TGF-β1 overexpression in severe COVID-19 survivors and its implications for early-phase fibrotic abnormalities and long-term functional impairment

Front Immunol. 2024 Aug 29:15:1401015. doi: 10.3389/fimmu.2024.1401015. eCollection 2024.

Abstract

Introduction: In post-COVID survivors, transforming growth factor-beta-1 (TGF-β1) might mediate fibroblast activation, resulting in persistent fibrosis.

Methods: In this study, 82 survivors of COVID-19-associated ARDS were examined at 6- and 24-months post-ICU discharge. At 6-months, quantitative CT analysis of lung attenuation was performed and active TGF-β1 was measured in blood and exhaled breath condensate (EBC).

Results: At 6-months of ICU-discharge, patients with reduced DmCO/alveolar volume ratio exhibited higher plasma and EBC levels of active TGF-β1. Plasma TGF-β1 levels were elevated in dyspneic survivors and directly related to the high-attenuation lung volume. In vitro, plasma and EBC from survivors induced profibrotic changes in human primary fibroblasts in a TGF-β receptor-dependent manner. Finally, at 6-months, plasma and EBC active TGF-β1 levels discriminated patients who, 24-months post-ICU-discharge, developed gas exchange impairment.

Discussion: TGF-β1 pathway plays a pivotal role in the early-phase fibrotic abnormalities in COVID-19-induced ARDS survivors, with significant implications for long-term functional impairment.

Keywords: acute respiratory distress syndrome; gas transfer components; lung fibrosis; post-COVID; transforming growth factor.

MeSH terms

  • Aged
  • COVID-19* / complications
  • COVID-19* / immunology
  • COVID-19* / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Middle Aged
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / metabolism
  • SARS-CoV-2*
  • Survivors
  • Transforming Growth Factor beta1* / blood
  • Transforming Growth Factor beta1* / metabolism

Substances

  • TGFB1 protein, human
  • Transforming Growth Factor beta1

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Instituto de Salud Carlos III (ISCIII) through the projects PI13/01512, PI16/00201 and PI19/01612, PI22/01262, P2022/BMD-7224 to FG-R; COV20/00207, CP18/00028, PI19/01363 and PI22/01257 to CC-Z; and PI-354 to MQ-D; and co-funded by the European Union, Ayudas Luis Alvarez 2021 FIBHULP. CL-F was supported by Investigo technician fellowship from Comunidad Autónoma de Madrid (CAM).