Alveolar epithelial type 2 cell specific loss of IGFBP2 activates inflammation in COVID-19.

Summary

IGFBP2 is markedly reduced in alveolar type 2 cells from COVID-19-ARDS lungs and associates with heightened inflammatory programs. Restoring IGFBP2 expression dampens cytokine/chemokine signaling in spike protein–injured epithelial cells, supporting IGFBP2 as a potential locally deliverable anti-inflammatory target in COVID-19.

Key Findings

• IGFBP2 mRNA is significantly downregulated in primary AEC2 from COVID-19-ARDS fibrotic regions compared with IPF alone or IPF with prior COVID-19.
• Multicolor immunohistochemistry shows reduced IGFBP2, IGF1, and IGF2 in AEC2 from COVID-ARDS, IPF, and IPF with COVID history versus donor controls.
• Lentiviral Igfbp2 expression suppresses S2 spike–induced proinflammatory genes (Tnf-α, Il1β, Il6, Stat3/6) and chemokine receptors (Ccr2, Ccr5) in mouse lung epithelial cells.
• AEC2 from COVID-ARDS patients exhibit higher TNF-α, IL-6, and CCR5 than AEC2 from IPF and IPF with COVID history.

Clinical Implications

While preclinical, findings suggest that localized IGFBP2 delivery to alveolar epithelium could modulate inflammation in COVID-19-associated ARDS. This supports exploring IGFBP2-based therapies and companion biomarkers in early-phase trials.

Limitations

• Sample sizes and patient-level covariates are not reported in detail
• In vitro spike protein injury model may not fully recapitulate in vivo SARS-CoV-2 infection; lack of in vivo therapeutic testing

Future Directions

Quantify AEC2 IGFBP2 across larger COVID-19-ARDS cohorts, test localized IGFBP2 delivery in animal models, and evaluate safety/PK in early-phase clinical trials with biomarker-guided selection.