Covid-19, Angiogenesis, and ARDS Endotypes Hariri, Lida; Hardin, C. Corey
New England journal of medicine/The New England journal of medicine,
07/2020, Letnik:
383, Številka:
2
Journal Article
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The SARS-CoV-2 pandemic has inspired new interest in understanding the fundamental pathology of acute respiratory distress syndrome (ARDS), which has been associated with severe coronavirus disease ...2019 (Covid-19). ARDS has long been recognized to be remarkably heterogeneous, with not only a wide range of causes but also a broad spectrum of severity, abnormalities on imaging, and gas-exchange impairment.
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The form of ARDS that is associated with Covid-19 is no different.
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A long-standing goal
3
has been to define endotypes that subdivide ARDS into groups on the basis of distinct biologic and pathologic processes in order to design higher-yield clinical trials and . . .
Like many critical care interventions, mechanical ventilation is lifesaving when indicated but is beset by potential complications as the duration of use increases. Early identification of patients ...who are ready to be liberated from ventilator support is therefore key to the management of respiratory failure. Because clinician judgment lacks both sensitivity and specificity for identifying such patients,
1
this task is best accomplished by means of protocolized spontaneous-breathing trials,
2,3
in which patients who meet a defined set of criteria undergo a test period of minimal or no ventilator support. Many, if not most, patients who meet the criteria for a spontaneous-breathing . . .
A central challenge in clinical studies of acute respiratory distress syndrome (ARDS) is its inherent heterogeneity. As documented in the landmark LUNG SAFE (Large Observational Study to Understand ...the Global Impact of Severe Acute Respiratory Failure) trial, patients with ARDS present with a spectrum of abnormalities in gas exchange and respiratory mechanics, a spectrum of clinical severity, and a spectrum of outcomes. Indeed, for this reason the Berlin definition of ARDS has been criticized as being overly broad. A major focus of ARDS clinical research has therefore been identification of subphenotypes or endotypes within ARDS that can be used to design trials and tailor treatment. To date, however, no subphenotype has been demonstrated to predict treatment response or improve outcomes in a prospective trial. Here, Hardin discusses the paper by Panwar et al. pointing out that such phenotypes were easily identifiable the pre-COVID-19 era.
Endothelial cell alignment along the direction of laminar fluid flow is widely understood to be a defining morphological feature of vascular homeostasis. While the role of associated signaling and ...structural events have been well studied, associated intercellular stresses under laminar fluid shear have remained ill-defined and the role of these stresses in the alignment process has remained obscure. To fill this gap, we report here the tractions as well as the complete in-plane intercellular stress fields measured within the human umbilical vein endothelial cell (HUVEC) monolayer subjected to a steady laminar fluid shear of 1 Pa. Tractions, intercellular stresses, as well as their time course, heterogeneity, and anisotropy, were measured using monolayer traction microscopy and monolayer stress microscopy. Prior to application of laminar fluid flow, intercellular stresses were largely tensile but fluctuated dramatically in space and in time (317 ± 122 Pa). Within 12 h of the onset of laminar fluid flow, the intercellular stresses decreased substantially but continued to fluctuate dramatically (142 ± 84 Pa). Moreover, tractions and intercellular stresses aligned strongly and promptly (within 1 h) along the direction of fluid flow, whereas the endothelial cell body aligned less strongly and substantially more slowly (12 h). Taken together, these results reveal that steady laminar fluid flow induces prompt reduction in magnitude and alignment of tractions and intercellular stress tensor components followed by the retarded elongation and alignment of the endothelial cell body. Appreciably smaller intercellular stresses supported by cell-cell junctions logically favor smaller incidence of gap formation and thus improved barrier integrity.
ECMO for Severe ARDS Hardin, C. Corey; Hibbert, Kathryn
The New England journal of medicine,
05/2018, Letnik:
378, Številka:
21
Journal Article
Recenzirano
The acute respiratory distress syndrome (ARDS), which is characterized by severe hypoxemic respiratory failure, affects as many as 10% of patients in the intensive care unit and is a common reason ...for the use of therapeutic mechanical ventilation.
1
On the basis of results of landmark clinical trials, there is substantial consensus around an initial approach to ARDS that combines invasive mechanical ventilation with limited tidal volumes,
2
the use of positive end-expiratory pressure (PEEP) to prevent derecruitment (the collapse of small airways and alveoli),
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and conservative fluid management.
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In patients with severe ARDS, defined as a ratio of partial pressure of . . .
Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a ...comprehensive mathematical framework based on the known mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, incorporating the renin-angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines, and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of comorbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age; comorbidities such as obesity, diabetes, and hypertension; and dysregulated immune response. We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8
T cells and sufficient control of the innate immune response. Furthermore, the best treatment-or combination of treatments-depends on the preinfection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.
Cells comprising a tissue migrate as part of a collective. How collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, because mechanical stresses ...exerted at cell-cell junctions have not been accessible experimentally. We report here maps of these stresses within and between cells comprising a monolayer. Within the cell sheet there arise unanticipated fluctuations of mechanical stress that are severe, emerge spontaneously, and ripple across the monolayer. Within that stress landscape, local cellular migrations follow local orientations of maximal principal stress. Migrations of both endothelial and epithelial monolayers conform to this behaviour, as do breast cancer cell lines before but not after the epithelial-mesenchymal transition. Collective migration in these diverse systems is seen to be governed by a simple but unifying physiological principle: neighbouring cells join forces to transmit appreciable normal stress across the cell-cell junction, but migrate along orientations of minimal intercellular shear stress.
Nutrition in Medicine — A New Review Article Series Lee, Clement D.; Hardin, C. Corey; Longo, Dan L. ...
New England journal of medicine/The New England journal of medicine,
04/2024, Letnik:
390, Številka:
14
Journal Article
Recenzirano
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The editors announce a new series focusing on fundamental and emerging concepts in nutrition, from the “pharmacodynamics” of food to the gut and immunity and the role of the gut microbiome in health ...and disease.
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