title: Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice.
abstract: Regulation of the adhesion of mononuclear cells to endothelial cells is considered to be a critical step for the treatment of inflammatory diseases, including autoimmune diseases. K-13182 was identified as a novel inhibitor for these adhesions. K-13182 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) on human umbilical vein endothelial cells (HUVECs) and on mouse vascular endothelial cell line (MAECs) induced by tumour necrosis factor (TNF)-alpha. K-13182 also inhibited the adhesion of mononuclear cells to these HUVECs and MAECs, indicating that K-13182 suppressed these adhesions mediated by cellular adhesion molecules including VCAM-1. To evaluate the therapeutic effect in autoimmune disease model mice, K-13182 was orally administered to non-obese diabetic (NOD) mice as Sjögren's syndrome (SS) model mice. Severe destructive inflammatory lesions were observed in the lacrimal glands of vehicle-treated control mice; however, 8-week administration of K-13182 inhibited the mononuclear cell infiltration into the inflammatory lesions of the lacrimal glands. In K-13182-treated mice, the decrease in tear secretion was also prevented compared to the control mice. In addition, the apoptosis and the expression of FasL (CD178), perforin, and granzyme A was suppressed in the lacrimal glands of K-13182-treated mice. Therefore, K-13182 demonstrated the possibility of therapeutic efficacy for the inflammatory region of autoimmune disease model mice. These data reveal that VCAM-1 is a promising target molecule for the treatment of autoimmune diseases as a therapeutic strategy and that K-13182 has the potential as a new anti-inflammatory drug for SS.
authors.affiliation: Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama, Japan; Sjögren's Syndrome Project, Shinanomachi Research Park, Keio University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishiyama
authors.forename: K
authors.initials: K
authors.lastname: Mishima
authors.forename: K
authors.initials: K
authors.lastname: Obara
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Doi
authors.forename: S
authors.initials: S
authors.lastname: Kondo
authors.forename: M
authors.initials: M
authors.lastname: Saka
authors.forename: Y
authors.initials: Y
authors.lastname: Tabunoki
authors.forename: Y
authors.initials: Y
authors.lastname: Hattori
authors.forename: T
authors.initials: T
authors.lastname: Kodama
authors.forename: K
authors.initials: K
authors.lastname: Tsubota
authors.forename: I
authors.initials: I
authors.lastname: Saito
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003607:Dacryocystitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D019010:Vascular Cell Adhesion Molecule-1