title: A novel nonhuman primate model of cigarette smoke-induced airway disease.
abstract: Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; The Lovelace Respiratory Research Institute, Albuquerque, New Mexico; Pulmonary Department, University of Parma, Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Polverino
authors.affiliation: The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Melanie
authors.initials: M
authors.lastname: Doyle-Eisele
authors.affiliation: The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Jacob
authors.initials: J
authors.lastname: McDonald
authors.affiliation: The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wilder
authors.affiliation: The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Christopher
authors.initials: C
authors.lastname: Royer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Maria
authors.initials: M
authors.lastname: Laucho-Contreras
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Emer M
authors.initials: EM
authors.lastname: Kelly
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Miguel
authors.initials: M
authors.lastname: Divo
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Victor
authors.initials: V
authors.lastname: Pinto-Plata
authors.affiliation: The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Joe
authors.initials: J
authors.lastname: Mauderly
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Bartolome R
authors.initials: BR
authors.lastname: Celli
authors.affiliation: The Lovelace Respiratory Research Institute, Albuquerque, New Mexico. Electronic address: ytesfaig@lrri.org.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; The Lovelace Respiratory Research Institute, Albuquerque, New Mexico. Electronic address: cowen@rics.bwh.harvard.edu.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000503:physiopathology*; D008252:Macaca fascicularis; D011014:Pneumonia / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D012129:Respiratory Function Tests; D012907:Smoking / Q000009:adverse effects* / Q000473:pathology / Q000503:physiopathology