Mechanisms of SARS‐CoV‐2‐induced lung vascular disease: potential role of complement

Abstract

The outbreak of COVID-19 disease, caused by SARS-CoV-2 beta-coronovirus, urges a focused search for the underlying mechanisms and treatment options. The lung is the major target organ of COVID-19, wherein the primary cause of mortality is hypoxic respiratory failure, resulting from acute respiratory distress syndrome, with severe hypoxemia, often requiring assisted ventilation. While similar in some ways to acute respiratory distress syndrome secondary to other causes, lungs of some patients dying with COVID-19 exhibit distinct features of vascular involvement, including severe endothelial injury and cell death via apoptosis and/or pyroptosis, widespread capillary inflammation, and thrombosis. Furthermore, the pulmonary pathology of COVID-19 is characterized by focal inflammatory cell infiltration, impeding alveolar gas exchange resulting in areas of local tissue hypoxia, consistent with potential amplification of COVID-19 pathogenicity by hypoxia. Vascular endothelial cells play essential roles in both innate and adaptive immune responses, and are considered to be “conditional innate immune cells” centrally participating in various inflammatory, immune pathologies. Activated endothelial cells produce cytokines/chemokines, dynamically recruit and activate inflammatory cells and platelets, and centrally participate in pro-thrombotic processes (thrombotic microangiopathies). Initial reports presented pathological findings of localized direct infection of vascular endothelial cells with SARS-CoV-2, yet emerging evidence does not support direct infection of endothelial or other vascular wall cell and thus widespread endothelial cell dysfunction and inflammation may be better explained as secondary responses to epithelial cell infection and inflammation. Endothelial cells are also actively engaged in a cross-talk with the complement system, the essential arm of innate immunity. Recent reports present evidence for complement deposition in SARS-CoV-2-damaged lung microcirculation, further strengthening the idea that, in severe cases of COVID-19, complement activation is an essential player, generating destructive hemorrhagic, capillaritis-like tissue damage, clotting, and hyperinflammation. Thus, complement-targeted therapies are actively in development. This review is intended to explore in detail these ideas.

Recent advancements in pulmonary arterial hypertension and right heart failure research: overview of selected abstracts from ATS2020 and emerging COVID‐19 research

“…COVID-19 pandemic caused by the SARS-CoV-2 virus continues to inflict significant morbidity and mortality around the globe . Recent studies suggest potential pathologic interactions between SARS-CoV-2 infection, RV function, pulmonary vascular damages and PH [76][77][78][79][80][81] . Lungs of some patients dying with COVID-19 demonstrated pulmonary vascular involvement in the form of severe endothelial injury, cell death and thrombosis 77,78,80,82 .…”

“…Recent studies suggest potential pathologic interactions between SARS-CoV-2 infection, RV function, pulmonary vascular damages and PH [76][77][78][79][80][81] . Lungs of some patients dying with COVID-19 demonstrated pulmonary vascular involvement in the form of severe endothelial injury, cell death and thrombosis 77,78,80,82 . Although the precise mechanisms remain elusive, complement deposition and activation have been suggested as plausible mechanisms for destructive hemorrhagic, capillaritis-like tissue damage, clotting, and hyper-inflammation in COVID-19-associated pulmonary vasculopathy 78 .…”

May macroglossia in COVID-19 be related not only to angioedema?

“…The main pathological features of the coronavirus disease (COVID-19) are pulmonary and cardiovascular involvement, nevertheless the infection with SARS-CoV-2 may lead to multisystem disease [ 1 ], affecting different organs, both directly or indirectly [ [2] , [3] , [4] , [5] ]. SARS-CoV-2 entry into host cells is mediated by specific binding to the angiotensin-converting enzyme 2 (ACE2) receptors [ 6 ], thus the multiorgan pathology could be enabled by the wide distribution of ACE-2 receptors in different tissues.…”

Association of abnormal pulmonary vasculature on CT scan for COVID-19 infection with decreased diffusion capacity in follow up: A retrospective cohort study

“…Much of the dyspnea can be explained by the degree of pneumonia present on imaging, but not uncommonly there is a disconnect between the degree of hypoxemia and visual extent of abnormal lung parenchyma [2]. There is now broad consensus that diverse vasculocentric processes contribute to the striking and surprisingly refractory hypoxemia observed in COVID-19 patients [3]. It has been shown in an autopsy series that those that died of COVID-19 had widespread thrombosis and microangiopathy of the pulmonary vessels [4] suggesting that pulmonary vascular disease plays an important role in the pathophysiology of hypoxemia in the infected patient.…”