(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Graft-vs-Host-Disease

Prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still to be explored. Statins are potent immunomodulatory agents that hold promise as novel and safe agents for aGVHD prophylaxis, yet the controversial effect and regulatory mechanism are incompletely understood. Here, in an MHC mismatched murine model, we found that Fluvastatin-pretreated donor cells could attenuate aGVHD severity by remission tissue pathological injury. Fluvastatin served to restrain effector T cells entry into aGVHD target organs from secondary lymphoid organs (SLOs). The potential mechanism of correcting the effector T cell biased distribution was that Fluvastatin elevated CD62L and CCR7 expression while decreased CXCR3 and CD44 levels, which were correlated with Kruppel-like factor 2 (KLF2) sustention in donor-derived cells. In addition, Fluvastatin was contributed to reducing cytokines IFN-

Topics: Animals; Cell Movement; Chemokines; Fluvastatin; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Inflammation Mediators; Kinetics; Kruppel-Like Transcription Factors; Male; Mice, Inbred C57BL; Protective Agents; T-Lymphocytes; Tissue Donors; Up-Regulation

To explore the effects of fluvastatin on expression of p38 mitogen-activated protein kinase (p38MAPK) in renal tissue of chronic graft versus host disease (cGVHD) lupus nephritis in mice.. Mice were randomly divided into 4 groups of model, low-dose fluvastatin intervention (5 mg×kg(-1)×d(-1)), high-dose fluvastatin intervention (10 mg×kg(-1)×d(-1)) and normal control. The 24 h total amount of urine protein was evaluated by biuret reaction colorimetric assay. And the protein and mRNA expression levels of p38MAPK, p-p38MAPK and TGF-β1 in renal tissue were detected by immunohistochemistry, Western blot and reverse transcription-polymerase chain reaction (RT-PCR) respectively.. Compared with the normal control group, 24 h total amount of urine protein, protein and mRNA expression levels of p38MAPK, p-p38MAPK and TGF-β1 increased significantly in the model group respectively ((7.84 ± 0.36) vs (1.15 ± 0.15) mg/24 h, 0.81 ± 0.03 vs 0.50 ± 0.01, 0.69 ± 0.02 vs 0.10 ± 0.01, 0.76 ± 0.02 vs 0.28 ± 0.02, 0.84 ± 0.04 vs 0.25 ± 0.02, 0.82 ± 0.04 vs 0.12 ± 0.02, all P < 0.01). Fluvastatin treatment suppressed markedly their increased expressions (P < 0.05). And high-dose fluvastatin treatment suppressed more significantly than low-dose group (P < 0.05).. The renal protection effect of fluvastatin may be achieved by inhibiting the signal pathway of p38MAPK.

Topics: Animals; Fatty Acids, Monounsaturated; Fluvastatin; Graft vs Host Disease; Indoles; Lupus Nephritis; MAP Kinase Signaling System; Mice; p38 Mitogen-Activated Protein Kinases; Transforming Growth Factor beta1