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

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.

Endothelial dysfunction and immunothrombosis in sepsis

“…Inhibitory monoclonal antibody (mAb) against CD14 led to decreased activation of the extrinsic coagulation pathway through suppression of TF expression in leukocytes while also enhancing fibrinolysis through decreasing plasma PAI-1 ( 285 ). Apart from anti-CD14 mAb, lidocaine could also inhibit LPS-induced TF expression in monocytes through upregulation of suppressor of cytokine signaling 3 (SOCS3), which in turn downregulated the TLR4-TF pathway ( 286 ). Another potential pathway that could serve as a therapeutic target for mitigating immunothrombosis was shown to be type 1 interferon (IFN-1)-induced upregulation of TF procoagulant activity.…”

PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications

“…Also, some drugs have been investigated for their ability in modulating TLR4 through various mechanisms. Among molecules interfering with TLR4 and its mRNA expression, there are many used for several applications, like chloroquine [204], ketamine [205][206][207], statins [208,209], and lidocaine [210]. Among drugs acting on the TLR4 transduction pathway, there are eritoran (E5564), resatorvid (TAK242), ketamine, opioids [211], vitamin D3, and lansoprazole.…”

Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications

“…For instance, in pre-clinical sepsis models and ex vivo preparations of human lungs perfused with LPS, ADAM15 could cleave PGs from the endothelial glycocalyx [56]. The concentration of MMPs in the plasma has similarly been shown to correlate with the severity of sepsis, and inhibiting MMPs has been demonstrated to prevent sepsis-induced ALI/ARDS, particularly MMPs-7, MMPs-9, and MMPs-13 [57][58][59][60]. The enzymatic degradation of the endothelial glycocalyx carries significant physiological implications, as the degradation products can disseminate through the bloodstream and affect distant sites, thereby influencing the severity of lung injury and prognosis.…”