A working-hypothesis
The key components of our “Epithelial-Endothelial cross-talk”
hypothesis for increased intrapulmonary shunt and silent hypoxemia in
COVID-19 are as follows (Fig. 1.):
- Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters
type-2 pneumocytes following binding to membrane angiotensin
converting enzyme 2 (ACE2), causing downregulation of ACE2 on the
alveolar-capillary membrane along with concurrent activation of
disintegrin and metalloproteinase domain-containing protein 17
(ADAM17) also known as tumor necrosis factor-α-(TNF-α)-converting
enzyme (TACE), and resulting in TNF-α and IL-6 amplification. This, in
turn, establishes a positive feedback loop of increased expression of
ACE, Ang II and AT1R on alveolar-capillary membrane
and pulmonary capillary smooth muscle cells. Ang II-ATIR-mediated
activation of alveolar endothelial cells now increases the release of
endothelin-1 and reactive oxygen species (ROS). Meanwhile, ACE 1-Ang
II-AT2-R and ACE2-Ang 1-7-masR-mediated constitutive endothelial
nitric oxide synthase (eNOS) activation and nitric oxide (NO) release
is inhibited.
- High local Ang II, endothelin-1 and ROS results in intense but
heterogenous pulmonary vasoconstriction of the precapillary
arterioles, resulting in reduced perfusion of alveolocapillary units.
Several other factors that may be contributory to pulmonary
vasoconstriction includes TNF-α that works synergistically with Ang II
and can induce mitochondrial ROS and can deplete endothelial cells of
NO. Plasminogen activation inhibitor-1 (PAI-1) and platelet activating
factors (PAF) are some other mediators that can not only potentiate
vasoconstriction, but microvascular thrombosis as well. As the
resulting vasoconstriction is severe but, uneven, the capillary beds
with relatively less vasoconstriction are disproportionately exposed
to elevated microvascular pressures, resulting in recruitment and
regional over-perfusion. This results in increased shunt fraction and
hypoxia, capillary-stress failure, and ground-glass opacities. The
proposed interplay of key mediators of pulmonary vasoconstriction
involved in the early COVID-19 pathophysiology is depicted in Fig. 2.
- As the disease worsens, endothelial dysfunction results in
proinflammatory and procoagulant activity. Thrombotic occlusion of
heterogeneous regions of pulmonary vasculature distal to subsegmental
vessels including alveolar capillary microthrombi can further increase
the shunt fraction and dead space. Recent evidence of high dead-space
ventilation in COVID-19 patients supports our hypothesis [32].
This also explains the findings of dilated proximal sub-segmental and
segmental vessels on dual-energy CT [10]. Thus, silent hypoxia of
COVID-19 can be mainly secondary to diffuse microvascular lung injury
with limited alveolar epithelial injury not amounting to diffuse
alveolar damage of ARDS.