title: Anti-inflammatory role of PGD2 in acute lung inflammation and therapeutic application of its signal enhancement.
abstract: We investigated the role of prostaglandin D2 (PGD2) signaling in acute lung injury (ALI), focusing on its producer-effector interaction in vivo. Administration of endotoxin increased edema and neutrophil infiltration in the WT mouse lung. Gene disruption of hematopoietic PGD synthase (H-PGDS) aggravated all of the symptoms. Experiments involving bone marrow transplantation between WT and H-PGDS-deficient mice showed that PGD2 derived from alveolar nonhematopoietic lineage cells (i.e., endothelial cells and epithelial cells) promotes vascular barrier function during the early phase (day 1), whereas neutrophil-derived PGD2 attenuates its own infiltration and cytokine expression during the later phase (day 3) of ALI. Treatment with either an agonist to the PGD2 receptor, DP, or a degradation product of PGD2, 15-deoxy-Δ(12,14)-PGJ2, exerted a therapeutic action against ALI. Data obtained from bone marrow transplantation between WT and DP-deficient mice suggest that the DP signal in alveolar endothelial cells is crucial for the anti-inflammatory reactions of PGD2. In vitro, DP agonism directly enhanced endothelial barrier formation, and 15-deoxy-Δ(12,14)-PGJ2 attenuated both neutrophil migration and cytokine expression. These observations indicate that the PGD2 signaling between alveolar endothelial/epithelial cells and infiltrating neutrophils provides anti-inflammatory effects in ALI, and suggest the therapeutic potential of these signaling enhancements.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan. amurata@mail.ecc.u-tokyo.ac.jp
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsubosaka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Maruyama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000208:Acute Disease; D055371:Acute Lung Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016026:Bone Marrow Transplantation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015230:Prostaglandin D2 / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D054834:Lipocalins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor