Previously, KGF secretion by MSC was found to be involved in restoring both vectorial ion and fluid transport in injured human alveolar epithelial type II cells and in increasing the antimicrobial properties of monocytes/macrophages[15]. Monsel et al.[103], using a model of Escherichia coli pneumonia in mice, demonstrated that administration of Msc Mvs improved survival and mitigated lung inflammation, protein permeability, and bacterial growth. The results suggested several potential mechanisms underlying the beneficial effects of MSC MVs: 1) Enhancement of monocyte phagocytosis of bacteria, which could be further increased by pre-stimulation of MSC with a toll-like receptor 3 agonist prior to the release of MVs; 2) The transfer of mRNA for cyclooxygenase 2 (COX2), the key enzyme in prostaglandin E2 (PGE2) synthesis, from MSC MVs to activated monocytes with a resultant increase in PGE2 secretion, causing a shift in monocytes toward an anti-inflammatory M2 phenotype. Surprisingly, the authors found no effect on CD163 or CD206 mRNA expression (M2 markers) in mo.Usion and investigated improvement of functional recovery and enhancement of neurite remodeling, neurogenesis, and angiogenesis. By evaluating functional recovery with a Foot-fault test[101] and a modified neurologic severity score[102], MSC exosomes treatment was associated with significant functional improvements following middle cerebral artery occlusion. MSC exosome treatment also significantly increased axonal density and synaptophysin-positive areas alongAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptExpert Opin Biol Ther. Author manuscript; available in PMC 2017 January 31.Monsel et al.Pagethe ischemic boundary zone of the cortex and striatum as well as the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. In summary, multiple extra-pulmonary organ injuries share common pathophysiological pathways with Inflammatory Lung Diseases including ALI. Therefore, understanding the therapeutic effects of MSC derived vesicles in these extra-pulmonary injury models may yield insights into its effects in ALI, especially in terms of suppressing inflammation, preventing apoptosis or enhancing cellular energetics as well as in ALI specific pathologies such as decreasing endothelial permeability or enhancing alveolar epithelial fluid absorption. C. Therapeutic Properties of Mesenchymal Stem Cell Extracellular Vesicles in Acute Lung Injury and Other Inflammatory Lung Diseases To date, only a few groups have studied the therapeutic effects of MSC vesicles in acute inflammatory lung diseases such as ALI[16, 103?05], pulmonary artery hypertension (PAH)[106, 107] and asthma[108]. Although the mechanisms of action have not been fully defined, these groups have demonstrated that MSC vesicles are as potent as their parent stem cells as therapy (Figure 4). Zhu et al. demonstrated a biologic effect of MVs derived from human bone marrow MSCs in a mouse model of endotoxin-induced ALI[16]. Treatment with MSC MVs was effective in restoring lung protein permeability, reducing inflammation (e.g., the influx of neutrophils and elevation of macrophage inflammatory protein-2 levels), and preventing the formation of pulmonary edema in the injured alveolus. KGF mRNA knockdown partially abrogated the therapeutic effects of MSC MVs, suggesting that KGF protein expression was important for the underlying mechanism. Previously, KGF secretion by MSC was found to be involved in restoring both vectorial ion and fluid transport in injured human alveolar epithelial type II cells and in increasing the antimicrobial properties of monocytes/macrophages[15].