Use of Mesenchymal Stem Cells in the Regulation of Inflammation: Novel Concept for Future Therapies in the Lung

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Bone marrow‐derived mesenchymal stem cells (BMDMSCs) appear to be important in the prevention of lung damage after acute and chronic inflammatory process; however the mechanisms in which these cells protect are unknown. Using an endotoxin‐induced Acute Lung Injury (ALI) model and a heterotopic trachea transplant model we demonstrate the ability of BMDMSC to regulate the immune response during acute and chronic inflammatory lung diseases respectively. First, we administrated BMDMSC in endotoxin induced ALI model in mice and pigs. We observed that BMDMSC suppressed the upregulation of pro‐inflammatory cytokines preventing inflammation and edema in the lung. The clinical relevance of these studies is shown by the observed association between the ability to induce mobilization of bone marrow derived cells and the survival of patients with ALI. Second, we studied the effect of BMDSC administration during heterotopic trachea transplant as a model of chronic transplant rejection. Lung transplantation is a viable treatment option for end‐stage pulmonary diseases, but development of obliterative bronchiolitis (OB), reduces survival, accounting for 30% of deaths after the third year. In this model of chronic inflammation, the systemic administration of BMDMSC prevents the development of OB. We were able to demonstrate the total inhibition of inflammation and fibrosis when the mice received a single dose of BMDMSC independent of the strain of mice from where the cells were obtained. To demonstrate the mechanism used by BMDMSC we realize co‐culture experiments and affimetrix analysis. These studies reveled that BMDMSC have the capacity to induce T‐regulatory cells and to produce soluble factors like TGFβ and sIL1‐R that mediate the suppression of the inflammatory immune response.