The vascular endothelium as decision maker in lung injury

Abstract

The vascular endothelium is the largest organ in the human body, capable of performing a wide range of cellular signaling and synthetic functions. It is also subjected to considerable mechanical stress due to the shear forces generated by blood flow, which amounts to approximately 10,000 L per day. The endothelial layer plays a crucial role in regulating vascular tone locally and controlling the extravasation of certain blood components. Additionally, it is integral to the coagulation process. The endothelium serves as the entry point for immune cells, which migrate from the bloodstream to surrounding tissues by passing through the endothelial layer. This underscores the importance of proper endothelial function for the health of the body's tissues and organs. When the endothelium fails to perform these functions adequately, leading to endothelial dysfunction, pathological conditions are more likely to develop. Notably, acute lung injury and its severe form, acute respiratory distress syndrome (ARDS), are often associated with endothelial dysfunction. ARDS refers to pulmonary edema with increased vascular permeability resulting from various pulmonary or systemic insults. In most cases, an exaggerated inflammatory and pro-thrombotic response to the initial insult causes disruption of the alveolar-capillary membrane and leakage of vascular fluid. This review emphasizes the central role of the vascular endothelium in acute conditions and seeks to clarify the concepts and interplay between endothelial activation, dysfunction, and damage.

Keywords: damage; endothelial activation; inflammation; lung injury; pulmonary endothelium; vascular dysfunction.

FIGURE 1

In a healthy state, mature endothelial cells (represented as red cells) are quiescent while performing a semi-permeable barrier function that regulates the supply of nutrients and oxygen to tissues and the removal of carbon dioxide and waste products. Nitric oxide (NO) produced through endothelial nitric oxide synthase (eNOS) is the primary regulator of blood flow and pressure. Upon activation, such as in response to pro-inflammatory cytokines and chemokines (e.g., TNF-alpha) or bacterial pathogens during lung infection or injury, inducible nitric oxide synthase (iNOS) becomes activated and generates high concentrations of NO through the activation of inducible nuclear factors, including NF-κB. Activated endothelial cells then upregulate cell adhesion molecules (selectins and integrins) to enhance leukocyte-endothelial cell interactions, facilitating the capture of circulating immune cells, such as neutrophils and monocytes, before extravasation into interstitial and alveolar spaces. Simultaneously, alterations in tight and adherens junctions allow excess extravasation of proteins, increasing endothelial permeability and leakage of bloodstream components. NO can reduce endothelial activation through inhibition of the transcription factor NF-κB and loss of NO increases endothelial cell activation. Endothelial activation can revert to its pre-inflammatory state, but prolonged/sustained activation can lead to irreversible endothelial dysfunction. Endothelial dysfunction in turn, leads to further increased permeability and transmigration of leukocytes through the endothelium, as well as to platelet activation and cytokine release. Together, these processes create a detrimental microenvironment, which damages the endothelial lining that can ultimately lead to endothelial cell death. Induced (sublethal) DNA damage and/or DNA repair deficiencies may also cause an activated endothelial state through activation of the genotoxic stress-induced NF-κB signaling pathway (“intrinsic” endothelial activation). In addition to endothelial DNA damage, the release of damage-associated molecular patterns (DAMPs) and the generation of reactive oxygen/nitrogen species (ROS/RNS) can further promote NF-κB activation. Superoxide (O₂ ·) as primary ROS/RNS species can rapidly react with NO to form peroxynitrite (ONOO−). Peroxynitrite in turn can cause multiple deleterious effects including tyrosine nitration of proteins and antioxidants inactivation finally mediating cell death and lung damage. Severe endothelial cell loss can occur as a long-term complication when the DNA-damaged and activated endothelial cells begin to proliferate. In most cases, endothelial cell death is apoptotic and involves the activation of acid sphingomyelinase (ASMase) and the subsequent formation of ceramides. In ALI, damage to both the vascular endothelium and alveolar epithelium occurs in response to systemic and local production of pro-inflammatory cytokines, resulting in the destruction of the endothelial and epithelial barriers in the lungs and the accumulation of edematous fluid and debris in the alveolar spaces.