Circulating markers of extracellular matrix remodelling in severe COVID-19 patients

BackgroundAbnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients.MethodsSerial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines.ResultsSeveral of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19.ConclusionOur findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19. image

Automated summary

This study investigates the role of ECM remodeling and excessive fibrogenesis in severe COVID-19. The findings demonstrate that certain ECM mediators such as OPN, S100A12, and YKL-40 are closely associated with disease severity and mortality. High levels of ECM mediators during hospitalization are related to thorax pathology after 3 months. In vitro experiments also show the release of certain markers (such as growth differentiation factor 15, galectin 3, and matrix metalloproteinase 9) from macrophages and lung cell lines after exposure to inactivated SARS-CoV-2, indicating a direct link between these mediators and the causal agent of COVID-19.