title: The Role of Lysophosphatidic Acid on Airway Epithelial Cell Denudation in a Murine Heterotopic Tracheal Transplant Model.
abstract: BACKGROUND
  Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Obliterative bronchiolitis (OB), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. However, there is currently no treatment for the disease. We hypothesized that lysophosphatidic acid (LPA) participates in the progression of OB. The aim of this study was to reveal the involvement of LPA on the lesion of OB.
  
  
  METHODS
  Ki16198, an antagonist specifically for LPA1 and LPA3, was daily administered into the heterotopic tracheal transplant model mice at the day of transplantation. At days 10 and 28, the allografts were isolated and evaluated histologically. The messenger RNA levels of LPAR in microdissected mouse airway regions were assessed to reveal localization of lysophosphatidic acid receptors. The human airway epithelial cell was used to evaluate the mechanism of LPA-induced suppression of cell adhesion to the extracellular matrix (ECM).
  
  
  RESULTS
  The administration of Ki16198 attenuated airway epithelial cell loss in the allograft at day 10. Messenger RNAs of LPA1 and LPA3 were detected in the airway epithelial cells of the mice. Lysophosphatidic acid inhibited the attachment of human airway epithelial cells to the ECM and induced cell detachment from the ECM, which was mediated by LPA1 and Rho-kinase pathway. However, Ki16198 did not prevent obliteration of allograft at day 28.
  
  
  CONCLUSIONS
  The LPA signaling is involved in the status of epithelial cells by distinct contribution in 2 different phases of the OB lesion. This finding suggests a role of LPA in the pathogenesis of OB.
authors: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Yukiko
authors: Y
authors: Tando
authors: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Chiharu
authors: C
authors: Ota
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Mitsuhiro
authors: M
authors: Yamada
authors: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Satoshi
authors: S
authors: Kamata
authors: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Mutsuo
authors: M
authors: Yamaya
authors: Department of Molecular and Cellular Biochemistry, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan.
authors: Kuniyuki
authors: K
authors: Kano
authors: Department of Molecular and Cellular Biochemistry, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan.
authors: Shinichi
authors: S
authors: Okudaira
authors: Department of Molecular and Cellular Biochemistry, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan.; CREST, Japan Science and Technology Agency, Saitama, Japan.
authors: Junken
authors: J
authors: Aoki
authors: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors: Hiroshi
authors: H
authors: Kubo