Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice

• Published in: American journal of physiology. Lung cellular and molecular physiology 2007-07, Vol.293 (1), p.L131-L141
• Main Authors: Xu, Jianguo, Woods, Charles R, Mora, Ana L, Joodi, Robert, Brigham, Kenneth L, Iyer, Smita, Rojas, Mauricio
• Format: Article
• Language: English
• Subjects: Animals; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cell Communication - drug effects; Cell Movement - drug effects; Cytokines - biosynthesis; Endotoxins; Female; Infusions, Intravenous; Lipopolysaccharides - pharmacology; Lung - drug effects; Lung - pathology; Lung Diseases - chemically induced; Lung Diseases - pathology; Lungs; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mice; Mice, Inbred C57BL; Pulmonary Edema - pathology; Rodents; Stem cells; Systemic Inflammatory Response Syndrome - chemically induced; Systemic Inflammatory Response Syndrome - prevention & control; Toll-Like Receptor 4 - metabolism; Toxins
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00431.2006

1 Division of Pulmonary, Allergy and Critical Care Medicine, 2 Center for Translational Research in the Lung, and 3 McKelvey Center for Lung Transplantation, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia Submitted 1 November 2006 ; accepted in final form 30 March 2007 Bone marrow-derived mesenchymal stem cells (BMDMSCs) appear to be important in repair of the chronic lung injury caused by bleomycin in mice. To determine effects of these BMDMSCs on an acute inflammatory response, we injected C57BL/6 mice intraperitoneally with 1 mg/kg endotoxin followed either by intravenous infusion of 5 x 10 5 BMDMSCs, the same number of lung fibroblasts, or an equal volume of normal saline solution. Lungs harvested 6, 24, and 48 h and 14 days after endotoxin showed that BMDMSC administration prevented endotoxin-induced lung inflammation, injury, and edema. Although we were able to detect donor cells in the lungs at 1 day after endotoxin, by 14 days no donor cells were detected. BMDMSC administration suppressed the endotoxin-induced increase in circulating proinflammatory cytokines without decreasing circulating levels of anti-inflammatory mediators. Ex vivo cocultures of BMDMSC and lung cells from endotoxemic animals demonstrated a bilateral conversation in which lung cells stimulated proliferation and migration of stem cells and suppressed proinflammatory cytokine production by lung cells. We conclude that BMDMSCs decrease both the systemic and local inflammatory responses induced by endotoxin. These effects do not require either lung engraftment or differentiation of the stem cells and are due at least in part to the production of stem cell chemoattractants by the lungs and to humoral and physical interactions between stem cells and lung cells. We speculate that mobilization of this population of BMDMSCs may be a general mechanism for modulating an acute inflammatory response. lung injury; lipopolysaccharide Address for reprint requests and other correspondence: M. Rojas, Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Research of the Lung, Emory Univ. School of Medicine, Atlanta, GA 30322 (e-mail: mrojas{at}emory.edu )