Razuprotafib Does Not Improve Microcirculatory Perfusion Disturbances nor Renal Edema in Rats on Extracorporeal Circulation

TL;DR

This study found that Razuprotafib does not improve microcirculation or kidney swelling in rats during extracorporeal circulation, despite some anti-inflammatory effects.

Contribution

The novel contribution is the evaluation of Razuprotafib's efficacy in mitigating microvascular dysfunction and edema during extracorporeal circulation in a rat model.

Findings

Razuprotafib had no effect on capillary perfusion or kidney edema in rats undergoing extracorporeal circulation.

Razuprotafib suppressed TNFα increase but did not affect other inflammatory markers or endothelial gene expression.

Razuprotafib improved oxygenation and reduced lung inflammation, but not microcirculatory or renal outcomes.

Abstract

Extracorporeal membrane oxygenation (ECMO) can be a life-saving intervention, but it is associated with high complication rates. ECMO induces systemic inflammation and endothelial hyperpermeability, thereby causing tissue edema, microcirculatory perfusion disturbances, and organ failure. This study investigated whether the inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP), a regulator of endothelial permeability, reduces extracorporeal circulation (ECC)-induced microvascular dysfunction. Rats were subjected to ECC after treatment with Razuprotafib (n = 11) or a placebo (n = 11), or they underwent a sham procedure (n = 8). Razuprotafib had no effect on the ECC-induced impairment of capillary perfusion, as assessed with intravital microscopy, nor did it influence the increased wet-to-dry weight ratio in kidneys, a marker of edema associated with ECC. Interestingly, Razuprotafib suppressed the ECC-induced increase in TNFα, whereas angiopoietin-2 even further increased, following the discontinuation of ECC. Circulating interleukin-6, ICAM-1, angiopoietin-1, and soluble Tie2 and tissue VE-PTP, Tie1, and Tie2 mRNA expression were not affected by Razuprotafib. Furthermore, Razuprotafib improved the PaO2/FiO2 ratio and reduced histopathological pulmonary interstitial inflammation following ECC compared to the placebo. To conclude, treatment with Razuprotafib did not improve ECC-induced microcirculatory perfusion disturbances nor renal edema.

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