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Review
. 2020 Nov 20;21(22):8793.
doi: 10.3390/ijms21228793.

Endothelial Damage in Acute Respiratory Distress Syndrome

Alice G Vassiliou  1 , Anastasia Kotanidou  1 , Ioanna Dimopoulou  1 , Stylianos E Orfanos  1   2
Affiliations
Review

Endothelial Damage in Acute Respiratory Distress Syndrome

Alice G Vassiliou et al. Int J Mol Sci. .

Abstract

The pulmonary endothelium is a metabolically active continuous monolayer of squamous endothelial cells that internally lines blood vessels and mediates key processes involved in lung homoeostasis. Many of these processes are disrupted in acute respiratory distress syndrome (ARDS), which is marked among others by diffuse endothelial injury, intense activation of the coagulation system and increased capillary permeability. Most commonly occurring in the setting of sepsis, ARDS is a devastating illness, associated with increased morbidity and mortality and no effective pharmacological treatment. Endothelial cell damage has an important role in the pathogenesis of ARDS and several biomarkers of endothelial damage have been tested in determining prognosis. By further understanding the endothelial pathobiology, development of endothelial-specific therapeutics might arise. In this review, we will discuss the underlying pathology of endothelial dysfunction leading to ARDS and emerging therapies. Furthermore, we will present a brief overview demonstrating that endotheliopathy is an important feature of hospitalised patients with coronavirus disease-19 (COVID-19).

Keywords: ARDS; biomarkers; coagulation; dysfunction; inflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Underlying pathology of endothelial dysfunction leading to acute respiratory distress syndrome (ARDS). ARDS is characterized by damage to the capillary endothelium and alveolar epithelium. Disruption of the endothelial barrier results in the movement of fluid and macromolecules into the interstitial space and pulmonary air spaces causing pulmonary oedema. The formation of a hyaline membrane in alveolar walls allows exudation of neutrophils and protein-rich fluid into the alveolar space. Transport across the endothelium can occur either via the endothelial cell (transcellular) or between adjacent cells, through inter-endothelial junctions (IEJs) (paracellular). The changes in the microvascular endothelial structure and function play a central role in the acute inflammatory response, in which the body tries to eliminate microbial invaders. To achieve this, the endothelium becomes leaky and inflamed, allowing innate immune cells and humoral effector molecules to cross the barrier to the site of infection. This defence mechanism may become deleterious, under overwhelming pathological conditions, leading to ARDS. The cells of the innate immune system release large amounts of pro- and anti-inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNF-α. The high levels of circulating cytokines can potentiate organ damage by endothelial injury and other routes. Endothelial damage is associated with activation of neutrophils and expression of neutrophil and endothelial adhesion molecules. E-selectin and P-selectin are early mediators of the adhesion of activated neutrophils to endothelia in inflammatory states, prior to their firm adhesion and diapedesis at sites of tissue injury and inflammation. Intercellular adhesion molecule-1 (ICAM-1) controls the firm adhesion of neutrophils on the endothelium and facilitates their subsequent transendothelial migration via the platelet-endothelial cell adhesion molecule-1 (PECAM-1) to infection sites. In addition to inflammation, coagulation and fibrinolysis are also critical host responses to infection and injury involved in ARDS. Endothelial cells (ECs) coordinate this response by shifting from their normal anti-thrombotic, anti-inflammatory, and pro-fibrinolytic phenotype to an activated state of endothelial dysfunction. ECs actively regulate haemostasis by producing a variety of proteins, including pro-thrombotic substances (von Willebrand factor, P-selectin), molecules restricting coagulation (thrombomodulin) and fibrinolytic factors (plasminogen activators). Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of fibrinolysis, whose upregulation leads to a shift from pro- to anti-fibrinolytic phenotypes. The protein C (PC) system provides important control of coagulation by virtue of the capacity of activated protein C (APC) to proteolytically inactivate the cofactors Va and VIIIa. The PC anticoagulant system also involves protein S, and the endothelial receptor thrombomodulin (TM). Conversion of protein C to the anti-coagulant APC is generated by TM-bound thrombin. The vascular endothelium has an important metabolic function with respect to vasoactive substances. Several vasoconstrictors and vasodilators are produced by the endothelium, such as endothelin-1, angiotensin-2, nitric oxide, and prostacyclin, which regulate vasomotor tone and the recruitment and activity of inflammatory cells and regulate thrombosis. In addition to breaking down bradykinin, ACE hydrolyses angiotensin I to angiotensin II and the balance between ACE and ACE2 has been suggested to be crucial for controlling angiotensin II levels. Vascular development strongly depends on the collaboration of growth factors. Vascular endothelial growth factor (VEGF) is a glycoprotein originally isolated as a permeability factor with unique specificity for vascular ECs. Angiopoietin-2 (Ang-2) disrupts the protective effects of Ang-1-Tie2 signalling, promoting vascular leakage. Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; APC, activated protein C; IEJs, inter-endothelial junctions; IL, interleukin; PAI-1, plasminogen activator inhibitor 1; PECAM-1, platelet-endothelial cell adhesion molecule-1; sICAM-1, soluble intercellular adhesion molecule-1; sTM, soluble thrombomodulin; TNF-α, tumour necrosis factor-alpha; VEGF, vascular endothelial growth factor; VEGF-R, VEGF receptor; vWF, von Willebrand factor.
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