TGF-β1 Overexpression in Severe COVID-19 Survivors: Implications for Early-Phase Fibrotic Abnormalities and Long-Term Functional Impairment

In post-COVID patients, transforming growth factor‑beta‑1 (TGF‑β1) overexpression might mediate the appearance of persistent fibrosis. We compared active TGF‑β1 expression in blood and airways of severe COVID‑19 survivors, with or without early alveolar-capillary membrane involvement. The discriminative capacity of active TGF‑β1 levels to identify long-term lung fibrosis functional patterns was explored. 82 survivors of COVID‑19‑associated severe acute respiratory distress syndrome (ARDS) were examined at 6- and 24‑months post-ICU discharge. Assessments included clinical and functional characteristics, with lung diffusing capacity for nitric oxide determining membrane component (DmCO). At 6 months, quantitative CT analysis of lung attenuation was performed. Active TGF-β1 and related molecules were measured in blood and exhaled breath condensate (EBC) and an in vitro model using human primary fibroblasts was explored. At 6 months of ICU‑discharge, patients with reduced DmCO/alveolar volume ratio exhibited higher plasma and EBC levels of active TGF‑β1, alongside elevated TGF‑β1 and matrix metalloproteinase 2 mRNA expression in PBMCs. The in vitro model confirmed that plasma and EBC from survivors induced profibrotic changes in primary fibroblasts in a TGF‑β receptor‑dependent manner. Finally, at 6‑months, plasma and EBC levels of active TGF‑β1 discriminated patients who, 24 months post-ICU-discharge, developed a restrictive disorder with gas exchange impairment. TGF‑β1 pathway plays a pivotal role in the early‑phase fibrotic abnormalities in survivors of COVID‑19‑induced ARDS, with significant implications for long‑term functional impairment.