Circulating markers of extracellular matrix remodelling in severe COVID‐19 patients
Sarah Louise Murphy, Bente Halvorsen, Jan Cato Holter, Camilla Huse, Anders Tveita, Marius Trøseid, Hedda Hoel, Anders Benjamin Kildal, Aleksander Rygh Holten, Tøri Vigeland Lerum, Ole Henning Skjønsberg, Annika E. Michelsen, Trond Mogens Aaløkken, Kristian Tonby, Andreas Lind, Susanne Dudman, Beathe Kiland Granerud, Lars Heggelund, Simen Bøe, Anne Ma Dyrholt‐Riise, Pål Aukrust, Andreas Barratt‐Due, Thor Ueland, Tuva B. Dahl
Abstract
BACKGROUND: Abnormal 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. METHODS: Serial 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. RESULTS: Several 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. CONCLUSION: Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19.