Vascular endotheliitis associated with infections: Its pathogenetic role and therapeutic implication

Abstract

Vascular endothelial cells are major participants in and regulators of immune responses and inflammation. Vascular endotheliitis is regarded as a host immune-inflammatory response of the endothelium forming the inner surface of blood vessels in association with a direct consequence of infectious pathogen invasion. Vascular endotheliitis and consequent endothelial dysfunction can be a principle determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Emerging evidence suggests the role of vascular endotheliitis in the pathogenesis of coronavirus disease 2019 (COVID-19) and its related complications. Thus, once initiated, vascular endotheliitis and resultant cytokine storm cause systemic hyperinflammation and a thrombotic phenomenon in COVID-19, leading to acute respiratory distress syndrome and widespread organ damage. Vascular endotheliitis also appears to be a contributory factor to vasculopathy and coagulopathy in sepsis that is defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection. Therefore, protecting endothelial cells and reversing vascular endotheliitis may be a leading therapeutic goal for these diseases associated with vascular endotheliitis. In this review, we outline the etiological and pathogenic importance of vascular endotheliitis in infection-related inflammatory diseases, including COVID-19, and possible mechanisms leading to vascular endotheliitis. We also discuss pharmacological agents which may be now considered as potential endotheliitis-based treatment modalities for those diseases.

Keywords: COVID-19; Endothelial cells; Endotheliitis; Organ dysfunction; Sepsis.

Graphical abstract

Fig. 1

Schematic diagram depicting endotheliitis to contribute to systemic complications in COVID-19. The ACE2 receptor is abundantly expressed in human tissues. It is also widely expressed on vascular endothelial cells in major organs, such as the lung, heart, kidney, and liver, allowing endothelial cells to be infected by SARS-CoV2 and leading to vascular endotheliitis. Vascular endotheliitis may be situated as the sequence of cellular events leading to endothelial injury and dysfunction. SARS-CoV2 infection can cause lung complications such as interstitial pneumonia ranging from mild to severe clinical conditions. While the subsequent immune reaction may lead to progressive interstitial and alveolar edema, impairing gas exchange and eventually resulting in ARDS, vascular endotheliitis likely plays a pivotal role in the development of ARDS. Widespread endotheliitis can also adversely affect other organs beyond the lung, importantly the heart, kidney, and liver.

Fig. 2

Scheme illustrating initiations of vascular endotheliitis. When endothelial cells are activated, expression on endothelial surfaces of adhesion molecules, such as ICAM-1, VCAM-1, E-selectin, and P-selectin, is promoted by activating NF-κB and AP-1, thereby facilitating leukocyte rolling, adherence, and transmigration. Endothelial firm adhesion of circulating leukocytes from the blood stream contributes to the development of endotheliitis through the release of pro-inflammatory cytokines and the generation of extracellular ROS. Endothelial ROS are formed and pro-inflammatory cytokines are produced by activated endothelial cells. They are also responsible for developing endotheliitis. Pro-inflammatory cytokines, which are induced by inflammation due to tissue damage or infection and are carried in the blood, also play a role in the endotheliitis development. EC = endothelial cells.