lung cancer of whom 68% had ztage IV disease. A total of 53 (25%) patients died within 3 months of ED presentation. These patients were older with more advanced disease compared to patients who were alive at 3 months. CONCLUSION: Emergent diagnosed patients are a significant proportion of the lung cancer population, presenting with advanced stage disease and increased short-term mortality. Future research should be directed at interventions, such as lung cancer screening program and/or community education, to reduce the need for patients to present to the ED with disabling lung cancer symptoms.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Masculino , Centros de Atenção Terciária , Estudos Retrospectivos , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Serviço Hospitalar de EmergênciaRESUMO
Chronic decreases in the second messenger cyclic AMP (cAMP) occur in numerous settings, but how cells compensate for such decreases is unknown. We have used a unique system-murine dendritic cells (DCs) with a DC-selective depletion of the heterotrimeric GTP binding protein Gαs-to address this issue. These mice spontaneously develop Th2-allergic asthma and their DCs have persistently lower cAMP levels. We found that phosphodiesterase 4B (PDE4B) is the primary phosphodiesterase expressed in DCs and that its expression is preferentially decreased in Gαs-depleted DCs. PDE4B expression is dynamic, falling and rising in a protein kinase A-dependent manner with decreased and increased cAMP concentrations, respectively. Treatment of DCs that drive enhanced Th2 immunity with a PDE4B inhibitor ameliorated DC-induced helper T cell response. We conclude that PDE4B is a homeostatic regulator of cellular cAMP concentrations in DCs and may be a target for treating Th2-allergic asthma and other settings with low cellular cAMP concentrations.
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Dandruff is a common and challenging complaint associated with type of scalp, skin and population. Scalp seborrheic dermatitis (SD) is a more severe manifestation of dandruff associated with very severe itching and inflammation. Histamine is an interesting biomarker released in scalp affected by dandruff and SD even though the mechanism is not well understood yet. A monocentre clinical study was conducted to confirm the relationship between dandruff/SD and scalp histamine level in an Indian population. Highly sensitive liquid chromatography coupled with mass spectrometry was used for histamine quantification in scalp from samples obtained non-invasively. Results showed that scalps with dandruff and mild to moderate SD had higher histamine levels compared with healthy scalps.
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Caspa , Dermatite Seborreica , Cromatografia Líquida , Histamina , Humanos , Couro Cabeludo , Espectrometria de Massas em TandemRESUMO
Inhaled long-acting ß-adrenergic agonists (LABAs) and short-acting ß-adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by ß2 adrenergic receptors (ß2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of ß2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. ß2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. ß2-AR agonists/cAMP also exert anti-inflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity. SIGNIFICANCE STATEMENT: Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with â¼40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of ß2 adrenergic receptors and cAMP. Early administration of inhaled ß2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.
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Agonistas Adrenérgicos beta , Células Endoteliais , Administração por Inalação , Corticosteroides , Agonistas Adrenérgicos beta/farmacologia , HumanosRESUMO
A workflow is described for assaying the expression of G protein-coupled receptors (GPCRs) in cultured cells, using a combination of methods that assess GPCR mRNAs. Beginning from the isolation of cDNA and preparation of mRNA, we provide protocols for designing and testing qPCR primers, assaying mRNA expression using qPCR and high-throughput analysis of GPCR mRNA expression via TaqMan qPCR-based, GPCR-selective arrays. We also provide a workflow for analysis of expression from RNA-sequencing (RNA-seq) assays, which can be queried to yield expression of GPCRs and related genes in samples of interest, as well as to test changes in expression between groups, such as in cells treated with drugs or from healthy and diseased subjects. We place priority on optimized protocols that distinguish signal from noise, as GPCR mRNAs are typically present in low abundance, necessitating techniques that maximize sensitivity while minimizing noise. These methods may also be applicable for assessing the expression of members of families of other low abundance genes via high-throughput analyses of mRNAs, followed by independent confirmation and validation of results via qPCR.
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Análise em Microsséries/métodos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptores Acoplados a Proteínas G/metabolismo , Análise de Sequência de RNA/métodos , Humanos , Cultura Primária de Células , RNA Mensageiro/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
BACKGROUND AND AIMS: Retrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE). METHODS: RAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5 mg orally daily compared to placebo for 14 days. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7 days, glomerular filtration rate < 40 mL/min or a systolic blood pressure (BP) < 100 mmHg or diastolic BP < 65 mmHg. Patients are randomized 2:1 to receive ramipril (2.5 mg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually. CONCLUSIONS: RAMIC is designed to assess the efficacy of treatment with ramipril for 14 days to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).
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COVID-19 , Ramipril , Adulto , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Biomarcadores/análise , COVID-19/complicações , COVID-19/mortalidade , COVID-19/terapia , COVID-19/transmissão , Cuidados Críticos/estatística & dados numéricos , Transmissão de Doença Infecciosa/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Masculino , Mortalidade , Ramipril/administração & dosagem , Ramipril/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial/estatística & dados numéricos , SARS-CoV-2 , Resultado do TratamentoRESUMO
Evolving information has identified disease mechanisms and dysregulation of host biology that might be targeted therapeutically in coronavirus disease 2019 (COVID-19). Thrombosis and coagulopathy, associated with pulmonary injury and inflammation, are emerging clinical features of COVID-19. We present a framework for mechanisms of thrombosis in COVID-19 that initially derive from interaction of SARS-CoV-2 with ACE2, resulting in dysregulation of angiotensin signaling and subsequent inflammation and tissue injury. These responses result in increased signaling by thrombin (proteinase-activated) and purinergic receptors, which promote platelet activation and exert pathological effects on other cell types (e.g., endothelial cells, epithelial cells, and fibroblasts), further enhancing inflammation and injury. Inhibitors of thrombin and purinergic receptors may, thus, have therapeutic effects by blunting platelet-mediated thromboinflammation and dysfunction in other cell types. Such inhibitors include agents (e.g., anti-platelet drugs) approved for other indications, and that could be repurposed to treat, and potentially improve the outcome of, COVID-19 patients. COVID-19, caused by the SARS-CoV-2 virus, drives dysregulation of angiotensin signaling, which, in turn, increases thrombin-mediated and purinergic-mediated activation of platelets and increase in inflammation. This thromboinflammation impacts the lungs and can also have systemic effects. Inhibitors of receptors that drive platelet activation or inhibitors of the coagulation cascade provide opportunities to treat COVID-19 thromboinflammation.
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COVID-19/complicações , Inflamação/etiologia , Receptores Ativados por Proteinase/metabolismo , Receptores Purinérgicos/metabolismo , SARS-CoV-2 , Trombose/etiologia , Humanos , Inflamação/tratamento farmacológico , Antagonistas Purinérgicos/farmacologia , Receptores Ativados por Proteinase/antagonistas & inibidores , Receptores Ativados por Proteinase/genética , Receptores Purinérgicos/genética , Trombose/prevenção & controleRESUMO
The role of the renin-angiotensin signaling (RAS) pathway in COVID-19 has received much attention. A central mechanism for COVID-19 pathophysiology has been proposed: imbalance of angiotensin converting enzymes (ACE)1 and ACE2 (ACE2 being the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus "receptor") that results in tissue injury from angiotensin II (Ang II)-mediated signaling. This mechanism provides a rationale for multiple therapeutic approaches. In parallel, clinical data from retrospective analysis of COVID-19 cohorts has revealed that ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial in COVID-19. These findings have led to the initiation of clinical trials using approved drugs that target the generation (ACEIs) and actions (ARBs) of Ang II. However, treatment of COVID-19 with ACEIs/ARBs poses several challenges. These include choosing appropriate inclusion and exclusion criteria, dose optimization, risk of adverse effects and drug interactions, and verification of target engagement. Other approaches related to the RAS pathway might be considered, for example, inhalational administration of ACEIs/ARBs (to deliver drugs directly to the lungs) and use of compounds with other actions (e.g., activation of ACE2, agonism of MAS1 receptors, ß-arrestin-based Angiotensin receptor agonists, and administration of soluble ACE2 or ACE2 peptides). Studies with animal models could test such approaches and assess therapeutic benefit. This Perspective highlights questions whose answers could advance RAS-targeting agents as mechanism-driven ways to blunt tissue injury, morbidity, and mortality of COVID-19.
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Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antirretrovirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Antirretrovirais/efeitos adversos , Antirretrovirais/farmacologia , Ensaios Clínicos como Assunto , Humanos , Proto-Oncogene MasRESUMO
BACKGROUND: Pulmonary emboli (PE), or blood clots in the lungs,can be potentially fatal. Anticoagulation is the first line therapy to prevent PE. In some instances anticoagulation fails to prevent more emboli, or cannot be given because the person has a high risk of bleeding. Inferior vena caval filters (VCFs) are metal alloy devices that mechanically trap fragmented emboli from the deep leg veins en route to the pulmonary circulation. Retrievable filters are designed to be introduced and removed percutaneously. Although their deployment seems of theoretical benefit, their clinical efficacy and adverse event profile is unclear. This is the third update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the evidence for the effectiveness and safety of vena caval filters (VCFs) in preventing pulmonary embolism (PE). SEARCH METHODS: For this review update, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 10 September 2019) and the Cochrane Register of Controlled Trials (CENTRAL) (2019, Issue 8) via the Cochrane Register of Studies Online. The CIS also searched MEDLINE Ovid, EMBASE Ovid, CINAHL, and AMED (1 January 2017 to 10 September 2019) and trials registries to 10 September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that examined the efficacy of VCFs in preventing PE. DATA COLLECTION AND ANALYSIS: For this update, studies were assessed and data extracted independently. We assessed study quality with Cochrane's 'Risk of bias' tool and used the GRADE approach to assess the overall certainty of the evidence. The outcomes of interest were PE, mortality, lower limb venous thrombosis, filter-related complications and major bleeding. MAIN RESULTS: We identified four new studies for this update, bringing the total to six included studies involving 1388 participants. The six studies were clinically heterogeneous and we were unable to carry out meta-analysis. Only two studies were considered to be both applicable in current clinical settings and of good methodological quality. One was a randomised open-label trial studying the effect of a retrievable inferior vena caval filter plus anticoagulation versus anticoagulation alone on risk of recurrent pulmonary embolism (PE) in 399 participants over three months. There was no evidence of a difference in the rates of PE, death, lower extremity deep vein thrombosis (DVT), or bleeding at three and six months after the intervention (moderate-certainty evidence). A filter was inserted in 193 people, but could only be successfully retrieved from 153. Minor filter complications were noted at six months. The second clinically relevant study was a randomised open-label trial of 240 participants who had sustained multiple traumatic injuries, allocated to a filter or no filter, three days after injury, in conjunction with anticoagulation and intermittent pneumatic compression. Prophylactic anticoagulation was initiated in both groups when it was thought safe to do so. There was no evidence of a difference in symptomatic PE, death, or lower limb venous thrombosis rates (moderate-certainty evidence). The only major filter complication was that one person required surgical removal of the filter. We are unable to draw any conclusions from the remaining four included studies. One study showed an increased incidence of long-term lower extremity DVT at eight years. Three studies are no longer clinically applicable because they utilised permanent filters which are seldom used now, or they did not use routine prophylactic anticoagulation which is current standard practice. The fourth study compared two filter types and was terminated prematurely as one filter group had a higher rate of thrombosis compared to the other filter type. AUTHORS' CONCLUSIONS: Two of the six identified studies were relevant for current clinical settings. One showed no evidence of a benefit of retrievable filters in acute PE for the outcomes of PE, death, DVT and bleeding during the initial three months in people who can receive anticoagulation (moderate-certainty evidence). The other study did not show any benefit for prophylactic filter insertion in people who sustained multiple traumatic injuries, with respect to symptomatic PE, mortality, or lower extremity venous thrombosis (moderate-certainty evidence). We can draw no firm conclusions regarding filter efficacy in the prevention of PE from the remaining four RCTs identified in this review. Further trials are needed to assess vena caval filter effectiveness and safety, and clinical differences between various filter types.
Assuntos
Embolia Pulmonar/prevenção & controle , Filtros de Veia Cava , Anticoagulantes/uso terapêutico , Terapia Combinada/métodos , Humanos , Dispositivos de Compressão Pneumática Intermitente , Traumatismo Múltiplo/complicações , Embolia Pulmonar/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Filtros de Veia Cava/efeitos adversos , Veia Cava Inferior , Trombose Venosa/complicaçõesRESUMO
In the search to rapidly identify effective therapies that will mitigate the morbidity and mortality of COVID-19, attention has been directed towards the repurposing of existing drugs. Candidates for repurposing include drugs that target COVID-19 pathobiology, including agents that alter angiotensin signalling. Recent data indicate that key findings in COVID-19 patients include thrombosis and endotheliitis. Activation of proteinase-activated receptor 1 (PAR1), in particular by the serine protease thrombin, is a critical element in platelet aggregation and coagulation. PAR1 activation also impacts on the actions of other cell types involved in COVID-19 pathobiology, including endothelial cells, fibroblasts and pulmonary alveolar epithelial cells. Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. We discuss evidence for a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and other as-yet non-approved antagonists of PAR1 and proteinase-activated receptor 4 (PAR4). LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
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Infecções por Coronavirus/tratamento farmacológico , Lactonas/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Piridinas/administração & dosagem , Receptor PAR-1/antagonistas & inibidores , Animais , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Lactonas/farmacologia , Pandemias , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia , Pneumonia Viral/virologia , Piridinas/farmacologia , Receptor PAR-1/metabolismo , Receptores de Trombina/antagonistas & inibidores , Receptores de Trombina/metabolismo , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
A prospective cohort study investigating patients with obstructive sleep apnoea (OSA) was conducted to determine the prevalence of dysfunctional breathing and if continuous positive airway pressure (CPAP) therapy improves associated symptoms. Almost half of newly diagnosed patients with OSA had dysfunctional breathing and CPAP was not an effective treatment. Dysfunctional breathing is common in patients with OSA.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Apneia Obstrutiva do Sono , Humanos , Polissonografia , Estudos Prospectivos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/terapia , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH, type 1 pulmonary hypertension) has a 3-year survival of ~50% and is in need of new, effective therapies. In PAH, remodelling of the pulmonary artery (PA) increases pulmonary vascular resistance and can result in right heart dysfunction and failure. Genetic mutations can cause PAH but it can also be idiopathic (IPAH). Enhanced contractility and proliferation of PA smooth muscle cells (PASMCs) are key contributors to the pathophysiology of PAH, but the underlying mechanisms are not well understood. EXPERIMENTAL APPROACH: We utilized RNA-sequencing (RNA-seq) of IPAH and control patient-derived PASMCs as an unbiased approach to define differentially expressed (DE) genes that may identify new biology and potential therapeutic targets. KEY RESULTS: Analysis of DE genes for shared gene pathways revealed increases in genes involved in cell proliferation and mitosis and decreases in a variety of gene sets, including response to cytokine signalling. ADGRG6/GPR126, an adhesion G protein-coupled receptor (GPCR), was increased in IPAH-PASMCs compared to control-PASMCs. Increased expression of this GPCR in control-PASMCs decreased their proliferation; siRNA knockdown of ADGRG6/GPR126 in IPAH-PASMCs tended to increase proliferation. CONCLUSION AND IMPLICATIONS: These data provide insights regarding the expression of current and experimental PAH drug targets, GPCRs and GPCR-related genes as potentially new therapeutic targets in PAH-PASMCs. Overall, the findings identify genes and pathways that may contribute to IPAH-PASMC function and suggest that ADGRG6/GPR126 is a novel therapeutic target for IPAH.
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Músculo Liso Vascular , Artéria Pulmonar , Proliferação de Células , Células Cultivadas , Hipertensão Pulmonar Primária Familiar/genética , Humanos , Miócitos de Músculo Liso , TranscriptomaRESUMO
Angiotensin Converting Enzyme2 is the cell surface binding site for the coronavirus SARS-CoV-2, which causes COVID-19. We propose that an imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing angiotensin II (Ang II) signalling is primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of Ang II to Ang peptides that counteract pathophysiological effects of ACE1-generated ANG II. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: (a) AT receptor antagonists; (b) ACE1 inhibitors (ACEIs); (iii) agonists of receptors activated by ACE2-derived peptides (e.g. Ang (1-7), which activates MAS1); (d) recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved AT antagonists and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.