Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
The acute respiratory distress syndrome
Michael A. Matthay, … , Lorraine B. Ware, Guy A. Zimmerman
Michael A. Matthay, … , Lorraine B. Ware, Guy A. Zimmerman
Published August 1, 2012
Citation Information: J Clin Invest. 2012;122(8):2731-2740. https://doi.org/10.1172/JCI60331.
View: Text | PDF
Review Series

The acute respiratory distress syndrome

  • Text
  • PDF
Abstract

The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.

Authors

Michael A. Matthay, Lorraine B. Ware, Guy A. Zimmerman

×

Figure 3

Molecular targets for new therapies that can lead to endothelial and epithelial barrier stabilization and reversal of increased permeability.

Options: View larger image (or click on image) Download as PowerPoint
Molecular targets for new therapies that can lead to endothelial and epi...
(A) Disrupted alveolar barrier function, resulting in increased permeability to water, proteins, and other solutes, is a hallmark of clinical and experimental ALI. Intra-alveolar accumulation of neutrophils, other leukocytes, and erythrocytes is also associated with altered endothelial and epithelial barrier function. TNF-α, IL-1, thrombin, and microbes and their toxins — including LPS, noxious agents, and factors generated by neutrophils and platelet-leukocyte interactions — can destabilize and disrupt alveolar barrier function, leading to increased permeability. (B) Disruption of VE-cadherin bonds is a central mechanism of altered endothelial barrier function in experimental ALI and in models of sepsis and systemic vascular destabilization. VE-cadherin is an endothelial-specific adherens junction protein that mediates Ca2+-dependent homophilic interactions at the lateral cell membranes of adjacent endothelial cells. VE-cadherin is regulated by cytoplasmic associations with catenins and actin and by cytoskeletal organization, in addition to intracellular signaling by Rho and Rac. Disruption of VE-cadherin bonds also facilitates transendothelial migration of leukocytes and, in some studies, is associated with accumulation of leukocytes and platelets in microvessels. (C) Stabilizing agonists (i) or small-molecule mimetics bind to stabilizing receptors (ii) on endothelial cells in alveolar and systemic vessels, restoring barrier integrity. Stabilizing agonists include S1P, Slit2N, Ang1, atrial natriuretic peptide, APC, and ATP; multiple intracellular pathways and mechanisms are implicated (iii) (reviewed in refs. 58, 61, 64). These intracellular mechanisms favorably influence cytoskeletal architecture, preserve catenin–VE-cadherin cytoplasmic interactions, prevent VE-cadherin internalization, and/or promote adherens junction formation (iv and v).
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts