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1.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34139154

RESUMO

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Assuntos
Biomarcadores/análise , COVID-19/patologia , Progressão da Doença , Proteoma/fisiologia , Fatores Etários , Contagem de Células Sanguíneas , Gasometria , Ativação Enzimática , Humanos , Inflamação/patologia , Aprendizado de Máquina , Prognóstico , Proteômica , SARS-CoV-2/imunologia
2.
EClinicalMedicine ; 28: 100579, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33073217

RESUMO

Background: In face of the Coronavirus Disease (COVID)-19 pandemic, best practice for mechanical ventilation in COVID-19 associated Acute Respiratory Distress Syndrome (ARDS) is intensely debated. Specifically, the rationale for high positive end-expiratory pressure (PEEP) and prone positioning in early COVID-19 ARDS has been questioned. Methods: The first 23 consecutive patients with COVID-19 associated respiratory failure transferred to a single ICU were assessed. Eight were excluded: five were not invasively ventilated and three received veno-venous ECMO support. The remaining 15 were assessed over the first 15 days of mechanical ventilation. Best PEEP was defined by maximal oxygenation and was determined by structured decremental PEEP trials comprising the monitoring of oxygenation, airway pressures and trans-pulmonary pressures. In nine patients the impact of prone positioning on oxygenation was investigated. Additionally, the effects of high PEEP and prone positioning on pulmonary opacities in serial chest x-rays were determined by applying a semiquantitative scoring-system. This investigation is part of the prospective observational PA-COVID-19 study. Findings: Patients responded to initiation of invasive high PEEP ventilation with markedly improved oxygenation, which was accompanied by reduced pulmonary opacities within 6 h of mechanical ventilation. Decremental PEEP trials confirmed the need for high PEEP (17.9 (SD ± 3.9) mbar) for optimal oxygenation, while driving pressures remained low. Prone positioning substantially increased oxygenation (p<0.01). Interpretation: In early COVID-19 ARDS, substantial PEEP values were required for optimizing oxygenation. Pulmonary opacities resolved during mechanical ventilation with high PEEP suggesting recruitment of lung volume. Funding: German Research Foundation, German Federal Ministry of Education and Research.

3.
Cell ; 182(6): 1419-1440.e23, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32810438

RESUMO

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Células Mieloides/imunologia , Mielopoese , Pneumonia Viral/imunologia , Adulto , Idoso , Antígenos CD11/genética , Antígenos CD11/metabolismo , COVID-19 , Células Cultivadas , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Feminino , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Células Mieloides/citologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Proteoma/genética , Proteoma/metabolismo , Proteômica , Análise de Célula Única
4.
Nat Biotechnol ; 38(8): 970-979, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32591762

RESUMO

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Sistema Respiratório/patologia , Análise de Célula Única , Transcriptoma , Adulto , Idoso , Enzima de Conversão de Angiotensina 2 , Líquido da Lavagem Broncoalveolar/virologia , COVID-19 , Comunicação Celular , Diferenciação Celular , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Humanos , Sistema Imunitário/patologia , Inflamação/imunologia , Inflamação/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Índice de Gravidade de Doença
5.
Am J Physiol Regul Integr Comp Physiol ; 317(1): R15-R24, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042402

RESUMO

Previous research suggested substantial interactions of growth hormone (GH) and sympathetic nervous activity. This cross talk can be presumed both during physiological (e.g., slow-wave sleep) and pathological conditions of GH release. However, microneurographic studies of muscle sympathetic nerve activity (MSNA) and assessment of baroreflex function during acute GH-releasing hormone (GHRH)-mediated GH release were not conducted so far. In a balanced, double-blind crossover design, GHRH or placebo (normal saline) were intravenously administered to 11 healthy male volunteers. MSNA was assessed microneurographically and correlated with blood pressure (BP) and heart rate (HR) at rest before (pre-) and 30-45 (post-I) and 105-120 min (post-II) after respective injections. Additionally, baroreflex function was assessed via graded infusion of vasoactive drugs. GHRH increased GH serum levels as intended. Resting MSNA showed significant net increases of both burst rate and total activity from pre- to post-I and post-II following GHRH injections compared with placebo (ANOVA for treatment and time, burst rate: P = 0.028; total activity: P = 0.045), whereas BP and HR were not altered. ANCOVA revealed that the dependent variable MSNA was not affected by the independent variables mean arterial BP (MAP) or HR (MAP: P = 0.006; HR: P = 0.003). Baroreflex sensitivity at baroreflex challenge was not altered. GHRH-mediated GH release is associated with a significant sympathoactivation at central nervous sites superordinate to the simple baroreflex feedback loop because GH induced a baroreflex resetting without altering baroreflex sensitivity.


Assuntos
Hormônio Liberador de Hormônio do Crescimento/farmacologia , Hormônio do Crescimento/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Adulto , Barorreflexo , Pressão Sanguínea , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Nitroglicerina/administração & dosagem , Nitroglicerina/farmacologia , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Simpatomiméticos/administração & dosagem , Simpatomiméticos/farmacologia , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia , Adulto Jovem
6.
J Clin Endocrinol Metab ; 99(2): E246-51, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24423295

RESUMO

CONTEXT: Insulin infused into the central nervous system of rats suppresses lipolysis in white adipose tissue, indicating a role of brain insulin in regulating systemic lipid metabolism. OBJECTIVE: We investigated whether central nervous insulin delivery suppresses lipolysis in healthy humans. DESIGN: Placebo-controlled, balanced within-subject comparisons were performed in both a main and an independent corroborative experiment. SETTING/PARTICIPANTS/INTERVENTION: Two groups of healthy volunteers were examined at the German University Clinics of Lübeck and Tübingen, respectively, with molecular analyses taking place at Mt Sinai School of Medicine (New York, New York). The 14 healthy male subjects of the main study and the 22 women and 5 men of the corroborative study each received 160 IU of human insulin intranasally. MAIN OUTCOME MEASURES: In the main study, we measured systemic levels of free fatty acids (FFAs), triglycerides, and glycerol and the rate of appearance of deuterated glycerol as an estimate of lipolysis before and after intranasal insulin administration. We also analyzed the expression of key lipolytic enzymes in sc fat biopsies and measured blood glucose and glucoregulatory hormones. In the corroborative study, FFA concentrations were assessed before and after intranasal insulin administration. RESULTS: In the main experiment, intranasal insulin suppressed circulating FFA concentrations and lipolysis (rate of appearance of deuterated glycerol) in the absence of significant changes in circulating insulin levels. Lipolytic protein expression in sc adipose tissue was not affected. The corroborative study confirmed that intranasal insulin lowers systemic FFA concentrations. CONCLUSIONS: Our findings indicate that brain insulin controls systemic lipolysis in healthy humans by predominantly acting on non-sc adipose tissue.


Assuntos
Insulina/administração & dosagem , Lipólise/efeitos dos fármacos , Gordura Subcutânea/efeitos dos fármacos , Administração Intranasal , Adulto , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Masculino , Gordura Subcutânea/metabolismo
7.
J Clin Endocrinol Metab ; 98(3): E491-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23393176

RESUMO

BACKGROUND: Obesity and arterial hypertension are tightly connected. Obese individuals show significant elevation of vasoconstrictory muscle sympathetic nerve activity (MSNA). Obesity-related hyperleptinemia might play a key role in mediating these effects. Leptin is synthesized in proportion to body fat mass and activates SNA in animal models. In humans, however, direct evidence linking hyperleptinemia to sympathetic activation has not yet been established. In the present study, we characterize the effects of acute hyperleptinemia on microneurographically recorded SNA in humans. METHODS: In a balanced, double-blind crossover design, 12 healthy normal-weight males received an iv bolus of leptin or placebo. MSNA (bursts per minute) was continuously recorded using a microneurographic technique. Ten-minute periods were analyzed at resting periods before (t-100) and at 20 (t20), 60 (t60), and 140 (t140) minutes after substance administration. Blood pressure and heart rate (HR) were recorded simultaneously. RESULTS: Baseline values of MSNA, blood pressure, and HR were comparable in both conditions (MSNA: t-100, 24.3 ± 1.6 vs 22.7 ± 1.7, not significant). After application of leptin, MSNA showed a significant increase (t20, 31.0 ± 1.9 vs. 24.9 ± 1.8, P = .05) that persisted until the end of the experiment (t60, P = .008; t140, P = .004). There were no significant changes in blood pressure and HR. CONCLUSIONS: Acute experimental hyperleptinemia has significant central nervous excitatory effects on vasoconstrictory sympathetic outflow as measured by MSNA in healthy men. These results suggest that leptin acts as an important mediator linking obesity to elevated MSNA and potentially to the development of hypertension.


Assuntos
Hipertensão/sangue , Hipertensão/induzido quimicamente , Leptina/sangue , Leptina/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Doença Aguda , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/fisiopatologia , Injeções Intravenosas , Leptina/efeitos adversos , Masculino , Músculo Esquelético/inervação , Obesidade/metabolismo , Obesidade/fisiopatologia , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/fisiologia , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/fisiologia , Adulto Jovem
8.
Am J Physiol Regul Integr Comp Physiol ; 302(11): R1305-12, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22492814

RESUMO

Ghrelin, a neuropeptide originally known for its growth hormone-releasing and orexigenic properties, exerts important pleiotropic effects on the cardiovascular system. Growing evidence suggests that these effects are mediated by the sympathetic nervous system. The present study aimed at elucidating the acute effect of ghrelin on sympathetic outflow to the muscle vascular bed (muscle sympathetic nerve activity, MSNA) and on baroreflex-mediated arterial blood pressure (BP) regulation in healthy humans. In a randomized double-blind cross-over design, 12 lean young men were treated with a single dose of either ghrelin 2 µg/kg iv or placebo (isotonic saline). MSNA, heart rate (HR), and BP were recorded continuously from 30 min before until 90 min after substance administration. Sensitivity of arterial baroreflex was repeatedly tested by injection of vasoactive substances based on the modified Oxford protocol. Early, i.e., during the initial 30 min after ghrelin injection, BP significantly decreased together with a transient increase of MSNA and HR. In the course of the experiment (>30 min), BP approached placebo level, while MSNA and HR were significantly lower compared with placebo. The sensitivity of vascular arterial baroreflex significantly increased at 30-60 min after intravenous ghrelin compared with placebo, while HR response to vasoactive drugs was unaltered. Our findings suggest two distinct phases of ghrelin action: In the immediate phase, BP is decreased presumably due to its vasodilating effects, which trigger baroreflex-mediated counter-regulation with increases of HR and MSNA. In the delayed phase, central nervous sympathetic activity is suppressed, accompanied by an increase of baroreflex sensitivity.


Assuntos
Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Grelina/fisiologia , Frequência Cardíaca/fisiologia , Sistema Nervoso Simpático/fisiologia , Sistema Vasomotor/fisiologia , Adulto , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Grelina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Adulto Jovem
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