PMID- 24791857 OWN - NLM STAT- MEDLINE DCOM- 20150324 LR - 20211021 IS - 1476-5551 (Electronic) IS - 0887-6924 (Linking) VI - 29 IP - 1 DP - 2015 Jan TI - Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking. PG - 145-56 LID - 10.1038/leu.2014.151 [doi] AB - The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction. FAU - Sato, A AU - Sato A AD - Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Nishida, C AU - Nishida C AD - 1] Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan [2] Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Sato-Kusubata, K AU - Sato-Kusubata K AD - Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Ishihara, M AU - Ishihara M AD - Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Tashiro, Y AU - Tashiro Y AD - Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Gritli, I AU - Gritli I AD - Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Shimazu, H AU - Shimazu H AD - Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Munakata, S AU - Munakata S AD - Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan. FAU - Yagita, H AU - Yagita H AD - Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan. FAU - Okumura, K AU - Okumura K AD - Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan. FAU - Tsuda, Y AU - Tsuda Y AD - Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan. FAU - Okada, Y AU - Okada Y AD - Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan. FAU - Tojo, A AU - Tojo A AD - Department of Hematology and Oncology, Center for Stem Cell Biology and Regenerative Medicine, Tokyo, Japan. FAU - Nakauchi, H AU - Nakauchi H AD - Department of Hematology and Oncology, Center for Stem Cell Biology and Regenerative Medicine, Tokyo, Japan. FAU - Takahashi, S AU - Takahashi S AD - Department of Hematology and Oncology, Center for Stem Cell Biology and Regenerative Medicine, Tokyo, Japan. FAU - Heissig, B AU - Heissig B AD - 1] Department of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan [2] Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan. FAU - Hattori, K AU - Hattori K AD - 1] Department of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo (IMSUT), Tokyo, Japan [2] Department of Immunology, Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140505 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (DNA Primers) RN - 0 (Inflammation Mediators) RN - EC 3.4.21.7 (Fibrinolysin) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Animals MH - Base Sequence MH - Biological Transport MH - Cell Line MH - DNA Primers MH - Disease Models, Animal MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Fibrinolysin/*antagonists & inhibitors MH - Graft vs Host Disease/enzymology/mortality/*prevention & control MH - Humans MH - Inflammation Mediators/*antagonists & inhibitors MH - Matrix Metalloproteinase 9/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Reverse Transcriptase Polymerase Chain Reaction MH - Severity of Illness Index EDAT- 2014/05/06 06:00 MHDA- 2015/03/25 06:00 CRDT- 2014/05/06 06:00 PHST- 2013/11/21 00:00 [received] PHST- 2014/04/01 00:00 [revised] PHST- 2014/04/21 00:00 [accepted] PHST- 2014/05/06 06:00 [entrez] PHST- 2014/05/06 06:00 [pubmed] PHST- 2015/03/25 06:00 [medline] AID - leu2014151 [pii] AID - 10.1038/leu.2014.151 [doi] PST - ppublish SO - Leukemia. 2015 Jan;29(1):145-56. doi: 10.1038/leu.2014.151. Epub 2014 May 5.