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

Abstract

Rationale: Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after passing the peak of viral load. However, the underlying mechanisms remain unclear. Objectives : Here, we assess whether alveolar epithelial cell necrosis and subsequent releases of damage associated molecular patterns (DAMPs) at an early disease stage aggravate ARDS with COVID-19 Methods: In patients with COVID-19 with and without ARDS and healthy adults, serum levels of the following were quantified: an epithelial total cell death marker, cytokeratin18-M65; an epithelial apoptosis marker, CK18-M30; HMGB-1; and alveolar epithelial and endothelial injury markers, sRAGE, angiopoietin-2, and surfactant protein-D. Molecular mechanisms of alveolar epithelial cell death and effects of HMGB-1 neutralization on alveolar tissue injury were assessed using a mouse model of COVID-19-induced ARDS. Measurements and main results: The levels of CK18-M65, CK18-M30, and alveolar tissue injury markers were elevated in early stages of ARDS. The median M30/M65 ratio, an epithelial apoptosis indicator, was 31.50% in patients with ARDS, a value significantly lower than that of non-ARDS patients or healthy subjects. Serum levels of HMGB-1, one of DAMPs released from necrotic cells, were also significantly elevated in ARDS versus non-ARDS patients. In a COVID-19-induced ARDS mouse model, alveolar epithelial cell necrosis involved two forms of programmed necrosis, necroptosis and pyroptosis. Finally, neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Conclusions: Necrosis, including necroptosis and pyroptosis, seems to be the primary form of alveolar epithelial cell death, and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

Mechanism of the Sars-Covid-Ii Infection of Respiratory Cells

“…SARS-CoV-2 вызывает острый респираторный дистресс-синдром, который характеризуется некрозом альвеолярного эпителия на ранней стадии заболевания. Некроз альвеолярных эпителиальных клеток включает два типа запрограммированного некроза, а именно: некроптоз и пироптоз [32]. Маркеры эпителиального некроза, и в особенности высокоподвижная группа box-1(HMGB-1), выходят в кровь.…”

Plasma markers of Covid-19 severity: A pilot study

“…Hitherto, changes in concentrations of D-dimer, cardiac troponin I, renal biomarkers, such as serum urea, creatinine and markers of glomerular filtration rate, C-reactive protein (CRP), ferritin, and certain cytokines/chemokines may have a diagnostic value [2][3][4]. Several studies reported that circulating levels of damage associated molecular patterns, such as cytoskeletal keratin-18 (CK18) fragment M30/M65 ratio (an indicator of cell apoptosis in relation to the total cell death), HMGB-1 or mitochondrial DNA may also reflect the severity of COVID-19 patients [5][6][7]. The activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13), a regulator of von Willebrand factor (VWF) multimer disruption, typically decline with the increasing extent of inflammatory responses [8].…”

Table1.XLSX

“…The primary network highlighted the fact that cell death, widely acknowledged as an essential and crucial step in disease pathogenesis (Deshpande and Zou, 2021;Li et al, 2022;Tojo, 2023;Yuan et al, 2023) was not present in any of the AOPs, hence in the network. Therefore, the KE "cell death" KE1825 present in the Wiki was added as a new node connecting "increased coronavirus production" (KE1847 from AOP430) to "increased, secretion of proinflammatory mediators (KE 1496 from AOP392).…”