title: Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung.
abstract: Children are uniquely susceptible to ozone because airway and lung growth continue for an extensive period after birth. Early-life exposure of the rhesus monkey to repeated ozone cycles results in region-specific disrupted airway/lung growth, but the mediators and mechanisms are poorly understood. Substance P (SP), neurokinin-1 receptor (NK-1R); and nuclear receptor Nur77 (NR4A1) are signaling pathway components involved in ozone-induced cell death. We hypothesize that acute ozone (AO) exposure during postnatal airway development disrupts SP/NK-1R/Nur77 pathway expression and that these changes correlate with increased ozone-induced cell death. Our objectives were to 1) spatially define the normal development of the SP/NK-1R/Nur77 pathway in conducting airways; 2) compare how postnatal age modulates responses to AO exposure; and 3) determine how concomitant, episodic ozone exposure modifies age-specific acute responses. Male infant rhesus monkeys were assigned at age 1 mo to two age groups, 2 or 6 mo, and then to one of three exposure subgroups: filtered air (FA), FA+AO (AO: 8 h/day × 2 days), or episodic biweekly ozone exposure cycles (EAO: 8 h/day × 5 days/14-day cycle+AO). O3 = 0.5 ppm. We found that 1) ozone increases SP/NK-1R/Nur77 pathway expression in conducting airways, 2) an ozone exposure cycle (5 days/cycle) delivered early at age 2 mo resulted in an airway that was hypersensitive to AO exposure at the end of 2 mo, and 3) continued episodic exposure (11 cycles) resulted in an airway that was hyposensitive to AO exposure at 6 mo. These observations collectively associate with greater overall inflammation and epithelial cell death, particularly in early postnatal (2 mo), distal airways.
authors: Center for Health and the Environment, University of California-Davis, Davis, California;
authors: Shannon R
authors: SR
authors: Murphy
authors: California National Primate Research Center, University of California-Davis, Davis, California; and.
authors: Karen L
authors: KL
authors: Oslund
authors: California National Primate Research Center, University of California-Davis, Davis, California; and School of Veterinary Medicine, Department of Anatomy, Physiology and Cell Biology, University of California-Davis, Davis, California.
authors: Dallas M
authors: DM
authors: Hyde
authors: California National Primate Research Center, University of California-Davis, Davis, California; and School of Veterinary Medicine, Department of Anatomy, Physiology and Cell Biology, University of California-Davis, Davis, California.
authors: Lisa A
authors: LA
authors: Miller
authors: Center for Health and the Environment, University of California-Davis, Davis, California; School of Veterinary Medicine, Department of Anatomy, Physiology and Cell Biology, University of California-Davis, Davis, California.
authors: Laura S
authors: LS
authors: Van Winkle
authors: California National Primate Research Center, University of California-Davis, Davis, California; and School of Veterinary Medicine, Department of Anatomy, Physiology and Cell Biology, University of California-Davis, Davis, California esschelegle@ucdavis.edu.
authors: Edward S
authors: ES
authors: Schelegle
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D010083:Oxidants, Photochemical / Q000009:adverse effects* / Q000494:pharmacology; D010126:Ozone / Q000009:adverse effects* / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010083:Oxidants, Photochemical; D018040:Receptors, Neurokinin-1; D010126:Ozone
keywords: NK-1R; bronchial epithelium; lung; neurokinin; substance P