title: The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis.
abstract: Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA) on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01), inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001), and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05). On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation) and by systemic autoimmune diseases.
authors.affiliation: The Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, Rochester, New York, United States of America.
authors.forename: Ajit A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Hsi-Min
authors.initials: HM
authors.lastname: Hsiao
authors.forename: Keith C
authors.initials: KC
authors.lastname: Olsen
authors.forename: Robert Matthew
authors.initials: RM
authors.lastname: Kottmann
authors.forename: Jason
authors.initials: J
authors.lastname: Morrissette
authors.forename: Terry W
authors.initials: TW
authors.lastname: Wright
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003094:Collagen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012129:Respiratory Function Tests; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005353:Fibronectins; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; D001761:Bleomycin; D009828:Oleanolic Acid; D003094:Collagen; C445068:bardoxolone methyl