Protective Effect of Oxytocin on Ventilator-Induced Lung Injury Through NLRP3-Mediated Pathways.

Xiaomei Yang,Baozhu Sun,Yicheng Lin,Feng Gao,Qiming Deng,Jianbo Wu,Peng Zhang,Shengqiang Li,Yuedong Hou,Dongsheng Xu,Cheng Wang,Wenjing Chen,Xiaona An

doi:10.3389/fphar.2021.722907

Abstract

Mechanical ventilation is an indispensable life-support treatment for acute respiratory failure in critically ill patients, which is generally believed to involve uncontrolled inflammatory responses. Oxytocin (OT) has been reported to be effective in animal models of acute lung injury. However, it is not clear whether Oxytocin has a protective effect on ventilator-induced lung injury (VILI). Therefore, in this study, we aimed to determine whether OT can attenuate VILI and explore the possible mechanism of this protection. To this end, a mouse VILI model was employed. Mice were pretreated with OT 30 min before the intraperitoneal injection of saline or nigericin and ventilation for 4 h, after which they were euthanized. Pathological changes, lung wet/dry (W/D) weight ratio, myeloperoxidase (MPO) activity, the levels of inflammatory cytokines [i.e., interleukin (IL)-1β, IL-6, and IL-18] in lung tissues and bronchoalveolar lavage fluid (BALF), and expression of NLRP3, Toll-like receptor 4 (TLR4), caspase-1, nuclear factor (NF)-κB, and GSDMD in lung tissues were measured. OT treatment could reduce pathological injury, the W/D ratio, and MPO activity in VILI mice. Our data also indicated that OT administration alleviated the expression of TLR4/My-D88 and the activation of NF-κB, NLRP3, and caspase-1 in lung tissues from the VILI mice model. Furthermore, OT also decreased the levels of IL-1β, IL-6, and IL-18 in the bronchoalveolar lavage fluid. Moreover, the OT administration may alleviate the activation of GSDMD partially through its effects on the NLRP3-mediated pathway. Collectively, OT exerted a beneficial effect on VILI by downregulating TLR4-and NLRP3-mediated inflammatory pathways.

Highlights

Mechanical ventilation (MV), as an essential life-support treatment for the acute respiratory failure in critically ill patients (Goligher et al, 2015; Lee et al, 2020), may lead to local and systemic inflammatory responses due to lung over-distension, which may cause the occurrence and development of ventilator-induced lung injury (VILI) (Slutsky and Ranieri, 2013)
The NLRP3 inflammasome, which is a NOD-like receptor located in the cytoplasm, It is composed of apoptosis-related speckle-like protein (ASC), caspase-1, and NLRP3
We identified that Toll-like receptor 4 (TLR4)-and NLRP3/gasdermin D (GSDMD)-mediated pyroptosis signaling were activated in VILI mice

Summary

Introduction

Mechanical ventilation (MV), as an essential life-support treatment for the acute respiratory failure in critically ill patients (Goligher et al, 2015; Lee et al, 2020), may lead to local and systemic inflammatory responses due to lung over-distension, which may cause the occurrence and development of ventilator-induced lung injury (VILI) (Slutsky and Ranieri, 2013). Toll-like receptor 4 (TLR4) primarily was thought to be the sensor of pathogen-associated molecular patterns (PAMPs) (Takeuchi et al, 1999) that acted by activating nuclear factor kappa-light-chainenhancer in activated B cells (NF-κB) and inducing the release of inflammatory chemokines and cytokines (Hu et al, 2010; GuijarroMuñoz et al, 2014; Hongli et al, 2018). The NLRP3 inflammasome, which is a NOD-like receptor located in the cytoplasm, It is composed of apoptosis-related speckle-like protein (ASC), caspase-1, and NLRP3

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