title: Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect.
abstract: Repetitive, acute inflammatory insults elicited by cigarette smoke (CS) contribute to the development of chronic obstructive pulmonary disease (COPD), a disorder associated with lung inflammation and mucus hypersecretion. Presently, there is a poor understanding of the acute inflammatory mechanisms involved in this process. The aims of this study were to develop an acute model to investigate temporal inflammatory changes occurring after CS exposure. Rats were exposed to whole body CS (once daily) generated from filtered research cigarettes. Initial studies indicated the generation of a neutrophilic/mucus hypersecreting lung phenotype in <4 days. Subsequent studies demonstrated that just two exposures to CS (15 h apart) elicited a robust inflammatory/mucus hypersecretory phenotype that was used to investigate mechanisms driving this response. Cytokine-induced neutrophil chemoattractants (CINCs) 1-3, the rat growth-related oncogene-alpha family homologs, and IL-1beta demonstrated time-dependent increases in lung tissue or lavage fluid over the 24-h period following CS exposure. The temporal changes in the neutrophil chemokines, CINCs 1-3, mirrored increases in neutrophil infiltration, indicative of a role in neutrophil migration. In addition, a specific CXCR2 antagonist, SB-332235, effectively inhibited CS-induced neutrophilia in a dose-dependent manner, supporting this conclusion. This modeling of the response of the rat airways to acute CS exposure indicates 1) as few as two exposures to CS will induce a phenotype with similarities to COPD and 2) a novel role for CINCs in the generation of this response. These observations represent a paradigm for the study of acute, repetitive lung insults that contribute to the development of chronic disease.
authors.affiliation: Novartis Institute of Biomedical Research, Respiratory Disease Area, Horsham, West Sussex, UK. Christopher.Stevenson@pharma.novartis.com
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.forename: Kevin
authors.initials: K
authors.lastname: Coote
authors.forename: Ruth
authors.initials: R
authors.lastname: Webster
authors.forename: Helinor
authors.initials: H
authors.lastname: Johnston
authors.forename: Hazel C
authors.initials: HC
authors.lastname: Atherton
authors.forename: Andrew
authors.initials: A
authors.lastname: Nicholls
authors.forename: June
authors.initials: J
authors.lastname: Giddings
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sugar
authors.forename: Alan
authors.initials: A
authors.lastname: Jackson
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Press
authors.forename: Zarin
authors.initials: Z
authors.lastname: Brown
authors.forename: Keith
authors.initials: K
authors.lastname: Butler
authors.forename: Henry
authors.initials: H
authors.lastname: Danahay
mesh_terms: D000818:Animals; D008024:Ligands; D008168:Lung / Q000378:metabolism*; D008297:Male; D009093:Mucus / Q000378:metabolism*; D011014:Pneumonia / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*
chemical_list: D008024:Ligands; D023063:Receptors, Interleukin-8B; D012906:Smoke