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Incomplete Knockdown of MyD88 Inhibits LPS-Induced Lung Injury and Lung Fibrosis in a Mouse Model

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Abstract

Acute lung injury (ALI) is a life-threatening disorder stemmed mainly from an uncontrolled inflammatory response. Lipopolysaccharide (LPS) is commonly used to induce ALI animal models. Toll-like receptor 4 (TLR4) is the main receptor for LPS, and myeloid differentiation factor 88 (MyD88) is a key adaptor protein molecule in the Toll-like receptor (TLR) signaling pathway. Thus, MyD88 knockdown heterozygous mice (MyD88+/−) were used to investigate the effect of incomplete knockout of the MyD88 gene on indirect LPS-induced ALI through intraperitoneal injection of LPS. The LPS-induced ALI significantly upregulated MyD88 expression, and heterozygous mice with incomplete knockout of the MyD88 gene (MyD88+/−) ameliorated LPS-induced histopathological injury and collagen fiber deposition. Heterozygous mice with incomplete knockout of the MyD88 gene (MyD88+/−) inhibited LPS-induced nuclear factor-κB (NF-κB) pathway activation, but TLR-4 expression tended to be upregulated. Incomplete knockdown of the MyD88 gene also downregulated LPS-induced expression of IL1-β, IL-6, TNF-α, TGF-β, SMAD2, and α-SMA. The transcriptome sequencing also revealed significant changes in LPS-regulated genes (such as IL-17 signaling pathway genes) after the incomplete knockdown of MyD88. In conclusion, this paper clarified that LPS activates the downstream NF-κB pathway depending on the MyD88 signaling pathway, which induces the secretion of inflammatory cytokines such as IL-1β/IL-6/TNF-α and ultimately triggers ALI. Incomplete knockdown of the MyD88 reverses LPS-induced lung fibrosis, which confirmed the vital role of MyD88 in LPS-induced ALI.

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Data Availability

This study did not include data deposited in external repositories. All relevant data are available in the manuscript.

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Author notes

  1. Hui Fan and Yanni Wang equally contributed to the work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Hui Fan, Yanni Wang, Kaochang Zhao, Li Su, Chong Deng & Guozhong Chen

  2. Research Center for Stem Cell Engineering and Technology, Institute of Industrial Technology, Chongqing University, Chongqing, China

    Jie Huang

  3. Better Biotechnology LLC, Chongqing, China

    Jie Huang

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  1. Hui Fan
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Contributions

Hui Fan and Yanni Wang designed the experiments and completed the manuscript. Kaochang Zhao, Li Su, and Chong Deng carried out the experiments. Guozhong Chen analyzed the data, and Jie Huang contributed to the final version of the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Guozhong Chen.

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This study was approved by the Laboratory Animal Management Committee of Chongqing Liangjiang Chuangxiang Medical Inspection and Certification Technology Co., Ltd. (No. 2022001). All experiments were performed in accordance with the National Institutes of Health guidelines.

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Fan, H., Wang, Y., Zhao, K. et al. Incomplete Knockdown of MyD88 Inhibits LPS-Induced Lung Injury and Lung Fibrosis in a Mouse Model. Inflammation 46, 2276–2288 (2023). https://doi.org/10.1007/s10753-023-01877-4

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