Pillay Janesh, Flikweert Antine W, van Meurs Matijs, Grootenboers Marco J, van der Sar-van der Brugge Simone, van der Voort Peter H J, Karsdal Morten A, Sand Jannie M B, Leeming Diana J, Burgess Janette K, Moser Jill
Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Respir Res. 2025 Jan 22;26(1):32. doi: 10.1186/s12931-025-03098-9.
Severe and critical COVID-19 is characterized by pulmonary viral infection with SARS-CoV-2 resulting in local and systemic inflammation. Dexamethasone (DEX) has been shown to improve outcomes in critically ill patients; however, its effect on tissue remodeling, particularly collagen turnover, remains unclear. This study investigated the association between circulating extracellular matrix (ECM) remodeling neo-epitopes and COVID-19 severity, their relationship with mortality, and the effect of DEX on these markers.
We conducted a multi-center prospective cohort study involving 226 COVID-19 patients: 157 with severe disease admitted to the ward and 69 with critical disease admitted to the ICU. Plasma samples were collected at ICU admission and at discharge or death. Circulating collagen degradation (C3M, C4Ma3, and C6M) and synthesis (PRO-C3, PRO-C4, and PRO-C6) neo-epitopes were measured. Longitudinal analysis of ECM neo-epitope changes during ICU stay and their association with mortality was performed, along with an evaluation of the impact of DEX treatment on these markers.
Critically ill patients exhibited higher levels of collagen degradation (reflecting inflammatory driven ECM destruction) (C3M, C6M) and collagen synthesis (strongly related to fibroblast activity) (PRO-C3, PRO-C6) neo-epitopes than severe patients. Increased collagen turnover, measured during ICU stay, was associated with mortality. Non-survivors displayed rising levels of collagen degradation and synthesis markers over time, whereas survivors had stable or declining levels. In non-survivors without DEX treatment, C6M and PRO-C6 levels were significantly increased, whereas these elevations were less pronounced in patients treated with DEX.
Our findings suggest that elevated collagen turnover is associated with poor outcomes in critically ill COVID-19 patients. DEX treatment appeared to attenuate ECM remodeling, although this effect was not linked to improved survival. Further studies are needed to confirm these observations and better understand the role of ECM remodeling in COVID-19 and the potential therapeutic impact of corticosteroids.
重症和危重症新型冠状病毒肺炎（COVID-19）的特征是由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的肺部病毒感染，导致局部和全身炎症。地塞米松（DEX）已被证明可改善危重症患者的预后；然而，其对组织重塑，尤其是胶原蛋白周转的影响仍不清楚。本研究调查了循环细胞外基质（ECM）重塑新表位与COVID-19严重程度之间的关联、它们与死亡率的关系以及DEX对这些标志物的影响。
我们进行了一项多中心前瞻性队列研究，纳入226例COVID-19患者：157例重症患者入住病房，69例危重症患者入住重症监护病房（ICU）。在入住ICU时以及出院或死亡时采集血浆样本。检测循环胶原蛋白降解（C3M、C4Ma3和C6M）和合成（PRO-C3、PRO-C4和PRO-C6）新表位。对ICU住院期间ECM新表位变化及其与死亡率的关联进行纵向分析，并评估DEX治疗对这些标志物的影响。
危重症患者的胶原蛋白降解（反映炎症驱动的ECM破坏）（C3M、C6M）和胶原蛋白合成（与成纤维细胞活性密切相关）（PRO-C3、PRO-C6）新表位水平高于重症患者。在ICU住院期间测得的胶原蛋白周转增加与死亡率相关。非幸存者的胶原蛋白降解和合成标志物水平随时间升高，而幸存者的水平稳定或下降。在未接受DEX治疗的非幸存者中，C6M和PRO-C6水平显著升高，而在接受DEX治疗的患者中，这些升高不那么明显。
我们的研究结果表明，胶原蛋白周转升高与危重症COVID-19患者的不良预后相关。DEX治疗似乎减弱了ECM重塑，尽管这种作用与生存率提高无关。需要进一步研究来证实这些观察结果，并更好地了解ECM重塑在COVID-19中的作用以及皮质类固醇的潜在治疗影响。
