Amelioration of lacrimal gland inflammation by oral administration of K-13182 in Sjögren's syndrome model mice
| Autor: | Tatsuhiko Kodama, Tatsuaki Nishiyama, Hiroko Inoue, S Kondo, Y. Tabunoki, Takeshi Doi, Kazuo Tsubota, Ichiro Saito, Yukio Hattori, Kumi Obara, Kenji Mishima, M. Saka |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Translational Studies Immunology Anti-Inflammatory Agents Drug Evaluation Preclinical Administration Oral Vascular Cell Adhesion Molecule-1 Lacrimal gland Lacrimal apparatus chemistry.chemical_compound Dacryocystitis Mice Mice Inbred NOD Cell Adhesion Immunology and Allergy Medicine Animals Tear secretion VCAM-1 Cell adhesion Cells Cultured Dose-Response Relationship Drug business.industry Cell adhesion molecule Reverse Transcriptase Polymerase Chain Reaction Endothelial stem cell Mononuclear cell infiltration Disease Models Animal medicine.anatomical_structure Sjogren's Syndrome chemistry Gene Expression Regulation Endothelium Vascular business |
| Zdroj: | Clinical and experimental immunology. 149(3) |
| ISSN: | 0009-9104 |
| Popis: | Summary 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)-α. 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. |
| Databáze: | OpenAIRE |
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