Comparison of thrombotic and clinical outcomes in SARS-CoV-2-pneumonia versus other viral pneumonia in an urban academic medical center

Goldberg, Rachel N; Ye, William; Johns, Kevin; Mucksavage, Jeffrey J.; Dhandapani, Sivashanmugam; Quigley, John G.; Shapiro, Nancy L.; Benken, Scott; Wenzler, Eric; Kim, Keri S.

doi:10.1016/j.hrtlng.2023.05.005

Cited by 1 publication

(2 citation statements)

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“…COVID-19 ARDS has a significantly higher prevalence of microthrombi in pulmonary capillaries as compared to non-COVID ARDS ( 5 – 12 ). The procoagulant glycoprotein tissue factor (TF) is a major mediator of thrombosis, since it interacts with circulating coagulation factor VII to trigger extrinsic coagulation.…”

Section: Resultsmentioning

confidence: 97%

“…A significantly increased level of circulating pro-inflammatory cytokines can be detected in both COVID and non-COVID ARDS. Yet, COVID-19 pneumonia has a significantly higher vasculopathy as compared to other viral or bacterial pneumonia ( 5 – 12 ). SARS-CoV2-induced oxidative stress in lung capillaries is of particular importance for endothelial dysfunction in COVID-19, since it not only affects barrier function directly, but also indirectly, by inducing tissue factor generation and subsequent coagulopathy ( 5 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein

Romero,

Yue,

Singla

et al. 2023

Front. Immunol.

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IntroductionAlthough both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this.MethodsIn this study, we use a combination of in vitro studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with in vivo studies in transgenic mice globally expressing human ACE2 and injected with RBD.ResultsWe show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.

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Section: Resultsmentioning

confidence: 97%