Lidocaine Alleviates Sepsis-Induced Acute Lung Injury in Mice by Suppressing Tissue Factor and Matrix Metalloproteinase-2/9.

Binbin Zheng,Hongbo Yang,Xia Zhu,Wen-Tao Liu,Yue Su,Hao Sun,Yulin Tang,Qilin Peng,Xueli Wang,Qian Li,Liping Jiang,Jianan Zhang,Xueming He,Fan Hu,Yixin Fan,Md Saquib Hasnain

doi:10.1155/2021/3827501

Abstract

Acute lung injury (ALI) is one of the fatal symptoms of sepsis. However, there were no effective clinical treatments. TF accumulation-induced fibrin deposit formations and coagulation abnormalities in pulmonary vessels contribute to the lethality of ALI. Suppressor of cytokine signaling 3 (SOCS3) acts as an endogenous negative regulator of the TLR4/TF pathway. We hypothesized that inducing SOCS3 expression using lidocaine to suppress the TLR4/TF pathway may alleviate ALI. Hematoxylin and eosin (H&E), B-mode ultrasound, and flow cytometry were used to measure the pathological damage of mice. Gelatin zymography was used to measure matrix metalloproteinase-2/9 (MMP-2/9) activities. Western blot was used to assay the expression of protein levels. Here, we show that lidocaine could increase the survival rate of ALI mice and ameliorate the lung injury of ALI mice including reducing the edema, neutrophil infiltration, and pulmonary thrombosis formation and increasing blood flow velocity. Moreover, in vitro and in vivo, lidocaine could increase the expression of p-AMPK and SOCS3 and subsequently decrease the expression of p-ASK1, p-p38, TF, and the activity of MMP-2/9. Taken together, our study demonstrated that lidocaine could inhibit the TLR4/ASK1/TF pathway to alleviate ALI via activating AMPK-SOCS3 axis.

Highlights

Acute lung injury (ALI) caused by sepsis is one of the main causes of death in ICU patients
It was found that LPS stimulation for 12 h significantly increased the ratio of wet-to-dry weight of mouse lung tissues from 4:52 ± 0:06 to 6:52 ± 0:76 (Figure 1(c)), and the B-mode ultrasound imaging indicated that LPS significantly induce pulmonary edema in mice (Figure 1(d)), whereas these effects could be reversed by lidocaine (Figures 1(c) and 1(d))
Further research show that lidocaine could significantly inhibit the LPS-induced activation of the ASK1-p38-Tissue factor (TF)/ matrix metalloproteinase-2/9 (MMP-2/9) signaling pathway in vivo and in vitro, which depends on AMPK-Suppressor of cytokine signaling 3 (SOCS3) axis

Summary

Introduction

Acute lung injury (ALI) caused by sepsis is one of the main causes of death in ICU patients. Therapies to prevent or treat ALI remain elusive. It is urgent to further investigate the pathogenesis of sepsis-induced ALI and find effective strategy. The pathological characteristics of ALI mainly include coagulation abnormalities, thrombus, hypoxemia, diffuse infiltration of the lungs, and decreased functional lung volume [1]. Tissue factor (TF) is a primary trigger for coagulation and thrombus formation, playing a pivotal role in blood clotting activation [2]. Recent study showed that the expression of tissue factor (TF) was significantly increased in LPS-

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Results

Conclusion