title: Severe airway epithelial injury, aberrant repair and bronchiolitis obliterans develops after diacetyl instillation in rats.
abstract: BACKGROUND
  Bronchiolitis obliterans (BO) is a fibrotic lung disease that occurs in a variety of clinical settings, including toxin exposures, autoimmunity and lung or bone marrow transplant. Despite its increasing clinical importance, little is known regarding the underlying disease mechanisms due to a lack of adequate small animal BO models. Recent epidemiological studies have implicated exposure to diacetyl (DA), a volatile component of artificial butter flavoring, as a cause of BO in otherwise healthy factory workers. Our overall hypothesis is that DA induces severe epithelial injury and aberrant repair that leads to the development of BO. Therefore, the objectives of this study were 1) to determine if DA, delivered by intratracheal instillation (ITI), would lead to the development of BO in rats and 2) to characterize epithelial regeneration and matrix repair after ITI of DA.
  
  
  RESULTS
  Male Sprague-Dawley rats were treated with a single dose of DA (125 mg/kg) or sterile water (vehicle control) by ITI. Instilled DA resulted in airway specific injury, followed by rapid epithelial regeneration, and extensive intraluminal airway fibrosis characteristic of BO. Increased airway resistance and lung fluid neutrophilia occurred with the development of BO, similar to human disease. Despite rapid epithelial regeneration after DA treatment, expression of the normal phenotypic markers, Clara cell secretory protein and acetylated tubulin, were diminished. In contrast, expression of the matrix component Tenascin C was significantly increased, particularly evident within the BO lesions.
  
  
  CONCLUSIONS
  We have established that ITI of DA results in BO, creating a novel chemical-induced animal model that replicates histological, biological and physiological features of the human disease. Furthermore, we demonstrate that dysregulated epithelial repair and excessive matrix Tenacin C deposition occur in BO, providing new insights into potential disease mechanisms and therapeutic targets.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, United States of America. palme002@mc.duke.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Flake
authors.forename: Fran L
authors.initials: FL
authors.lastname: Kelly
authors.forename: Helen L
authors.initials: HL
authors.lastname: Zhang
authors.forename: Julia L
authors.initials: JL
authors.lastname: Nugent
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Kirby
authors.forename: Julie F
authors.initials: JF
authors.lastname: Foley
authors.forename: William M
authors.initials: WM
authors.lastname: Gwinn
authors.forename: Dan L
authors.initials: DL
authors.lastname: Morgan
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000139:chemically induced / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D049109:Cell Proliferation; D003931:Diacetyl; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D007322:Instillation, Drug; D008297:Male; D009504:Neutrophils / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000473:pathology* / Q000503:physiopathology; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: D012333:RNA, Messenger; C556389:SCGB1A1 protein, human; D019063:Tenascin; D014598:Uteroglobin; D003931:Diacetyl