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.):
  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.
  2. 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.
  3. 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.