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Lidocaine pretreatment attenuates inflammatory response and protects against sepsis-induced acute lung injury via inhibiting potassium efflux-dependent NLRP3 activation

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Abstract

Objective

Sepsis may often result in acute lung injury (ALI), with a high mortality and morbidity. Available evidence indicates that activation of NLRP3 inflammasome to induce macrophage inflammation plays a crucial role in the inflammation progression of ALI and lidocaine can attenuate inflammatory responses. We hypothesized that lidocaine may attenuate inflammatory response and sepsis-induced ALI by inhibiting potassium efflux-dependent NLRP3 activation.

Methods

C57BL/6N mice were randomized and divided into six groups (n = 6) receiving different treatments. Lung vascular permeability and histological changes in the lungs were evaluated by Evans blue dye, bronchoalveolar lavage analysis and hematoxylin and eosin staining. J774A.1 macrophages were divided into 12 groups receiving different treatments. The expression of both NLRP3 inflammasome activation-related protein and P2X7 in the macrophages was measured by immunofluorescence staining and Western blots. The whole cell currents were determined by a voltage-patch clamp technique.

Results

Challenge with LPS led to ALI in mice with an increased lung injury score (0.54 ± 0.09), which was significantly attenuated by lidocaine pretreatment (0.20 ± 0.08, P < 0.0001). Lidocaine pretreatment significantly decreased the NLRP3 activation and IL-1β release in the macrophages. Furthermore, lidocaine pretreatment down-regulated the expression of P2X7 receptors, inhibited LPS- and ATP-induced sodium (Na+) inward flow, and maintained the intracellular K+ level in the macrophages. In addition, activation of Na+ influx did not eliminate anti-inflammatory effect of lidocaine. The activation of NLRP3 could be suppressed by extracellular K+ level in a dose-dependent model. However, lidocaine pretreatment eliminated NLRP3 activation and IL-1β release induced by K+ efflux, and decreased outward K+ current and extracellular K+ level in the macrophages challenged by LPS/ATP.

Conclusions

Lidocaine pretreatment can attenuate the sepsis-induced ALI by an anti-inflammatory mechanism of inhibiting K+ efflux-dependent NLRP3 activation.

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Data availability

The datasets used during the present study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Hua Wei, Ph.D. (Core Facilities Centre, Capital Medical University) for the help with the patch clamp.

Funding

This work was supported by the Funds for Beijing Municipal Natural Science Foundation (No. 7214221, to Kai Su), Capital Health Improvement and Research (No. 2018-4-1116, to Kai Su) and Bethune Charitable Foundation (No. SX2022009, to Kai Su).

Author information

Author notes

  1. Kai Su and Xin-Tao Li contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, People’s Republic of China

    Kai Su, Xin-Tao Li, Fang-Xiao Hong, Mu Jin & Fu-Shan Xue

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  1. Kai Su
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Contributions

K. Su, X.T. Li, M. Jin and F. S. Xue conceived and designed the research; K. Su, X. T. Li and M. Jin performed the experiments; M. Jin and F. S. Xue analyzed the data; K. Su, F. X. Hong and F.S. Xue interpreted the results of experiments; K. Su and X.T. Li prepared the figures; K.Su, X. T. Li and F. S. Xue drafted the manuscript; M. Jin, F. X. Hong and F. S. Xue edited and revised the manuscript; K. Su, X.T. Li, F. X. Hong, M. Jin and F. S. Xue approved the final version of manuscript.

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Correspondence to Mu Jin or Fu-Shan Xue.

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11_2023_1810_MOESM1_ESM.tif

Effect of lidocaine pretreatment on IL-1β in the THP-1 macrophages challenged with the LPS. Data represent means ± SD. LPS, lipopolysaccharide; ATP, Adenosine triphosphate; Lido, lidocaine; p17, IL-1β p17. A and B: Expressions of IL-1β by western blotting. A, the independent western blots for IL-1β (17, 31 kDa) and GAPDH (37 kDa; loading control). B, quantification of western blotting data for IL-1β p17 as shown in A (n = 3. ★P < 0.05, §P < 0.0001). C: IL-1β level in the supernatant of cultured THP-1 macrophages (n = 6. §P < 0.0001). Supplementary file1 (TIF 1207 KB)

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Su, K., Li, XT., Hong, FX. et al. Lidocaine pretreatment attenuates inflammatory response and protects against sepsis-induced acute lung injury via inhibiting potassium efflux-dependent NLRP3 activation. Inflamm. Res. 72, 2221–2235 (2023). https://doi.org/10.1007/s00011-023-01810-3

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