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1 3 I H I G H L I G H T S 2 0 2 3

PRINCIPAL PUBLICATION AND AUTHORS

Lobular ischemia and fibrotic remodelling drive the fatal trajectory of pulmonary COVID-19, M. Ackermann (a,b), J.C. Kamp (c,d), C. Werlein (d,e), C.L. Walsh (f), H. Stark (d,e), V. Prade (g), R. Surabattula (h), W.L. Wagner (i,j), C. Disney (k), A.J. Bodey (l), T. Illig (d,m), D.J. Leeming (m), M.A. Karsdal (n), A. Tzankov (o), P. Boor (p), M.P. Kuehnel (d,e), F.P. Laenger (d,e), S.E. Verleden (q), H.M. Kvasnicka (a), H.H. Kreipe (e), A. Haverich (d,r), S.M. Black (s), A. Walch (n), P. Tafforeau (t), P.D. Lee (m), M.M Hoeper (c,d), T. Welte (c,d), B. Seeliger (c,d), S. David (u), D. Schuppan (h,v), S.J. Mentzer (w), D.D. Jonigk (d,e), eBioMedicine 85, 104296 (2022); https:/doi.org/10.1016/j.ebiom.2022.104296 (a) Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke (Germany) (b) Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University, Mainz (Germany) (c) Department of Respiratory Medicine, Hannover Medical School (Germany) (d) Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) (Germany) (e) Institute of Pathology, Hannover Medical School (Germany) (f) Centre for Advanced Biomedical Imaging, University College London (UK) (g) Research Unit Analytical Pathology, Helmholtz-Zentrum München - German Research Center for Environmental Health, Neuherberg (Germany) (h) Institute of Translational Immunology and Research Center for Immune Therapy, University (Medical Center, Johannes Gutenberg University, Mainz (Germany) (i) Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg (Germany) (j) Member of the German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg (TLRC) (Germany) (k) Department of Mechanical Engineering, University College London (UK) (l) Diamond Light Source, Oxford (UK) (m) Hannover Unified Biobank, Hannover Medical School (Germany) (n) Nordic Bioscience Biomarkers and Research, Herlev (Denmark) (o) Institute of Medical Genetics and Pathology, University Hospital Basel (Switzerland) (p) Institute of Pathology, RWTH Aachen University Hospital (Germany) (q) Department of Thoracic Surgery, University Hospital Antwerp Edegem (Belgium) (r) Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School (Germany) (s) Department of Cellular Biology and Pharmacology, Center for Translational Research, Florida International University (USA) (t) ESRF (u) Institute of Intensive Care Medicine, University Hospital Zürich (Switzerland) (v) Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (USA) (w) Laboratory of Adaptive and Regenerative Biology, Harvard Medical School, Brigham & Women s Hospital, Boston (USA)

post-COVID pulmonary fibrosis, which varies greatly in its extent and progression and can only be predicted very imprecisely by routine clinical imaging. Until now, the underlying mechanisms of this scarring and of specific blood markers that can predict this process were unknown.

This work aimed to uncover how severe COVID-19 modifies the lung s connective tissue and to identify molecular markers of this damage in the blood of patients that might ultimately help diagnose and treat the condition. Samples of intact, severely diseased lungs were examined at beamline BM18 using hierarchical phase- contrast tomography (HiP-CT) to reveal the microscopic tissue alterations in this scarring process (Figure 1). The HiP-CT imaging results were compared to clinical results, demonstrating that, in comparison to other fibrotic lung diseases and to influenza A, changes in COVID-19 are driven by micro-clots (secondary lobular microischemia) and new blood vessel formation via a specific mechanism, intussusceptive angiogenesis. This blood vessel formation,

which is typical of COVID-19, increases significantly over the course of the disease.

In order to identify potential therapeutic targets or progression biomarkers, blood serum and biopsy tissue from patients with different COVID-19 progressions, pulmonary fibrosis and acute lung injury were analysed. By correlating early morphological and molecular features of the development of pulmonary fibrosis with increased levels of certain proteins in the blood, three key blood- biomarkers were identified as predictive of the progression of the scarring process.

This study contributes substantially to the current knowledge on the pathophysiology of severe COVID-19. The identification of complementary blood markers could serve as predictors of disease severity and therapeutic response in COVID-19. The work was supported by the European Research Council, the US National Institutes of Health, the German Deutsche Forschungsgemeinschaft, the Chan Zuckerberg Initiative and the UK Wellcome Trust.