Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-dependent Manner

Background: Mesenchymal stem cell have shown therapeutic effect on acute lung injury, MSC could be activated when added to inflammatory environment and in turn suppress inflammation, yet the mechanism is complex and not understood. Methods: To determine the effect of MSC on ALI and alveolar macrophage activation, MSCs were administered to ALI mice and co-cultured with activated MH-S cells (alveolar macrophage cell line). To find the genes critical for MSC’s immunosuppressive effects, rest and activated MSCs induced by inflammatory MH-S cells were harvested for RNA-seq. To prove that PGE2 participates in the immunosuppressive effects of MSC, COX2 inhibitor and PGE2 receptor antagonist were added to the co-culture system and administrated to ALI mice. Results: The intratracheal administration of MSCs attenuated ALI and suppressed alveolar macrophages activation in vivo, the activation of MH-S cells was also significantly reduced after co-culturing with MSCs in vitro. The RNA-seq data of rest and activated MSCs suggested that the Ptgs2 gene may play an important role in MSC exerting immunosuppressive effects. Correspondingly, we found that the COX2 protein and PGE2 released by activated MSCs were increased dramatically after co-culturing with MH-S. The use of COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppressive effect on macrophages activation of MSCs in vitro. Furthermore, GW627368X, a selective antagonist of PGE2 receptor (EP4 receptor), also reversed the inhibitory effects of MSCs on alveolar macrophages and their protective effects on ALI mice.Conclusions: MSC attenuate ALI partly through suppressing alveolar macrophage activation via PGE2 binding to EP4 receptor.

Exploring the Correlation between the Cognitive Benefits of Drug Combinations in a Clinical Alzheimer Disease Database and the Efficacies of the Same Drug Combinations Predicted from a Computational Model

INTRODUCTIONIdentification of drug combinations that could be effective in Alzheimer’s treatment is made difficult by the number of possible combinations. This analysis identifies as potentially therapeutic those drug combinations that rank highest when their efficacy is determined jointly from two independent data sources.METHODSEstimates of the efficacy of the same drug combinations were derived from a clinical dataset and from pre-clinical data, in the form of a computational model of neuroinflammation. Standard linear regression was used to show that the two sets of estimates were correlated, and to rule out possible confounds.RESULTSThe ten highest ranking, jointly determined drug combinations most frequently consisted of COX2 inhibitors and aspirin, along with various antihypertensive medications.DISCUSSIONTen combinations of from five to nine drugs, and the three-drug combination of a COX2 inhibitor, aspirin, and a calcium-channel blocker, are discussed as candidates for consideration in future clinical and pre-clinical studies.

Modulation of Cytokines Production by Indomethacin Acute Dose during the Evolution of Ehrlich Ascites Tumor in Mice

The aim of the present study was to investigate the influence of a nonselective COX1/COX2 inhibitor (indomethacin) on tumor growth of Ehrlich Ascites Tumor (EAT) in mice, using as parameters the tumor growth and cytokine profile. Mice were inoculated with EAT cells and treated with indomethacin. After 1, 3, 6, 10, and 13 days the animals were evaluated for the secretion of TNFα, IL-1α, IL-2, IL-4, IL-6, IL-10, and IL-13 and PGE2level in peritoneal cavity. The results have shown that EAT induces PGE2production and increases tumor cells number from the 10th day. The cytokine profile showed EAT induces production of IL-6 from 10th day and of IL-2 on 13th day; the other studied cytokines were not affected in a significant way. The indomethacin treatment of EAT-bearing mice inhibited the tumor growth and PGE2synthesis from the 10th day. In addition, the treatment of EAT-bearing mice with indomethacin has stimulated the IL-13 production and has significantly inhibited IL-6 in the 13th day of tumor growth. Taken together, the results have demonstrated that EAT growth is modulated by PGE2and the inhibition of the tumor growth could be partly related to suppression of IL-6 and induction of IL-13.