scholarly journals Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
István Vadász
Keyword(s):  
Molecular Mechanisms ◽  
Distress Syndrome ◽  
Epithelial Barrier ◽  
Membrane Transporter ◽  
Alveolar Fluid Clearance ◽  
Barrier Integrity ◽  
Alveolar Epithelial ◽  
Barrier Failure ◽  
Number Of Patients ◽  
Plasma Membrane Transporter

A significant number of patients with coronavirus disease 2019 (COVID‑19) develop acute respiratory distress syndrome (ARDS) that is associated with a poor outcome. The molecular mechanisms driving failure of the alveolar barrier upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) infection remain incompletely understood. The Na,K‑ATPase is an adhesion molecule and a plasma membrane transporter that is critically required for proper alveolar epithelial function by both promoting barrier integrity and resolution of excess alveolar fluid, thus enabling appropriate gas exchange. However, numerous SARS-CoV‑2-mediated and COVID‑19-related signals directly or indirectly impair the function of the Na,K-ATPase, thereby potentially contributing to disease progression. In this Perspective, we highlight some of the putative mechanisms of SARS-CoV-2-driven dysfunction of the Na,K‑ATPase, focusing on expression, maturation and trafficking of the transporter. A therapeutic mean to selectively inhibit the maladaptive signals that impair the Na,K-ATPase upon SARS-CoV‑2 infection might be effective in reestablishing the alveolar epithelial barrier and promoting alveolar fluid clearance (AFC) and thus advantageous in patients with COVID‑19-associated ARDS.

scholarly journals Alveolar Epithelial Cell Type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation.

2020 ◽  
Author(s):  
Maurizio Carcaterra ◽  
Cristina Caruso
Keyword(s):  
Molecular Mechanisms ◽  
Virus Disease ◽  
Clinical Manifestations ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Cell Type ◽  
Alveolar Cells ◽  
Alveolar Epithelial ◽  
Corona Virus ◽  
Number Of Patients

Abstract Background: The Corona Virus Disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) requires a rapid solutionand global collaborative efforts in order to define preventive and treatment strategies.Methods: One of the major challenges of this disease is the high number of patients needing advanced respiratory support due to the Acute Respiratory Distress Syndrome (ARDS) as the lung is the major –although not exclusive-target of the virus. The molecular mechanisms, pathogenic drivers and the target cell type(s) in SARSCoV-2 infection are still poorly understood, but the development of a “hyperactive” immune response is proposed to play a role in the evolution of the disease and it is envisioned as a major cause of morbidity and mortality.Results: Here we propose a theory by which the main targets for SARS-CoV-2 are the Type II Alveolar Epithelial Cells and the clinical manifestations of the syndrome are a direct consequence of their involvement. We hypotize the existence of a vicious cycle by which once alveolar damage starts in AEC II cells, the inflammatory state is supported by macrophage proinflammatory polarization (M1), cytokines release and by the activation of the NF-κB pathway.Conclusions: If this theory is confirmed, future therapeutic efforts can be directed to target Type 2 alveolar cells and the molecular pathogenic drivers associated with their dysfunction with currently available therapeutic strategies.

Pathophysiology of acute respiratory distress syndrome

2016 ◽  
Author(s):  
Lorraine B. Ware
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Failure ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Pulmonary Oedema ◽  
Molecular Mechanisms ◽  
Distress Syndrome ◽  
Cigarette Smoke Exposure ◽  
Alveolar Epithelial ◽  
Severe Traumatic Injury

The acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure characterized by the acute onset of non-cardiogenic pulmonary oedema due to increased lung endothelial and alveolar epithelial permeability. Common predisposing clinical conditions include sepsis, pneumonia, severe traumatic injury, and aspiration of gastric contents. Environmental factors, such as alcohol abuse and cigarette smoke exposure may increase the risk of developing ARDS in those at risk. Pathologically, ARDS is characterized by diffuse alveolar damage with neutrophilic alveolitis, haemorrhage, hyaline membrane formation, and pulmonary oedema. A variety of cellular and molecular mechanisms contribute to the pathophysiology of ARDS, including exuberant inflammation, neutrophil recruitment and activation, oxidant injury, endothelial activation and injury, lung epithelial injury and/or necrosis, and activation of coagulation in the airspace. Mechanical ventilation can exacerbate lung inflammation and injury, particularly if delivered with high tidal volumes and/or pressures. Resolution of ARDS is complex and requires coordinated activation of multiple resolution pathways that include alveolar epithelial repair, clearance of pulmonary oedema through active ion transport, apoptosis, and clearance of intra-alveolar neutrophils, resolution of inflammation and fibrinolysis of fibrin-rich hyaline membranes. In some patients, activation of profibrotic pathways leads to significant lung fibrosis with resultant prolonged respiratory failure and failure of resolution.

scholarly journals Tissue Factor Enhances the Alveolar Epithelial Barrier Integrity during Acute Lung Injury

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Holly Sucharski ◽  
Nathan Putz ◽  
Ciara Shaver ◽  
Lorraine Ware ◽  
Julie Bastarache
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tissue Factor ◽  
Epithelial Barrier ◽  
Barrier Integrity ◽  
Alveolar Epithelial

scholarly journals Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Franco Conforti ◽  
Robert Ridley ◽  
Christopher Brereton ◽  
Aiman Alzetani ◽  
Benjamin Johnson ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Epithelial Barrier ◽  
Barrier Integrity ◽  
Alveolar Epithelial ◽  
And Function

scholarly journals PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubrey N. Michi ◽  
Bryan G. Yipp ◽  
Antoine Dufour ◽  
Fernando Lopes ◽  
David Proud
Keyword(s):  
Host Defense ◽  
Barrier Function ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Cellular Damage ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Epithelial Damage

AbstractHuman rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.

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