title: Inhibition of transglutaminase 2, a novel target for pulmonary fibrosis, by two small electrophilic molecules.
abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrotic destruction of normal lung architecture. Due to a lack of effective treatment options, new treatment approaches are needed. We previously identified transglutaminase (TG)2, a multifunctional protein expressed by human lung fibroblasts (HLFs), as a positive driver of fibrosis. TG2 catalyzes crosslinking of extracellular matrix proteins, enhances cell binding to fibronectin and integrin, and promotes fibronectin expression. We investigated whether the small electrophilic molecules 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) inhibit the expression and profibrotic functions of TG2. CDDO and 15d-PGJ2 reduced expression of TG2 mRNA and protein in primary HLFs from control donors and donors with IPF. CDDO and 15d-PGJ2 also decreased the in vitro profibrotic effector functions of HLFs including collagen gel contraction and cell migration. The decrease in TG2 expression did not occur through activation of the peroxisome proliferator activated receptor γ or generation of reactive oxidative species. CDDO and 15d-PGJ2 inhibited the extracellular signal-regulated kinase pathway, resulting in the suppression of TG2 expression. This is the first study to show that small electrophilic compounds inhibit the expression and profibrotic effector functions of TG2, a key promoter of fibrosis. These studies identify new and important antifibrotic activities of these two small molecules, which could lead to new treatments for fibrotic lung disease.
authors.affiliation: 1 Department of Microbiology and Immunology.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Olsen
authors.forename: Amali P
authors.initials: AP
authors.lastname: Epa
authors.forename: Ajit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Kottmann
authors.forename: Claire E
authors.initials: CE
authors.lastname: McCarthy
authors.forename: Gail V
authors.initials: GV
authors.lastname: Johnson
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019204:GTP-Binding Proteins; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D009828:Oleanolic Acid; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D019204:GTP-Binding Proteins; D015230:Prostaglandin D2