Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

Kentaro Tojo; Natsuhiro Yamamoto; Nao Tamada; Takahiro Mihara; Miyo Abe; Mototsugu Nishii; Ichiro Takeuchi; Takahisa Goto

doi:10.1016/j.isci.2022.105748

Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

iScience. 2023 Jan 20;26(1):105748. doi: 10.1016/j.isci.2022.105748. Epub 2022 Dec 6.

Authors

Kentaro Tojo¹, Natsuhiro Yamamoto¹, Nao Tamada^{1

2}, Takahiro Mihara³, Miyo Abe¹, Mototsugu Nishii⁴, Ichiro Takeuchi⁴, Takahisa Goto¹

Affiliations

¹ Department of Anesthesiology and Critical Care Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
² Department of Paramedic, Kyorin University Faculty of Health Sciences, Mitaka, Tokyo, Japan.
³ Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Kanagawa, Japan.
⁴ Department of Emergency Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.

Abstract

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of the viral load has passed; however, its underlying mechanisms remain unclear. In the present study, analysis of the alveolar tissue injury markers and epithelial cell death markers in patients with COVID-19 revealed that COVID-19-induced ARDS was characterized by alveolar epithelial necrosis at an early disease stage. Serum levels of HMGB-1, one of the DAMPs released from necrotic cells, were also significantly elevated in these patients. Further analysis using a mouse model mimicking COVID-19-induced ARDS showed that the alveolar epithelial cell necrosis involved two forms of programmed necrosis, namely necroptosis, and pyroptosis. Finally, the neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Collectively, necrosis, including necroptosis and pyroptosis, is the predominant form of alveolar epithelial cell death at an early disease stage and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

Keywords: Cell biology; Health sciences; Pathophysiology.