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Indomethacin Combined with Ciprofloxacin Improves the Prognosis of Mice under Severe Traumatic Infection via the PI3K/Akt Pathway in Macrophages

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Abstract

The prevention and treatment strategies for traumatic infection often focus on the use of antibiotics, while eschew the combined treatment of the bacteria, their toxins, and inflammatory mediators. This might be a main reason the prognosis of wound victims has not improved. Although our previous work found that the combination of indomethacin (IND) and ciprofloxacin (CIP) could promote skin wound repair and enhance the immune function, the efficacy and safety of this strategy for severe traumatic infection-mediated complications remain unknown. Additionally, there is no study on the relevant target cells and molecular mechanisms. In this study, C57BL/6 adult male mice were modeled for severe traumatic infection, and the optimal doses of IND and CIP alone were determined. After that, the efficacy and safety of IND plus CIP in traumatic infection mice were explored. Then the differentially expressed genes of activated macrophages in this process were analysed and verified by transcriptomic methods and conventional experimental techniques. The role of a candidate signalling pathway (PI3K/Akt) in regulating macrophage function and drug combination therapy was evaluated. The results showed that IND plus CIP increased the survival rate, reduced the degree of inflammatory response, and enhanced the bacteriostatic effect in mice under traumatic infection. This combined therapy did not cause significant damage to the functions of important organs (liver, kidney, heart). In addition, IND combined with CIP induced macrophages to significantly change their expression levels of several cytokines, including interleukin (IL) -1β, IL-6, IL-10, IL-22, IL-23A, IL-17A, IL-17F, cluster of differentiation (CD) 11b and other genes/encode proteins. Further study showed that intervention with the PI3K inhibitor LY294002 modulated the secretion function of the above-mentioned macrophages and Akt activation (phosphorylation at serine 473). IND plus CIP can regulate macrophage function through the PI3K/Akt signalling pathway and improve the prognosis of severe traumatic infected mice. This may be a new therapeutic strategy for the prevention and treatment of severe traumatic infection.

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Data Availability

Data will be made available on request.

Abbreviations

AKT:

Protein kinase B

Alb:

Albumin

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

ANOVA:

Analysis of variance

AST:

Aspartate aminotransferase

CD:

Cluster of differentiation

cfu:

Colony forming unit

CIP:

Ciprofloxacin

CK:

Creatine kinase

CK-MB:

Creatine kinase isoenzyme-MB

Crea:

Creatinine

DBil:

Direct bilirubin

ELISA:

Enzyme-linked immunosorbent assay

Glb:

Globulin

GGT:

Gamma-glutamyl transferase

g:

Gram

IBil:

Indirect bilirubin

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-10:

Interleukin-10

IL-17A:

Interleukin-17A

IL-17F:

Interleukin-17F

IL-22:

Interleukin-22

IL-23A:

Interleukin-23A

IND:

Indomethacin

LDH:

Lactic dehydrogenase

LPS:

Lipopolysaccharide

μL:

Microliter

mL:

Milliliter

min:

Minutes

NSAID(s):

Nonsteroidal anti-inflammatory drug

PA:

Prealbumin

PI3K:

Phosphatidylinositol 3 kinase

qRT-PCR:

Quantitative real-time poly-enzyme chain reaction

SPF:

Specific pathogen free

TBil:

Total bilirubin

TNF-α:

Tumor necrosis factor-α

TP:

Total protein

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Funding

The study was supported by Science and Technology Innovation Enhancement Project of Army Medical University (Third Military Medical University) (2019XYY22) and Major Project of National Science and Technology (2019ZX09301-167).

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Authors and Affiliations

  1. Department of Special War Wound, State Key Laboratory of Trauma and Chemical Poisoning, Research Institute of Surgery, Da** Hospital, Army Medical University, Third Military Medical University), Chongqing, 400042, China

    Ke Liu, Yu ** Hospital, Army Medical University, Third Military Medical University), Chongqing, 400042, China

    Wei** Lu & Shaoli Deng

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  1. Ke Liu
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  2. Yu **a
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  3. Leiting Zhang
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  4. Wei** Lu
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  5. Shaoli Deng
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  6. Suiyan Li
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  7. **g Yu
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  8. Jun Yan
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Contributions

K L mainly performed the experiments and drafted the manuscript. Y X and L Z participated in the study. W L and S D provided detection platform of clinical laboratory. S L guided the study. J Yu administrated the study and drew the schematic diagram. J Yan designed the study, rewrote the manuscript and supplied financial support. All authors read and approved the final manuscript.

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Correspondence to **g Yu or Jun Yan.

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The authors declare no competing interests.

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The authors declare that no conflict of interest exists.

Ethics Approval and Consent to Participate

This study was approved by Laboratory Animal Welfare and Ethics Committee of Army Medical University (Third Military Medical University).

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Liu, K., **a, Y., Zhang, L. et al. Indomethacin Combined with Ciprofloxacin Improves the Prognosis of Mice under Severe Traumatic Infection via the PI3K/Akt Pathway in Macrophages. Inflammation (2024). https://doi.org/10.1007/s10753-024-02008-3

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  • DOI: https://doi.org/10.1007/s10753-024-02008-3

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