Evidence for a thromboembolic pathogenesis of lung cavitations in severely ill COVID-19 patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) induces lung injury of varying severity, potentially causing severe acute respiratory distress syndrome (ARDS). Pulmonary injury patterns in COVID-19 patients differ from those in patients with other causes of ARDS. We aimed to explore the frequency and pathogenesis of cavitary lung lesions in critically ill patients with COVID-19. Retrospective study in 39 critically ill adult patients hospitalized with severe acute respiratory syndrome coronavirus 2 including lung injury of varying severity in a tertiary care referral center during March and May 2020, Berlin/Germany. We observed lung cavitations in an unusually large proportion of 22/39 (56%) COVID-19 patients treated on intensive care units (ICU), including 3/5 patients without mechanical ventilation. Median interquartile range (IQR) time between onset of symptoms and ICU admission was 11.5 (6.25-17.75) days. In 15 patients, lung cavitations were already present on the first CT scan, performed after ICU admission; in seven patients they developed during a subsequent median (IQR) observation period of 48 (35-58) days. In seven patients we found at least one cavitation with a diameter>2 cm (maximum 10 cm). Patients who developed cavitations were older and had a higher body mass index. Autopsy findings in three patients revealed that the cavitations reflected lung infarcts undergoing liquefaction, secondary to thrombotic pulmonary artery branch occlusions. Lung cavitations appear to be a frequent complication of severely ill COVID-19 patients, probably related to the prothrombotic state associated with COVID-19

NOTCH Signaling Is Activated through Mechanical Strain in Human Bone Marrow-Derived Mesenchymal Stromal Cells

Skeletal development and remodeling of adult bone are critically controlled by activated NOTCH signaling in genetically modified mice. It is yet unclear whether NOTCH signaling is activated by mechanical strain sensed by bone cells. We found that expression of specific NOTCH target genes is induced after in vivo tibial mechanical loading in wild-type mice. We further applied mechanical strain through cyclic stretching in human bone marrow-derived mesenchymal stromal cells (BMSCs) in vitro by using a bioreactor system and detected upregulation of NOTCH target gene expression. Inhibition of the NOTCH pathway in primary BMSCs as well as telomerase-immortalized human BMSCs (hMSC-TERT) through the gamma-secretase inhibitor GSI XII blocked mechanotransduction and modulated actin cytoskeleton organization. Short-hairpin RNA gene silencing identified NOTCH2 as the key receptor mediating NOTCH effects on hMSC-TERT cells. Our data indicate a functional link between NOTCH activation and mechanotransduction in human BMSCs. We suggest that NOTCH signaling is an important contributor to molecular mechanisms that mediate the bone formation response to mechanical strain