title: Bronchiolitis obliterans induced by intratracheal papaverine: a novel animal model.
abstract: Constrictive bronchiolitis obliterans (CBO), a highly fatal syndrome seen following toxicant exposure and lung transplantation, is in need of mechanistic study. This report creates an animal model of toxicant induced CBO, validates its pathology and suggests a physiologic mechanism for its origin. Papaverine, the alkaloid in Sauropus plants and responsible for human toxicant-induced CBO, was used to create the rat model. A mini-osmotic pump delivered papaverine intratracheally for up to 28 days (0.25 microL/hr, totaling 6.4 mg). Bronchoalveolar lavage (BAL) was measured. Lung tissue was evaluated for signs of CBO (H&E and Trichrome staining). Cytokines deregulated in human CBO were also measured (TGF-beta and eNOS). Peribronchial inflammation, extensive denudation and destruction of bronchial mucosa, as well as increased peribronchial collagen (all classic signs of CBO) were observed as early as 7 days in papaverine treated animals, with more extensive damage after 28 days. Significant elevations of TGF-beta and eNOS were seen in lung homogenates. Our toxicant induced model of CBO via a novel delivery method of intratracheal papaverine accurately reproduces pathology and cytokine profiles of human CBO. Papaverine has potential for producing CBO by multiple routes. This model introduces a vehicle for both understanding and development of innovative treatment for CBO.
authors.affiliation: University of Missouri-Kansas City School of Medicine, Pulmonary Research Laboratory, Gold 5 Lab of Pulmonary Research, M5-210, 2411 Holmes St., Kansas City, Missouri 64108, USA. svetlecicj@umkc.edu
authors.forename: J
authors.initials: J
authors.lastname: Svetlecic
authors.forename: A
authors.initials: A
authors.lastname: Molteni
authors.forename: B
authors.initials: B
authors.lastname: Herndon
mesh_terms: D000818:Animals; D001980:Bronchi / Q000473:pathology; D001989:Bronchiolitis Obliterans / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D018893:Bronchoalveolar Lavage; D004195:Disease Models, Animal; D008297:Male; D010208:Papaverine / Q000008:administration & dosage / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000032:analysis
chemical_list: D016212:Transforming Growth Factor beta; D010208:Papaverine