title: Bladder pain relief by HMGB1 neutralization and soluble thrombomodulin in mice with cyclophosphamide-induced cystitis.
abstract: High mobility group box 1 (HMGB1), one of damage-associated molecular patterns (DAMPs), plays roles in not only inflammation but also processing of somatic pain. Given that no evidence for roles of HMGB1 in visceral pain signaling is available, we asked if HMGB1 participates in bladder pain accompanying cystitis caused by cyclophosphamide in mice, using the anti-HMGB1 neutralizing antibody and recombinant human soluble thrombomodulin (rhsTM) that sequesters HMGB1 and promotes its degradation by thrombin. Cyclophosphamide, administered i.p., caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms including increased bladder weight, an indicator of edema, in mice. The cyclophosphamide-induced bladder pain and referred hyperalgesia, but not increased bladder weight, were prevented by i.p. preadministration of the anti-HMGB1 neutralizing antibody or rhsTM. HMGB1, given i.p., facilitated the bladder pain and referred hyperalgesia caused by a subeffective dose of cyclophosphamide, an effect blocked by rhsTM. In the cyclophosphamide-treated mice, HMGB1 levels greatly decreased in the bladder tissue, particularly in the urothelial cells, but did not change in the plasma. Low molecular weight heparin, known to inhibit the receptor for advanced glycation end products (RAGE), but not lipopolysaccharide from Rhodobacter sphaeroides, an inhibitor of toll-like receptor 4 (TLR4), blocked the cyclophosphamide-induced bladder pain and referred hyperalgesia. Thus, our data indicate involvement of HMGB1 in the cyclophosphamide-induced bladder pain signaling, but not cystitis itself, and suggest that targeting HMGB1 with rhsTM or blocking RAGE might serve as a novel therapeutic strategy for the management of bladder pain.
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan; Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ishikura
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Tsubota
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tsujiuchi
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Murai
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Umemura
authors.affiliation: Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. Electronic address: kawabata@phar.kindai.ac.jp.
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D003520:Cyclophosphamide; D003556:Cystitis / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D024243:HMGB1 Protein / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D007155:Immunologic Factors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D059226:Nociceptive Pain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053591:Referred Pain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D012242:Rhodobacter sphaeroides; D018180:Thrombomodulin / Q000627:therapeutic use*; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D019459:Urothelium / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000700:Analgesics; D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D007155:Immunologic Factors; D008070:Lipopolysaccharides; C546931:THBD protein, human; D018180:Thrombomodulin; D003520:Cyclophosphamide; D006493:Heparin
keywords: Bladder pain; Cystitis; High mobility group box 1 (HMGB1); Receptor for advanced glycation end products (RAGE); Thrombomodulin; Visceral pain