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Microcirculation Dysfunction in Sepsis is Attenuated by Nox2 Inhibition in Mice
Abstract

Microcirculation Dysfunction in Sepsis is Attenuated by Nox2 Inhibition in Mice

Franccesco Boeno, Cole Lukasiewicz, Gisienne Reis, Diana Muller, Timothy li, Cole Tarter, Youngil Lee, Michele Moraes, Bruno Teixeira, Russel Hepple, …
Physiology (Bethesda, Md.), Vol.41(S1)
American Physiology Summit (2026)
05/2026
DOI: https://doi.org/10.1152/physiol.2026.41.S1.2299412

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Abstract

Background: In the United States, the annual cost of sepsis exceeds $24 billion. Advances in critical care have reduced in-hospital mortality to approximately 26–28%, a major clinical achievement. However, this success has created a new healthcare burden, as many sepsis survivors develop sustained skeletal muscle weakness, atrophy, and cardiometabolic dysfunction. Microcirculatory dysfunction is an early predictor of mortality during acute sepsis, but whether it contributes to the development of skeletal muscle abnormalities after recovery remains unknown. Excessive production of reactive oxygen species (ROS) plays a key role in disrupting the microcirculation, and NADPH oxidase 2 (Nox2) is a major endothelial source of ROS that may drive this impairment during sepsis. Here, we pharmacologically inhibit Nox2 to determine its protective role in preserving skeletal muscle microcirculation in a mouse model of sepsis. Methods: Male C57BL/6 mice (12 weeks old) underwent cecal ligation and puncture (CLP) or sham surgery. An additional cohort of CLP animals received intraperitoneal injections of gp91ds-tat (10 mg/kg/day), an inhibitor of Nox2 assembly, for 5 consecutive days, after which terminal assessments were performed across all groups prior to euthanasia (Sham n = 8; CLP n = 8; CLP + gp91ds-tat n = 8). Forelimb grip strength was assessed to determine muscle force-generating capacity. Animals were then injected retro-orbitally with 50 μL of Griffonia simplicifolia lectin (GSL; 1 mg/mL) to label α-galactose residues on the surface of endothelial cells, thereby identifying perfused capillaries. Intravital microscopy was performed on the triceps surae of the hindlimbs to assess skeletal muscle microcirculation (4-25 μm). Mitochondrial respiration was evaluated in permeabilized fibers from the red region of the tibialis anterior (TA) muscle. Hindlimb muscles were subsequently dissected, weighed, and prepared for histological analysis. Muscle fiber cross-sectional area and CD31-positive cells were quantified using immunofluorescence. Results: Sepsis induced pronounced body and skeletal muscle wasting accompanied by significant weakness, effects that were significantly attenuated by Nox2 inhibition (p< 0.05). Notably, Nox2 blockade restored triceps surae microvascular density (Sham 2.76±0.8; CLP 1.27±0.3; CLP+gp91ds-tat 4.49±1.1mm/mm2; p< 0.05) and increased red blood cell velocity (Sham 98.44±11.8; CLP 69.3±6.4; CLP+gp91ds-tat 117±10.9 μm/sec; p< 0.05) within 4–10 µm capillaries, alterations that were accompanied by an elevation in total capillary blood volume (Sham 1.45±0.5; CLP 0.59± 0.14; CLP+gp91dstat 2.76±0.9 μm³/mm 2 ; p,0.05). Furthermore, sepsis reduced the number of perfused capillaries in the tibialis anterior muscle, an effect that was prevented by Nox2 inhibition (p< 0.05). Lastly, sepsis induced impaired skeletal muscle state 3 respiration in permeabilized fibers (p < 0.05), an effect that was not attenuated by Nox2 inhibition. Conclusion: Our findings indicate that Nox2 contributes to sepsis-induced microcirculatory dysfunction, and that systemic inhibition of Nox2 protects against this impairment but does not prevent skeletal muscle mitochondrial dysfunction five days after infection in mice. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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