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The Pannexin-1 Channel Inhibitor Probenecid Attenuates Skeletal Muscle Cellular Energy Crisis and Histopathological Injury in a Rabbit Endotoxemia Model

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Abstract

This study aimed to investigate the effect of probenecid (Pro) as an inhibitor of the pannexin-1 (Panx-1) channel-mediated release of intracellular ATP to the extracellular compartment on inflammation, cellular energy crisis, and organ injury in a rabbit sepsis model induced by Escherichia coli lipopolysaccharides (LPS). A total of 24 anesthetized and ventilated rabbits were randomly assigned to receive one of four treatments: infusion of LPS without Pro (LPS group), infusion of LPS with Pro (LPS + Pro group), sham operation without Pro (normal group), and sham operation with Pro (normal + Pro group). The LPS group had significantly higher serum ATP levels, serum inflammatory factor levels (TNF-α, IL-6, and IL-1β), and lower ATP concentrations and ATP/ADP ratios in the skeletal muscle tissue than the normal group. Compared to that at baseline, the expression of Panx-1 in peripheral blood cells increased significantly after the infusion of LPS (fluorescence intensity of Panx-1: T0 (baseline) vs. T1 (post-LPS) = 10 ± 1.2 vs. 84 ± 48, P < 0.0001; paired differences 73 ± 46, P = 0.024). Moreover, the LPS group exhibited higher expression of Panx-1 in the skeletal muscle tissue than the normal group. The serum ATP level was significantly positively correlated with IL-1β (R = 0.602, P = 0.001), IL-6 (R = 0.381, P = 0.033), and TNF-α (R = 0.514, P = 0.005) in 24 paired measurements. Compared to the LPS group, the LPS + Pro group had significantly lower levels of inflammatory factors (TNF-α, IL-6, and IL-1β) and serum ATP. In the skeletal muscle tissue, the LPS + Pro group also had a higher ATP concentration (1.1 ± 0.15 vs. 1.33 ± 0.17, P = 0.041) and ATP/ADP ratio (0.37 ± 0.03 vs. 0.51 ± 0.06, P = 0.002) and a lower histopathological damage score (4.67 ± 0.52 vs. 3 ± 0.63, P = 0.004). An overexpression of Panx-1 channel might be responsible for the strong inflammatory response, high serum ATP level, and skeletal muscle cellular energy crisis and histopathological damages in sepsis. Inhibiting Panx-1 channel-mediated release of intracellular ATP could decrease the above-mentioned injuries, and Panx-1 might be a potential therapeutic target in sepsis.

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Abbreviations

ATP:

adenosine triphosphate

ADP:

adenosine diphosphate

Pro:

probenecid

Panx-1:

pannexin 1

LPS:

lipopolysaccharides

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Funding

This project was funded by the Beijing Municipal Natural Science Foundation (Youth project no. 7174341).

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Authors and Affiliations

  1. Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China

    Huaiwu He, Dawei Liu, Yun Long, Xiaoting Wang & Bo Yao

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  1. Huaiwu He
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  2. Dawei Liu
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  3. Yun Long
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  4. Xiaoting Wang
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  5. Bo Yao
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Contributions

Huaiwu He, Yun Long, Dawei Liu, Xiaoting Wang, and Bo Yao drafted the manuscript and revised it for important intellectual content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Dawei Liu.

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Key Message

• A overhigh expression of Panx-1 might be related to an unregulated inflammatory response, a high serum ATP and cellular energy crisis in sepsis.

• The inhibition of Panx-1 channel could reduce serum ATP and restore the skeletal tissue cellular ATP, attenuation of inflammatory response, and histopathological damage in sepsis.

• Panx-1 might be a potential therapeutic target in sepsis.

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He, H., Liu, D., Long, Y. et al. The Pannexin-1 Channel Inhibitor Probenecid Attenuates Skeletal Muscle Cellular Energy Crisis and Histopathological Injury in a Rabbit Endotoxemia Model. Inflammation 41, 2030–2040 (2018). https://doi.org/10.1007/s10753-018-0846-z

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  • DOI: https://doi.org/10.1007/s10753-018-0846-z

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