# Therapeutic Galectin‐3 Apheresis Improves Sepsis Outcomes Through Coordinated Neutrophil Modulation and Endothelial Barrier Preservation: A Translational Study

## TL;DR

Removing Galectin-3 through apheresis improves survival in sepsis by reducing inflammation and protecting blood vessel barriers in both animal models and human patients.

## Contribution

This study demonstrates that Gal-3 apheresis is a novel therapeutic strategy for sepsis, showing clinical and preclinical benefits through coordinated neutrophil and endothelial modulation.

## Key findings

- Gal-3 removal significantly improved survival in rat and pig sepsis models.
- Treatment preserved endothelial barrier integrity and reduced neutrophil activation and tissue infiltration.
- Gal-3 apheresis lowered vasopressor requirements and pulmonary edema while modulating survival signaling pathways.

## Abstract

Sepsis remains a leading cause of global mortality, characterized by uncontrolled inflammation and multi‐organ dysfunction. Galectin‐3 (Gal‐3) is a damage‐associated molecular pattern (DAMP) protein that amplifies inflammatory cascades during sepsis and represents a potential therapeutic target. We conducted an integrated translational investigation combining clinical observation (87 septic patients, 27 healthy volunteers) with preclinical Gal‐3 removal using an anti‐Gal‐3 apheresis column in two sepsis models: a rat cecal ligation and puncture (CLP) model (n = 48) and a porcine lipopolysaccharide (LPS)‐induced model (n = 31). Mechanistic assessments included serum testing, multi‐omics profiling, invasive hemodynamic monitoring, and histopathology. Patients with sepsis exhibited markedly elevated Gal‐3 levels (p < 0.001), and survivors showed progressive Gal‐3 decline compared with non‐survivors (p < 0.01). Gal‐3 removal significantly improved survival in rats (57.1% vs. 25.0%, p = 0.003) and pigs (68.8% vs. 26.7%, p = 0.004). Treatment attenuated neutrophil activation and tissue infiltration, preserved endothelial barrier integrity, and modulated pro‐survival and hypoxia‐response signaling pathways, accompanied by reduced vasopressor requirements and pulmonary edema. Collectively, these findings demonstrate that Gal‐3 removal improves survival and reduces organ damage in preclinical sepsis models in association with coordinated neutrophil modulation and endothelial barrier preservation, highlighting Gal‐3 as a promising therapeutic target in sepsis.

Gal‐3 apheresis reduces neutrophil hyperactivation (CXCL2/CXCL8, MPO, NETs), preserves endothelial barrier function (tight junctions, vWF/VCAM‐1/ICAM‐1), and attenuates PI3K/AKT/HIF‐1α signaling. These coordinated effects significantly improve hemodynamics, reduce pulmonary edema (ELWI), lower vasopressor and fluid requirements, and increase survival, highlighting Gal‐3 as a therapeutic target in sepsis
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