间充质干细胞治疗对肺部重塑时间进程的影响取决于小鼠肺部损伤的病因。

Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice.

机构信息

1Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 2Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 3The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. 4Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada. 5Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 6Laboratory of Inflammation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 7The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

出版信息

Crit Care Med. 2013 Nov;41(11):e319-33. doi: 10.1097/CCM.0b013e31828a663e.

DOI:10.1097/CCM.0b013e31828a663e

PMID:23760104

Abstract

OBJECTIVE

Recent evidence suggests that mesenchymal stem cells may attenuate lung inflammation and fibrosis in acute lung injury. However, so far, no study has investigated the effects of mesenchymal stem cell therapy on the time course of the structural, mechanical, and remodeling properties in pulmonary or extrapulmonary acute lung injury.

DESIGN

Prospective randomized controlled experimental study.

SETTING

University research laboratory.

SUBJECTS

One hundred forty-three females and 24 male C57BL/6 mice.

INTERVENTIONS

Control mice received saline solution intratracheally (0.05 mL, pulmonary control) or intraperitoneally (0.5 mL, extrapulmonary control). Acute lung injury mice received Escherichia coli lipopolysaccharide intratracheally (2 mg/kg in 0.05 mL of saline/mouse, pulmonary acute lung injury) or intraperitoneally (20 mg/kg in 0.5 mL of saline/mouse, extrapulmonary acute lung injury). Mesenchymal stem cells were intravenously injected (IV, 1 × 10 cells in 0.05 mL of saline/mouse) 1 day after lipopolysaccharide administration.

MEASUREMENTS AND MAIN RESULTS

At days 1, 2, and 7, static lung elastance and the amount of alveolar collapse were similar in pulmonary and extrapulmonary acute lung injury groups. Inflammation was markedly increased at day 2 in both acute lung injury groups as evidenced by neutrophil infiltration and levels of cytokines in bronchoalveolar lavage fluid and lung tissue. Conversely, collagen deposition was only documented in pulmonary acute lung injury. Mesenchymal stem cell mitigated changes in elastance, alveolar collapse, and inflammation at days 2 and 7. Compared with extrapulmonary acute lung injury, mesenchymal stem cell decreased collagen deposition only in pulmonary acute lung injury. Furthermore, mesenchymal stem cell increased metalloproteinase-8 expression and decreased expression of tissue inhibitor of metalloproteinase-1 in pulmonary acute lung injury, suggesting that mesenchymal stem cells may have an effect on the remodeling process. This change may be related to a shift in macrophage phenotype from M1 (inflammatory and antimicrobial) to M2 (wound repair and inflammation resolution) phenotype.

CONCLUSIONS

Mesenchymal stem cell therapy improves lung function through modulation of the inflammatory and remodeling processes. In pulmonary acute lung injury, a reduction in collagen fiber content was observed associated with a balance between metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 expressions.

摘要

目的

最近的证据表明，间充质干细胞可能减轻急性肺损伤中的肺炎症和纤维化。然而，到目前为止，还没有研究调查间充质干细胞治疗对肺内或肺外急性肺损伤的结构、力学和重塑特性的时间过程的影响。

设计

前瞻性随机对照实验研究。

地点

大学研究实验室。

实验对象

143 只雌性和 24 只雄性 C57BL/6 小鼠。

干预措施

对照组小鼠经气管内（0.05 mL，肺内对照）或腹腔内（0.5 mL，肺外对照）给予生理盐水。急性肺损伤小鼠经气管内给予大肠杆菌脂多糖（2 mg/kg，溶于 0.05 mL 生理盐水/只，肺内急性肺损伤）或腹腔内给予生理盐水（20 mg/kg，溶于 0.5 mL 生理盐水/只，肺外急性肺损伤）。间充质干细胞于脂多糖给药后 1 天经静脉内（IV，0.05 mL 生理盐水/只，1×10 个细胞）注射。

测量和主要结果

在第 1、2 和 7 天，肺内和肺外急性肺损伤组的静态肺弹性和肺泡塌陷量相似。在两组急性肺损伤中，第 2 天的炎症明显增加，表现为支气管肺泡灌洗液和肺组织中的中性粒细胞浸润和细胞因子水平。相反，胶原沉积仅在肺内急性肺损伤中记录。间充质干细胞在第 2 和 7 天减轻了弹性、肺泡塌陷和炎症的变化。与肺外急性肺损伤相比，间充质干细胞仅在肺内急性肺损伤中减少了胶原沉积。此外，间充质干细胞增加了肺内急性肺损伤中的基质金属蛋白酶-8 表达，降低了组织金属蛋白酶抑制剂-1 的表达，提示间充质干细胞可能对重塑过程有影响。这种变化可能与巨噬细胞表型从 M1（炎症和抗微生物）向 M2（伤口修复和炎症消退）表型的转变有关。