Intrapulmonary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Survival and Attenuates Endotoxin-Induced Acute Lung Injury in Mice

Abstract

Recent in vivo and in vitro work suggests that mesenchymal stem cells (MSC) have anti-inflammatory properties. In this study, we tested the effect of administering MSC directly into the airspaces of the lung 4 h after the intrapulmonary administration of Escherichia coli endotoxin (5 mg/kg). MSC increased survival compared with PBS-treated control mice at 48 h (80 vs 42%; p < 0.01). There was also a significant decrease in excess lung water, a measure of pulmonary edema (145 ± 50 vs 87 ± 20 μl; p < 0.01), and bronchoalveolar lavage protein, a measure of endothelial and alveolar epithelial permeability (3.1 ± 0.4 vs 2.2 ± 0.8 mg/ml; p < 0.01), in the MSC-treated mice. These protective effects were not replicated by the use of further controls including fibroblasts and apoptotic MSC. The beneficial effect of MSC was independent of the ability of the cells to engraft in the lung and was not related to clearance of the endotoxin by the MSC. MSC administration mediated a down-regulation of proinflammatory responses to endotoxin (reducing TNF-α and MIP-2 in the bronchoalveolar lavage and plasma) while increasing the anti-inflammatory cytokine IL-10. In vitro coculture studies of MSC with alveolar macrophages provided evidence that the anti-inflammatory effect was paracrine and was not cell contact dependent. In conclusion, treatment with intrapulmonary MSC markedly decreases the severity of endotoxin-induced acute lung injury and improves survival in mice.

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…13,24 A growing number of studies have shown that MSCs have immunomodulatory and anti-infl ammatory eff ects despite minimum or absent engraftment. [25][26][27][28] Consequently, research has shifted towards identifi cation of alternative pathways through which MSCs interact with host tissue, including interactions between cells, direct interactions with the host immune system, and mitochondrial transfer. The pathway with the most robust supporting evidence is the ability of MSCs to coordinate tissue repair through the release of soluble paracrine factors.…”

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

“…In the context of alveolar tissue MSC have been shown to contribute to lung regeneration in numerous experimental settings, including homing and attenuation of endotoxininduced acute lung injury (Gupta et al 2007;Lee et al 2009). Promising potential of MSC has been studied in several ways and detectable therapeutic benefits were often attributed to paracrine mechanisms, since engraftment was low (van Haaften et al 2009).…”

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

“…To further test the role of MSCs and LXA 4 in acute lung injury, we studied the effect of the ALX/FPR2 receptor agonist and antagonist using an in vivo experimental model of acute lung injury induced by LPS, a model we have used in a prior study (2). The percentage of apoptotic human MSCs at the time of i.t.…”

“…Gravimetric lung water determination was done by standard methods as we have reported (2,25). Lungs from endotoxin injured with or without treatment with LXA 4 and MSCs were excised at 48 h. The lungs were inflated with 0.5 ml air and the trachea was ligated.…”

“…Pathophysiologic mechanisms of ALI and ARDS include inflammation and increased endothelial and epithelial permeability to protein, resulting in extravascular accumulation of protein-rich edema fluid and alveolar epithelial injury (1). Several preclinical studies have demonstrated that bone marrow-derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of ALI induced by endotoxin (2,3), live Escherichia coli bacteria (4,5), or following sepsis (6)(7)(8). Much of the therapeutic benefit of MSCs appears to derive from the release of paracrine soluble factors, which stabilize the injured alveolar epithelium and lung endothelium, reduce inflammation, increase the absorption of pulmonary edema fluid, and have antimicrobial activity (9).…”