scholarly journals The role of stretch-activated ion channels in acute respiratory distress syndrome: finally a new target?

2016 ◽  
Vol 311 (3) ◽  
pp. L639-L652 ◽  
Author(s):  
Andreas Schwingshackl
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Ion Channels ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Oxygen Toxicity ◽  
Inflammatory Cells ◽  
Future Research ◽  
Stretch Activated Ion Channels

Mechanical ventilation (MV) and oxygen therapy (hyperoxia; HO) comprise the cornerstones of life-saving interventions for patients with acute respiratory distress syndrome (ARDS). Unfortunately, the side effects of MV and HO include exacerbation of lung injury by barotrauma, volutrauma, and propagation of lung inflammation. Despite significant improvements in ventilator technologies and a heightened awareness of oxygen toxicity, besides low tidal volume ventilation few if any medical interventions have improved ARDS outcomes over the past two decades. We are lacking a comprehensive understanding of mechanotransduction processes in the healthy lung and know little about the interactions between simultaneously activated stretch-, HO-, and cytokine-induced signaling cascades in ARDS. Nevertheless, as we are unraveling these mechanisms we are gathering increasing evidence for the importance of stretch-activated ion channels (SACs) in the activation of lung-resident and inflammatory cells. In addition to the discovery of new SAC families in the lung, e.g., two-pore domain potassium channels, we are increasingly assigning mechanosensing properties to already known Na+, Ca2+, K+, and Cl− channels. Better insights into the mechanotransduction mechanisms of SACs will improve our understanding of the pathways leading to ventilator-induced lung injury and lead to much needed novel therapeutic approaches against ARDS by specifically targeting SACs. This review 1) summarizes the reasons why the time has come to seriously consider SACs as new therapeutic targets against ARDS, 2) critically analyzes the physiological and experimental factors that currently limit our knowledge about SACs, and 3) outlines the most important questions future research studies need to address.

Extracorporeal Membrane Oxygenation (ECMO) for Lung Injury in Severe Acute Respiratory Distress Syndrome (ARDS): Review of the Literature

2016 ◽  
Vol 26 (6) ◽  
pp. 747-762 ◽  
Author(s):  
Summer Paolone
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Extracorporeal Membrane Oxygenation ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Future Research ◽  
High Morbidity ◽  
Ecmo Circuit ◽  
Membrane Oxygenation

Despite advances in mechanical ventilation, severe acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality rates ranging from 26% to 58%. Extracorporeal membrane oxygenation (ECMO) is a modified cardiopulmonary bypass circuit that serves as an artificial membrane lung and blood pump to provide gas exchange and systemic perfusion for patients when their own heart and lungs are unable to function adequately. ECMO is a complex network that provides oxygenation and ventilation and allows the lungs to rest and recover from respiratory failure while minimizing iatrogenic ventilator-induced lung injury. In critical care settings, ECMO is proven to improve survival rates and outcomes in patients with severe ARDS. This review defines severe ARDS; describes the ECMO circuit; and discusses recent research, optimal use of the ECMO circuit, limitations of therapy including potential complications, economic impact, and logistical factors; and discusses future research considerations.

scholarly journals Does activation of the FcγRIIa play a role in the pathogenesis of the acute lung injury/acute respiratory distress syndrome?

2010 ◽  
Vol 118 (8) ◽  
pp. 519-526 ◽  
Author(s):  
Rafal Fudala ◽  
Agnieszka Krupa ◽  
Dorota Stankowska ◽  
Timothy C. Allen ◽  
Anna K. Kurdowska
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Immune Complexes ◽  
Distress Syndrome ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Contributing Factors

ALI (acute lung injury) and its more severe form ARDS (acute respiratory distress syndrome) are inflammatory diseases of the lung characterized by hypoxaemia and diffuse bilateral infiltrates. Disruption of epithelial integrity and injury to endothelium are contributing factors of the development of ALI/ARDS, and alveolar damage is the most pronounced feature of ALI/ARDS. The resulting increase in lung microvascular permeability promotes influx of inflammatory cells to the alveolar spaces. Oedema fluid contains pro-nflammatory mediators and plasma proteins, including Igs (immunoglobulins). Moreover, several reports describe the presence of autoantibodies and immune complexes [anti-IL-8 (interleukin-8) autoantibody/IL-8 complexes] in lung fluids (oedema and bronchoalveolar lavage fluids) from patients with ALI/ARDS. These immune complexes associate with FcγRIIa (Fcγ IIa receptor) in lungs of patients with ARDS. Furthermore, the expression of FcγRIIa is substantially elevated in lungs of these patients. FcγRIIa appears on virtually all myeloid cells, platelets and endothelial cells. It is a low-affinity receptor for IgG that preferentially binds aggregated immunoglobulins and immune complexes. FcγRs regulate phagocytosis and cell-mediated cytotoxicity, and initiate the release of inflammatory mediators. It should be noted that immune complexes formed between either anti-neutrophil autoantibodies and their specific antigens or anti-HLA (human leucocyte antigen) antibodies and target antigens are implicated in the pathogenesis of TRALI (transfusion-related acute lung injury), and importantly, animal studies indicate that FcγRs are essential for these complexes to cause damage to the lungs. Therefore, we hypothesize that FcγRs such as FcγRIIa could contribute to the pathogenesis of ALI/ARDS.

scholarly journals Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Asbjørn G. Petersen ◽  
Peter C. Lind ◽  
Anne-Sophie B. Jensen ◽  
Mark A. Eggertsen ◽  
Asger Granfeldt ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Primary Endpoint ◽  
Bronchoalveolar Lavage Fluid ◽  
Distress Syndrome ◽  
Pulmonary Hemorrhage ◽  
Lavage Fluid

Abstract Background Senicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio. Methods ARDS was induced in female pigs (42–49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h. Results Final senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of senicapoc on alveolar–capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid. Conclusions In summary, senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.

Sign in / Sign up

Export Citation Format

Share Document