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Intrapulmonary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Survival and Attenuates Endotoxin-Induced Acute Lung Injury in Mice¹

Naveen Gupta^2,*, Xiao Su^*, Boris Popov, Jae Woo Lee^*, Vladimir Serikov and Michael A. Matthay^*

^* Cardiovascular Research Institute, University of California, San Francisco, CA 94143; and Children’s Hospital of Oakland Research Institute, Oakland, CA 94609

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant HL-51854 (to M.A.M.) and the California Institute of Regenerative Medicine Training Grant (to N.G.).

² Address correspondence and reprint requests to Dr. Naveen Gupta, Cardiovascular Research Institute, University of California, San Francisco, HSW 825, 505 Parnassus Avenue, San Francisco, CA 94143-0130. E-mail address: naveen.gupta{at}ucsf.edu

³ Abbreviations used in this paper: ALI, acute lung injury; MSC, mesenchymal stem cell(s); GM, growth medium; BAL, bronchoalveolar lavage; MPO, myeloperoxidase; i.t., intratracheal(ly).

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