Early and late pulmonary effects of nebulized LPS in mice: An acute lung injury model.

Natália De Souza Xavier Costa,Marisa Dolhnikoff,Luiz Fernando Ferraz Da Silva,Paulo Hilário Nascimento Saldiva,Gabriel Ribeiro Júnior,Adair Aparecida Dos Santos Alemany,Mariana Matera Veras,Luciano Belotti,Douglas Hidalgo Zati,Susan Ribeiro,Esper Georges Kallás,Marcela Frota Cavalcante,Nades Palaniyar

doi:10.1371/journal.pone.0185474

Natália De Souza Xavier Costa, Marisa Dolhnikoff + Show 11 more

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https://doi.org/10.1371/journal.pone.0185474

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Abstract

Background and objectiveAcute respiratory distress syndrome (ARDS) has a high mortality rate of 35–46% depending on its severity. Animal models are crucial to better understand the pathophysiology of diseases, including ARDS. This study presents a feasible animal model of acute lung injury (ALI) using nebulized lipopolysaccharide (LPS) in a non-invasive approach, focusing on its short and long-term effects.MethodsMice received nebulized LPS or vehicle only (control group). Blood, BALF and lung tissue were collected 24 hours (LPS 24h) or 5 weeks (LPS 5w) after the nebulized LPS-induced lung injury. Inflammatory cytokines were assessed in the blood serum, BALF and lung tissue. Stereological analyses and remodeling changes were assessed by histology and immunohistochemistry at the specified time points.ResultsThe LPS 24h group showed increased pro-inflammatory cytokine levels, intense cell influx, increased total septal volume, septal thickening and decreased surface density of the alveolar septa. The LPS 5w group showed persistent lung inflammation, septal thickening, increased total lung volume, accentuated collagen deposition, especially of collagen type I, and decreased MMP-2 protein expression.ConclusionWe present a feasible, reproducible and non-invasive nebulized-LPS animal model that allows the assessment of both the acute and late phases of acute lung injury. The presence of lung remodeling with collagen deposition after 5 weeks makes it useful to study the pathophysiology, complications, and possible therapeutic intervention studies that aim to understand and reduce pulmonary fibrosis in the late phases of ALI.

Highlights

Reproducible and non-invasive nebulized-LPS animal model that allows the assessment of both the acute and late phases of acute lung injury
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a complex disease characterized by acute onset, bilateral lung infiltration, diffuse alveolar damage and proteinrich edema that can lead to severe hypoxemia and decreased lung compliance [1,2]
The most recent definition published by Ranieri et al [2] classifies ARDS into three subgroups according to hypoxemia severity: mild, moderate and severe

Summary

Introduction

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a complex disease characterized by acute onset, bilateral lung infiltration, diffuse alveolar damage and proteinrich edema that can lead to severe hypoxemia and decreased lung compliance [1,2]. To better understand the several aspects underlying ALI/ARDS, many animal models have been developed, but none can reproduce all the characteristics of the syndrome in humans. Most of these models are based on clinical conditions that are associated with the syndrome, such as sepsis, aspiration of gastric content and mechanical ventilation [5]. This study presents a feasible animal model of acute lung injury (ALI) using nebulized lipopolysaccharide (LPS) in a non-invasive approach, focusing on its short and long-term effects.

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