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Vol. 302, Issue 2, 814-821, August 2002

Goblet Cell Hyperplasia, Airway Function, and Leukocyte Infiltration after Chronic Lipopolysaccharide Exposure in Conscious Guinea Pigs: Effects of Rolipram and Dexamethasone

Toby J. Toward and Kenneth J. Broadley

Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom

The effects of chronic exposures (nine, 48 h apart) of conscious guinea pigs to lipopolysaccharide (LPS) (30 µg · ml-1, 1 h) on airway function, airway histology (in particular, goblet cell numbers), and inflammatory cell infiltration of the lungs were examined as a model of chronic inflammatory lung disease, such as chronic obstructive pulmonary disease. The sensitivity of these parameters to treatment with the corticosteroid, dexamethasone, or the phosphodiesterase-4 (PDE4) inhibitor, rolipram, was determined. As the number of LPS exposures increased, there was a progressively persistent bronchoconstriction after each exposure. After nine LPS exposures, there was evidence on histological examination of airway infiltration of, predominantly, neutrophils in perivascular, peribronchial, and alveolar tissues. After chronic LPS exposure, the airway epithelium possessed a marked goblet cell hyperplasia and evidence of inflammatory edema, features contributory to reduced airway caliber. Treatment with dexamethasone (20 mg · kg-1) or rolipram (1 mg · kg-1), administered (i.p.) 24 and 0.5 h before exposure and 24 and 47 h after each subsequent exposure, attenuated the inflammatory cell infiltration into the airway, goblet cell hyperplasia, and inflammatory edema. Dexamethasone exacerbated, whereas rolipram reversed, the chronic LPS-induced bronchoconstrictions. This study demonstrates that chronic LPS causes persistent bronchoconstriction, neutrophilic airway inflammation, goblet cell hyperplasia, and edema. These rolipram-sensitive features suggest the potential of PDE4 inhibitors in chronic inflammatory lung diseases.

0022-3565/02/3022-0814$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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