# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 3 Pathogenesis of COVID-19-Induced Lung Injury
### Microvascular Dysfunction  
Numerous studies point toward microvascular dysfunction in COVID-19 as a key contributor to hypoxemia and worse outcomes [91; 92; 93; 94; 95; 96; 97; 98; 99]. This phenomenon appears to involve endothelial dysfunction, coagulopathy, and dysregulation of ACE2. Loss of barrier integrity and adoption of a pro-coagulative state in the vascular endothelium, termed endothelitis, is proposed to be a major contributor to COVID-19 lung injury [100]. Plasma markers of endothelial injury (angiopoietin-2, follistatin, PAI-1) were elevated and demonstrated to have a strong mortality-predictive capacity in a study on hospitalized COVID-19 patients. VEGF was also shown to be increased and associated with intussusceptive capillary angiogenesis [101]. Mechanisms driving endothelitis may be related to ACE2-mediated viral infection of endothelial cells, which has been observed in in vitro organoid models and on autopsy of lung and other organs [102]. Moreover, viral presence in autopsy samples colocalized with caspase-3 staining, indicating induction of endothelial apoptosis [103]. It is likely that host-mediated effects also drive the development of endothelitis in severe COVID-19 via high levels of pro-inflammatory cytokines and DAMPs. Collectively, this shift in endothelial status has critical consequences for the host. In addition to impairing the alveolar-capillary barrier function, endothelitis is suggested to cause the observed loss of hypoxic vasoconstriction in severe COVID-19, which exacerbates V/Q mismatch and hypoxemia [104]. The activated and disrupted endothelium acts synergistically with other processes to drive coagulopathy in COVID-19. Circulating levels of tissue factor-expressing extracellular vesicles are associated with disease severity and incidence of venous thromboembolism (VTE) [105]. Possibly driven by the pro-inflammatory milieu or direct infection, platelets in COVID-19 are hyperreactive and display enhanced P-selectin expression and immune cell-aggregation capacity [106]. NETs also appear to be a massive contributor to coagulation due to high levels of tissue factor expression and findings of aggregated NETs occluding microvessels in autopsy studies [80]. Critically, upregulation of genes encoding pro-coagulative factors (e.g., vWF) were accompanied by downregulation of genes encoding anticoagulative factors (e.g., thrombomodulin) in COVID-19 patient BALF, signaling a profound shift to a procoagulative state [107]. These observed mechanisms of coagulation are consistent with autopsy findings of capillary microthrombi and high incidence of VTE (21-69%) in severe COVID-19 [108]. Furthermore, interactions among S protein, fibrin, and immune cells contribute to the formation of pro-inflammatory blood clots that exacerbate thrombotic inflammation and pathology [109,110]. Dysregulated ACE2 activity may also contribute to vascular dysfunction. ACE2 performs important hemostatic roles in the renin-angiotensin-aldosterone system (RAAS), by converting angiotensin II (ang II) to angiotensin (1-7) (ang (1-7)), and the kallikrein-kinin system (KKS), by inactivating des-Arg9-bradykinin (DABK). Consequently, ACE2 prevents build-up of both ang II and DABK, which could otherwise be detrimental to the host [53]. In the RAAS, Ang II exerts vasoconstrstrictive and pro-inflammatory effects via the angiotensin receptor 1 (AT1), whereas ang (1-7) exerts counterbalancing vasodilatory and anti-inflammatory effects via the MAS receptor. Meanwhile, in the KKS, DABK promotes vasodilation and vascular permeability via the bradykinin 2 receptor (B2K) [111]. Following SARS-CoV-2 binding, ACE2 is thought to be internalized and downregulated or proteolytically shed, leading to a soluble ACE2 (sACE2) [53,112]. These mechanisms reduce ACE2 activity and cause deleterious effects via ang II and DABK; however, clinical data have yet to show clear trends in COVID-19-induced changes in ACE2 expression or function [113].