Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome.

Chaomin Wu,Xiaojia Huang,Yuanlin Song,Hua Jin,You-Yang Zhao,Zhiyu Dai,Xianming Zhang,Colin E Evans,Guochang Hu,Xiao Su

doi:10.1371/journal.pone.0174327

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia respiratory failure, bilateral pulmonary infiltrates, and pulmonary edema of non-cardiac origin. Effective treatments for ARDS patients may arise from experimental studies with translational mouse models of this disease that aim to delineate the mechanisms underlying the disease pathogenesis. Mouse models of ARDS, however, can be limited by their rapid progression from injured to recovery state, which is in contrast to the course of ARDS in humans. Furthermore, current mouse models of ARDS do not recapitulate certain prominent aspects of the pathogenesis of ARDS in humans. In this study, we developed an improved endotoxemic mouse model of ARDS resembling many features of clinical ARDS including extended courses of injury and recovery as well as development of fibrosis following i.p. injection of lipopolysaccharide (LPS) to corn oil-preloaded mice. Compared with mice receiving LPS alone, those receiving corn oil and LPS exhibited extended course of lung injury and repair that occurred over a period of >2 weeks instead of 3–5days. Importantly, LPS challenge of corn oil-preloaded mice resulted in pulmonary fibrosis during the repair phase as often seen in ARDS patients. In summary, this simple novel mouse model of ARDS could represent a valuable experimental tool to elucidate mechanisms that regulate lung injury and repair in ARDS patients.

Highlights

Acute respiratory distress syndrome (ARDS) remains a major cause of mortality in intensive care units worldwide [1,2,3]
Human ARDS develops over a 7day period; in this time frame, the initial exudative/inflammatory stage is followed by a proliferative tissue repair stage; and after 3 weeks, the repair phase can culminate in pulmonary fibrosis [7,8,9]
The primary aim of this study was to determine whether the course of LPSinduced lung injury and subsequent repair could be extended to a length comparable to that commonly seen in ARDS patients and to determine whether a mouse model with extended lung injury and repair will better recapitulate the pathogenesis of ARDS seen in patients including development of pulmonary fibrosis

Summary

Introduction

Acute respiratory distress syndrome (ARDS) remains a major cause of mortality in intensive care units worldwide [1,2,3]. Mouse models of sepsis-induced inflammatory lung injury can be used to improve understanding of the mechanisms that control sepsis-induced lung injury and subsequent repair [4, 11]. It is desirable for such mouse models to recapitulate the pathogenesis of human ARDS as closely as possible. The primary aim of this study was to determine whether the course of LPSinduced lung injury and subsequent repair could be extended to a length comparable to that commonly seen in ARDS patients and to determine whether a mouse model with extended lung injury and repair will better recapitulate the pathogenesis of ARDS seen in patients including development of pulmonary fibrosis. The model we present here provides a means of studying mechanisms that regulate ARDS pathogenesis and resolution in mice

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Conclusion