Regorafenib modulation of the angiopoietin/TIE2 axis in a mouse model of sepsis-induced lung injury

TL;DR

This study shows that regorafenib reduces lung injury in sepsis by lowering inflammation and affecting specific proteins involved in blood vessel regulation.

Contribution

The study reveals regorafenib's protective effects in sepsis-induced lung injury via modulation of the angiopoietin/TIE2 axis.

Findings

Regorafenib significantly reduced inflammatory markers like TNF-α, IL-1β, and Ang-2 in sepsis-induced lung injury.

Regorafenib increased VE-cadherin mRNA expression in lung tissue, suggesting a protective effect on blood vessels.

Ang-1 levels were elevated in the regorafenib group compared to the sepsis-only group.

Abstract

Sepsis, often resulting from an immune response overreaction to microorganisms and their products, can lead to acute lung injury through inflammation mediated by excessive cytokines. This study aimed to investigate the effects of regorafenib on lung injury in mice following the induction of sepsis. We divided mice into four groups (n=6 each): a sham group (undergoing laparotomy without cecal ligation and puncture [CLP]), a CLP group, a vehicle group, and a regorafenib-treated group (30 mg/kg IP, administered one hour before CLP). TNF-α, IL-1β, VEGF, MPO, caspase-11, and Ang-2 levels were significantly increased (p<0.05) in the CLP group compared to the sham group, while the regorafenib group showed significant reductions in these markers versus the CLP group (p< 0.05). In contrast, Ang-1 levels, which were reduced in the CLP group (p<0.05) compared to the sham group, were elevated in the regorafenib group compared to the CLP group. Quantitative real-time PCR revealed a significant decrease in TIE2 and VE-cadherin mRNA expression in the lung tissue of the CLP group compared to the sham group. There were no significant differences in mRNA expression of the TIE2 gene between the regorafenib and CLP group. However, VE-cadherin significantly increased after regorafenib treatment. Regorafenib demonstrated lung-protective effects through its anti-inflammatory and antiangiogenic activities and its influence on lung tissue mRNA expression of the cadherin gene.

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