3. Pathophysiology of COVID-19
Since the prevalence of COVID-19 has nowadays become a major global burden around the world, there has been a necessity to perform the precious pathophysiological researches that will aim at recognizing the involved biological markers and the clear mechanisms through which the disease pathogenicity induced by SARS-CoV-2 can be explained.
Obviously, the coronavirus genome cannot be replicated outside the cytoplasmic membranes, so it continuously seeks to penetrate living cells for ensuring its survival. For viral replication, polyproteins should be firstly hydrolyzed into functional proteins by a variety of proteolytic enzymes, which are more commonly known to RNA viruses such as RNA dependent RNA polymerase (RdRp), 3 chymotrypsin like protease (3CL protease), papain like protease and helicase (Ziebuhr, 2005).
At present, several studies showed that penetrating pneumocytes is considered as the main way for SARS-CoV-2 replication within the human body. The finding which is ensured from the evidence of utilizing angiotensin-converting enzyme 2 (ACE-2) enzyme as receptors for viral entry, Figure 1 (Zhang et al., 2020a). ACE-2 was found to be highly expressed in alveolar and bronchial membranes, in type II pneumocytes and possibly on vascular endothelial cells (EC) within lungs (Jia, 2016); explaining why the common signs and symptoms of respiratory infection will develop in coinciding with COVID-19 disease.
Simultaneously, ACE-2 protein was also detected to be distributed in various human organs other than lungs involving oral and nasal mucosa, GIT, skin, heart, liver, kidney, and brain (Hamming et al., 2004); elucidating the reason for developing other extra-pulmonary manifestations associated with COVID-19 infection.
Binding of SARS-CoV-2 with ACE-2 may downregulate ACE-2 and subsequently, inhibit the ACE-2-regulated generation of angiotensin (1–7) peptide which can, via MAS-receptor (MasR), perform several beneficial activities as vasodilator, anti-inflammatory, anti-hypertrophy, anti-proliferative, anti-fibrosis and antioxidant (Kuba et al., 2005).
Concerning the pulmonary RAS, cutting off the ACE-2/Ang (1–7)/MasR axis will activate the vasopressor ACE/Angiotensin (Ang) II /Ang II type 1 receptor (AT1) axis on the other side. The axis which may dive the airway inflammatory cascades, as a result of significant increase in Ang II level. Ang II, through activating the AT1 receptor, could promote the release of multiple inflammatory cytokines especially TNF-α, IL-6, GM-CSF and MCP-1 (Sprague and Khalil, 2009).