After some fruitful discussion in Comments with 'bob 1', and a review of several articles cited below, the likely answer to the question is that, in spite of the fact that ACE 2 expressed on the atmospheric side of type 2 epithelial pneumocytes cannot in the ordinary circumstance be exposed to circulating Angiotensin [1 or 2], its expression and activity appears to be strongly protective of lung tissue in conditions of inflammation or infection, as these two excerpts attest. Whether this is due to the mitigating effect of ACE 2 during cell rupture or leakage of Angiotensin 2 into the interstitium or alveolar space is unclear, but would seem likely.
At the same time, as mentioned in the following, the fact that ACE2 has two distinct binding sites at this level suggests that its role is not restricted to that protective function generally; rather, more specifically its very presence as a portal with an allied tissue protective function presumably serves to mitigate the inflammatory effect of binding by SARS-CoViruses themselves, 1 and 2, notwithstanding the destructive effect on ACE2 of that process. This interplay between ACE2 expression and viral load/virulence may help to explain the widely varying clinical impact of COVID-19.
Article 3 further below suggests the manner in which such an interaction between host and virus would have evolved.
[a] Article 1 entitled' ACE 2: SARS-CoV 2 Receptor and Regulator of RAS' (Gheblawi etal.).
Lung epithelial cells express high levels of ACE2, which positively
correlates with airway epithelial differentiation. Involvement of ACE2
in Acute Respiratory Distress Syndrome [ARDS], which is triggered by
multiple diseases including SARS-CoV and SARS-CoV-2, has been
established in multiple animal models. ACE2 Knocked-Out mice exhibit
severe pathology of ARDS.
Additional ACE deficiency, or treatment with AR1R blockers of ACE2 KO
mice rescues them from ARDS implicating the benefit of ACE2 and the
critical balance of the protective versus pro-inflammatory and
fibrotic axes of the Renin-Angiotensin System [RAS]. These findings
are consistent with evidence of a beneficial effect of rhACE2 on
pulmonary blood flow and oxygenation in a pig model of
lipopolysaccharide-induced ARDS. Age-related loss of ACE2 in the
lungs correlates with the increased mortality and worsened phenotype
in elderly patients with COVID-19.
[b] Direct Protective Actions of ACE2 on Lung Alveolar Epithelial Cells 2 [Article, 'ACE 2, Much More Than Just a Receptor for SARS-CoV2'].
In addition to its protective role in the cardiovascular system, ACE2
has a direct protective role in alveolar epithelial cells. In the
lungs ACE2 has numerous physiological functions, most of which are
protective against lung injury. Similar to the endothelial site, ACE2
degrades the octapeptide Ang II by removing a single amino acid from
the C-terminal end of the peptide to generate the heptapeptide Ang1-7.
Our laboratory and others have shown that ACE2 protects against lung
injury by: (a) degrading Ang II, which is vasoconstrictive and
proapoptotic for lung epithelial cells (Wang et al., 1999) and
profibrotic (Li et al., 2008; Uhal et al., 2011), and (b) by producing
the peptide Ang1-7, which inhibits the actions of Ang II through
binding to the MAS receptor (Gopallawa and Uhal, 2014).
In support of this protective role for ACE2, pharmaceutical
preparations of recombinant ACE2, when administered to experimental
animals, protect against lung cell death, inhibit acute lung injury
and prevent lung fibrosis after chronic injury to the lungs (Li et
al., 2008; Rey-Parra et al., 2012).
As further evidence, the application of a specific competitive
inhibitor of ACE2, DX600, to primary cultures of isolated ACEs
increases the level of Ang II released into the serum-free culture
medium by autocrine mechanisms, reduces the amount of released Ang1-7
and, importantly, induces apoptosis inhibitable by the AT1 receptor
blocker (Menter et al., 2020). Thus, functional ACE2 normally
expressed by alveolar epithelial cells can be viewed as a critical
survival factor for these lung cells. In addition, the enzymatic
product of ACE2, the Ang1-7, itself protects against lung cells death
by antagonizing that actions of Ang II (le Tran and Forster, 1997).
If Ang1-7 is applied to cultures of lung epithelial cells, it can
prevent lung cell death in response to either Ang II or the ER stress
inducer MG132 (Nguyen and Uhal, 2016). The Ang1-7 receptor MAS and the
JNK-selective phosphatase MKP-2 appear to be critical in this
protective action of Ang1-7 response, because iRNAs or antisense
knockdowns of MAS or MKP-2 can eliminate the ability of Ang1-7 to
prevent lung cell death (Gopallawa and Uhal, 2016). Indeed, Ang1-7
itself and congeners of the peptide, such as cyclic Ang1-7 (Gopallawa
and Uhal, 2016), have already been shown to protect the lungs in
preclinical models of acute lung injury.
However, the not unrelated possibility also remains that since there are two distinct binding sites on the ACE2 found in these alveolar epithelial cells, one of which is the catalytic site implicated in its modifying effects on Angiotensin, and the other, the N-terminal protease domain which specifically binds the spike protein of coronaviruses, SARS-CoV2 in particular, at least part of the role of this binding domain has persisted for the purpose of facilitating entry of coronaviruses, more especially with as little immediate inflammatory damage to the portal as possible.
From the same article mentioned 1, the key observation is as follows;
ACE2 has an extracellular facing N-terminal domain and a C-terminal
transmembrane domain with a cytosolic tail. The N-terminal portion of
the protein contains the claw-like protease domain (PD), while the
C-terminal domain is referred to as the Collectrin-like domain. The
receptor-binding domain (RBD) of SARS-CoV-2 binds with the PD of ACE2,
forming the RBD-PD complex distinct from the ACE2 catalytic site.
This observation may suggest a type of evolutionary symbiosis between coronaviruses generally, SARS-CoV2 in particular, and the human organism which has adapted to permit the entry of those viruses via the N-terminal protease domain which is evidently distinct from the ACE2 catalytic site. Naturally this sort of speculation presupposes that the role of this protease is not restricted to some ordinary physiological function, such as enhancing reabsorption of surfactant by alveolar macrophages for example.
Here it may be interesting to insert an excerpt from another article 3 from 2012 quoted below and dealing with the original SARS-CoV.
Article 3, 'Evidence for ACE2-Utilising Coronaviruses in SARS in Bats'.
In 2002, severe acute respiratory syndrome (SARS)-coronavirus (CoV)
appeared as a novel human virus with high similarity to bat
coronaviruses. However, while SARS-CoV uses the human
angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry, no
coronavirus isolated from bats appears to use ACE2. Here we show that
signatures of recurrent positive selection in the bat ACE2 gene map
almost perfectly to known SARS-CoV interaction surfaces. Our data
indicate that ACE2 utilization preceded the emergence of SARS-CoV-like
viruses from bats.
Cell-surface receptors often play a key role in defining viral host
range. New diseases can emerge when existing viruses evolve the
ability to bind the ortholog of their cell-surface receptor in a new
species. Indeed, the principal genetic component defining host range
in coronaviruses is the spike protein on the surface of the virus and,
in particular, its receptor-binding domain (RBD).
It is believed that the severe acute respiratory syndrome (SARS)
epidemic resulted from the zoonotic transmission of a coronavirus from
bats to humans. The central role of the RBD in the SARS-coronavirus
(CoV) zoonosis was crystallized in an experiment in which a bat
coronavirus became infectious in primate cells when it was altered to
contain the RBD of human SARS-CoV.
Over long periods of time, co-evolutionary dynamics can develop
between viruses and their hosts. For example, host populations will
experience natural selection for receptor mutations that reduce virus
interaction affinity, and viruses will, in turn, be selected for
mutations that increase affinity with new receptor variants. This
back-and-forth selection will result in the rapid evolution of both
the host receptor and the virus surface protein.
The protein evolutionary rate can be analyzed by studying the rates of
accumulation of non-synonymous (dN; changing the encoded amino acid)
and synonymous (dS; silent) mutations in the underlying gene. Most
genes retain far fewer non-synonymous mutations than synonymous
mutations (dN/dS ≪ 1) because protein-altering mutations tend to be
deleterious.
These are some further pertinent extracts from the article 1 by M. Gheblawi etal. entitled 'ACE 2: SARS-CoV 2 Receptor and Regulator of RAS'.
Knowledge of the underlying biology and physiology of ACE2
(angiotensin-converting enzyme 2) has accumulated over the last 20
years since its discovery and has provided a major stimulus to further
our understanding of the renin-angiotensin system (RAS). ACE2 has
distinct roles ranging from catalytic activities with various
substrates, as functional receptors for severe acute respiratory
syndrome coronaviruses (SARS-CoV), and as an amino acid transporter.
ACE2 functions as a master regulator of the RAS mainly by converting
Ang (angiotensin) I and Ang II into Ang 1–9 and Ang 1–7, respectively.
Whereas somatic ACE contains 2 active sites, ACE2 possesses only a
single catalytic domain. Both ACE and ACE2 act as zinc
metallopeptidases but of differing substrate specificities defining
their distinct and counterbalancing roles in the RAS. Whereas ACE
cleaves C-terminal dipeptide residues from susceptible substrates (a
peptidyl dipeptidase), ACE2 acts as a simple carboxypeptidase able to
hydrolyze Ang I, forming Ang 1–9 and Ang II to Ang 1–7.
ACE2 does not cleave bradykinin, further distinguishing its
specificity from that of ACE while it is also insensitive to
conventional ACE inhibitors. The C-terminal domain of ACE2, which has
no similarity with ACE, is a homolog of a renal protein, collectrin,
which regulates the trafficking of amino acid transporters to the cell
surface, endowing ACE2 with multiple and distinctive physiological
functions. It is the multiplicity of physiological roles that ACE2
plays that has allowed it to be hijacked by SARS-CoV-2 as a receptor.
ACE2 is expressed in the vascular system (endothelial cells, migratory
angiogenic cells, and vascular smooth muscle cells), heart (cardiac
fibroblasts, cardiomyocytes, endothelial cells, pericytes, and
epicardial adipose cells) and kidneys (glomerular endothelial cells,
podocytes and proximal tubule epithelial cells). ACE2 is also
expressed and functions in the local RAS of the liver (cholangiocytes
and hepatocytes), retina (pigmented epithelial cells, rod and cone
photoreceptor cells and Müller glial cells), enterocytes of the
intestines, circumventricular organs of the central nervous system,
upper airway (goblet and ciliated epithelial cells), and alveolar
(Type II) epithelial cells of the lungs and pulmonary vasculature.
The entry of both SARS-CoV and SARS-CoV-2 into cells is facilitated by
the interaction between viral S-protein with extracellular domains of
the transmembrane ACE2 proteins, followed by subsequent
down-regulation of surface ACE2 expression.
From the same article, the following details of intestinal expression of ACE 2 may or may not suggest a similar role in pulmonary epithelium.
ACE2 As a Chaperone Protein for the Amino Acid Transporter, B0AT1
(SLC6A19).
B0AT1 is highly expressed in the intestines and kidneys with function
in the absorption of neutral amino acids. The ACE2-B(0)AT1 complex is
assembled as a dimer of heterodimers, with the collectrin-like domain
of ACE2 mediating homo-dimerization. ACE2 has a RAS-independent
function, regulating intestinal amino acid homeostasis, expression of
antimicrobial peptides, and the gut microbiome. ACE2 is necessary for
the expression of the Hartnup transporter in the intestine, and the
differential functional association of mutant B(0)AT1 transporters
with ACE2 in the intestine regulates the phenotypic heterogeneity of
human Hartnup disorder.
Evidently ACE2 facing the gut lumen also serves to inhibit dysbiosis, and although it is considered unlikely by researchers to exert any corresponding function in the generally aseptic lower respiratory tract, it may play some such role in the upper tract. Altogether, it is an extremely interesting enzyme, a zinc metallo-enzyme no less, whose importance is yet to be fully appreciated.
