Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect.
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.
Stevenson
Christopher S
CS
Novartis Institute of Biomedical Research, Respiratory Disease Area, Horsham, West Sussex, UK. Christopher.Stevenson@pharma.novartis.com
Coote
Kevin
K
Webster
Ruth
R
Johnston
Helinor
H
Atherton
Hazel C
HC
Nicholls
Andrew
A
Giddings
June
J
Sugar
Rosemary
R
Jackson
Alan
A
Press
Neil J
NJ
Brown
Zarin
Z
Butler
Keith
K
Danahay
Henry
H
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*
D008024:Ligands; D023063:Receptors, Interleukin-8B; D012906:Smoke