SARS-CoV-2–induced Acute Respiratory Distress Syndrome: Pulmonary Mechanics and Gas-Exchange Abnormalities

Barbeta, Enric; Motos, Ana; Torres, Antoni; Ceccato, Adrián; Ferrer, Miquel; Bueno, Leticia; Badia, Joan R.; Castro, Pedro; Ferrando, Carlos; Andrea, Rut; Castellà, Manuel; Fernández, Javier; Soriano, Álex; Mellado, Ricard; López-Aladid, Rubén; Yang, Hua; Yang, Minlan; Fernández-Barat, Laia; Palomeque, Andrea; Vollmer, Iván; Nicolás, José M.

doi:10.1513/annalsats.202005-462rl

Cited by 31 publications

(35 citation statements)

References 23 publications

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“…In contrast, mice at 7 dpi had marked increases in tissue damping ( Fig 3v ) and elastance ( Fig 3w ); these parameters measure the dissipation and storage of oscillatory energy in parenchymal tissue and reflect tissue and peripheral airway resistance and elastic recoil ( i.e ., tissue stiffness), respectively. The measurements of mechanical properties of the respiratory system suggest that SARS-CoV-2 infection in K18-hACE2 mice predominantly causes disease in the alveoli and lung parenchyma, and not in the conducting airways, which is consistent with both our histopathological analysis in mice and measurements of pulmonary function in humans with viral pneumonia and respiratory failure including COVID-19 16 .…”

Section: Resultssupporting

confidence: 84%

SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

Winkler

Bailey

Kafai

et al. 2020

Preprint

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Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.

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Section: Resultssupporting

confidence: 84%

SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

Winkler

Bailey

Kafai

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This is exactly what has been shown using dual-energy CT in patients with SARS-CoV-2 ( Fig. 2, C and D ) ( 26 – 28 , 84 ). The apparent regional vasodilation in the collapsed or edema-filled tissue was hypothesized to be caused by a dysfunctional and diffuse inflammatory process ( 28 ).…”

Section: Alteration Of Pulmonary Perfusion: a Ramification Of Severe Endothelial Cell Injurysupporting

confidence: 87%

Functional pathophysiology of SARS-CoV-2-induced acute lung injury and clinical implications

Habashi

Camporota

Gatto

et al. 2021

Journal of Applied Physiology

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The worldwide pandemic caused by the SARS-CoV-2 virus has resulted in over 84,407,000 cases with over 1,800,000 deaths when this paper was submitted, with comorbidities such as gender, race, age, body mass, diabetes, and hypertension greatly exacerbating mortality. This review will analyze the rapidly increasing knowledge of COVID-19 induced lung pathophysiology. Although controversial, the acute respiratory distress syndrome (ARDS) associated with COVID-19 (CARDS) seems to present as two distinct phenotypes: Type-L and Type-H. The 'L' refers to Low elastance, ventilation/perfusion ratio, lung weight, and recruitability, and the 'H' refers to High pulmonary elastance, shunt, edema, and recruitability. However, the LUNG SAFE and ESICM Trials Groups has shown that ~13% of the mechanically ventilated non-COVID-19 ARDS patients have the Type-L phenotype. However, other studies have shown that CARDS and ARDS respiratory mechanics overlap and that standard ventilation strategies apply to these patients. The mechanisms causing alterations in pulmonary perfusion could be caused by some combination of: 1) renin-angiotensin system (RAS) dysregulation, 2) thrombosis caused by loss of endothelial barrier, 3) endothelial dysfunction causing loss of hypoxic pulmonary vasoconstriction (HPV) perfusion control, and 4) hyper-perfusion of collapsed lung tissue that has been directly measured and supported by a computational model. A flow chart has been constructed highlighting the need for personalized and adaptive ventilation strategies, such as the time controlled adaptive ventilation (TCAV) method to set and adjust the airway pressure release ventilation (APRV) mode, which recently was shown effective at improving oxygenation and reducing FiO2, vasopressors, and sedation in COVID-19 patients.

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“…The measurements of mechanical properties of the respiratory system suggest that SARS-CoV-2 infection in K18-hACE2 mice predominantly causes disease in the alveoli and lung parenchyma, and not in the conducting airways, which is consistent with both our histopathological analysis in mice and measurements of pulmonary function in humans with viral pneumonia and respiratory failure including COVID-19 (ref. 17 ).…”

Section: Pathophysiology Of Sars-cov-2 Infectionmentioning

confidence: 99%

SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function

et al. 2020

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Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

show abstract

SARS-CoV-2–induced Acute Respiratory Distress Syndrome: Pulmonary Mechanics and Gas-Exchange Abnormalities

Cited by 31 publications

References 23 publications

SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

Functional pathophysiology of SARS-CoV-2-induced acute lung injury and clinical implications

SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function

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