Keratinocyte growth factor gene delivery via mesenchymal stem cells protects against lipopolysaccharide-induced acute lung injury in mice.

Jie Chen,Yanqin Li,Ling Yu,Xiaoyi Xiao,Xiaofang Gao,Chonghui Li,Chunsun Li,Liangan Chen,Zhixin Liang,You-Yang Zhao

doi:10.1371/journal.pone.0083303

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality, and have no specific therapy. Keratinocyte growth factor (KGF) is a critical factor for pulmonary epithelial repair and acts via the stimulation of epithelial cell proliferation. Mesenchymal stem cells (MSCs) have been proved as good therapeutic vectors. Thus, we hypothesized that MSC-based KGF gene therapy would have beneficial effects on lipopolysaccharide(LPS)-induced lung injury. After two hours of intratracheal LPS administration to induce lung injury, mice received saline, MSCs alone, empty vector-engineered MSCs (MSCs-vec) or KGF-engineered MSCs (MSCs-kgf) via the tail vein. The MSCs-kgf could be detected in the recipient lungs and the level of KGF expression significantly increased in the MSCs-kgf mice. The MSC-mediated administration of KGF not only improved pulmonary microvascular permeability but also mediated a down-regulation of proinflammatory responses (reducing IL-1β and TNF-α) and an up-regulation of anti-inflammatory responses (increasing cytokine IL-10). Furthermore, the total severity scores of lung injury were significantly reduced in the MSCs-kgf group compared with the other three groups. The underlying mechanism of the protective effect of KGF on ALI may be attributed to the promotion of type II lung epithelial cell proliferation and the enhancement of surfactant synthesis. These findings suggest that MSCs-based KGF gene therapy may be a promising strategy for ALI treatment.

Highlights

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions of acute respiratory failure, which are caused by direct or indirect injury to the lung [1]
We report that Mesenchymal stem cells (MSCs)-based Keratinocyte growth factor (KGF) gene therapy can deliver KGF to the injured lung tissues and attenuates LPS-induced ALI mice
We found that transplanted KGF genemodified MSCs were retained in the lung and enhanced KGF expression in the lungs of LPS-challenged mice

Summary

Introduction

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions of acute respiratory failure, which are caused by direct or indirect injury to the lung [1]. The disruption of alveolar epithelial integrity is a major contributor to increased permeability and alveolar flooding with protein-rich edema fluid, a hallmark of ALI/ARDS. Pharmacological therapies that target the enhancement or restoration of lung epithelial cell functions have not yet been translated to effective clinical treatment options, and innovative therapies are urgently needed [3]. Keratinocyte growth factor (KGF), known as fibroblast growth factor (FGF)-7, is a potent mitogenic factor for alveolar epithelial cells [4]. KGF can induce alveolar type II cell proliferation in vitro, stimulate surfactant synthesis, improve edema clearance and decrease apoptosis [5,6]. The administration of exogenous rhKGF has so far demonstrated only limited effectiveness in a variety of animal models of lung injury induced by radiation [7], bleomycin [8] and acid aspiration [9]. Methods to ensure the sustained expression of KGF in the injured lung have important clinical applications

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