Abstract
To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein–Kinin (KKS), the Coagulation/Fibrinolysis and the Renin–Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg9]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.
Highlights
Starting in December 2019 in Wuhan (Hubei Province, China), a novel coronavirus, designated SARS-CoV-2, has caused an international outbreak of a respiratory illness (COVID-19), rapidly evolving into a pandemic
We try to address the complex link between the pathophysiology of COVID-19 and the different proteolytic defense systems operating in human vasculature, investigating the role of the mediators involved and speculating on the possibility of pharmacological modulation
The hypothesis of the involvement of different human proteolytic defense systems operating in the vasculature in the pathogenesis of COVID-19 has recently been proposed by other authors. van de Veerdonk et al [79] hypothesized that a kinin-dependent local lung angioedema via B1 receptor (B1R) and eventually B2 receptor (B2R) is an important feature of COVID-19 and proposed that blocking the B2R and inhibiting plasma KAL activity might be beneficial in early disease, preventing acute respiratory distress syndrome (ARDS)
Summary
Starting in December 2019 in Wuhan (Hubei Province, China), a novel coronavirus, designated SARS-CoV-2, has caused an international outbreak of a respiratory illness (COVID-19), rapidly evolving into a pandemic. ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; Ang I, Angiotensin I; Ang II, Angiotensin II; Ang [1,2,3,4,5,6,7], Angiotensin 1-7; Ang [1,2,3,4,5,6,7,8,9], Angiotensin 1-9; AT1R, ATII type 1 receptor; AT2R, ATII type 2 receptor; B1R, B1 receptor; B2R, B2 receptor; BK, bradykinin; C1-INH, C1-inhibitor; DABK, [des-Arg9]-BK; FXI, coagulation factor XI; FXII, coagulation factor XII; HK, high-molecular-weight kininogen; IL-6, interleukin-6; KAL, plasma kallikrein; MasR, Mas receptor; PK, plasma prekallikrein; t-PA, tissue plasminogen activator.
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