title: A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration.
abstract: OBJECTIVE
  Macrophage (Mϕ) migration rests on the adhesion/detachment between Mϕ surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences Mϕ motility through an action distinct from its classical modulation of the plasmin-based fibrinolytic process. We rely here on a small molecule PAI-1 inhibitor (TM5275) to investigate the role of PAI-1 in Mϕ migration in the pathogenesis of renal injury.
  
  
  RESULTS
  Mϕ migration was inhibited both in vitro and in vivo by TM5275. It was also reduced in T-cell-deficient nude mice, but not in PAI-1-deficient mice. Mϕ migration hinged on the interaction of PAI-1 with low-density lipoprotein receptor-related protein, an interaction prevented by TM5275, but not with vitronectin, urokinase-type plasminogen activator, or tissue-type plasminogen activator. Fed to rats with anti-Thy-1-induced nephritis, TM5275 significantly decreased Mϕ accumulation and ameliorated the progression of renal injury.
  
  
  CONCLUSIONS
  These findings suggest that a small molecule PAI-1 inhibitor represents a novel class of anti-inflammatory agents targeting Mϕ migration by the inhibition of the interaction of PAI-1 with low-density lipoprotein receptor-related protein.
authors.affiliation: Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ichimura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaki
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Sato
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
authors.forename: Fan-Fan
authors.initials: FF
authors.lastname: Hou
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D005921:Glomerulonephritis / Q000473:pathology; D007518:Isoantibodies / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D051381:Rats; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D000893:Anti-Inflammatory Agents; D007518:Isoantibodies; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010879:Piperazines; D017395:Plasminogen Activator Inhibitor 1; C035678:anti-Thy antibody; D062366:para-Aminobenzoates