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

Abstract

The effects of chronic exposures (nine, 48 h apart) of conscious guinea pigs to lipopolysaccharide (LPS) (30 g ⅐ ml Ϫ1 , 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 ⅐ kg Ϫ1 ) or rolipram (1 mg ⅐ kg Ϫ1 ), 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.Chronic mucus hypersecretion is an important symptomatic and pathological feature of a heterogeneous group of chronic respiratory diseases that includes chronic bronchitis, chronic obstructive pulmonary disease (COPD), and asthma (Rogers, 1994;Jackson, 2001). Persistent mucus overproduction contributes to reduced airway caliber and the occlusion of small airways (reduced FEV 1 ), productive cough, and labored breathing (Jackson, 2001). Individuals with chronic mucus hypersecretion also suffer from an increased frequency and duration of respiratory infection, causing further exacerbation of their original respiratory pathology (Jackson, 2001).The two major sources of mucus secretion in the respiratory tract are the surface epithelial goblet cells and mucous cells of the submucosal glands. In normal lungs, goblet cells are present in the large bronchi, becoming increasingly sparse toward the bronchioles. The submucosal glands are restricted to the large airways with their density decreasing with airway caliber, such that they are absent in the bronchioles. In chronic respiratory diseases, such as COPD and asthma, submucosal glands increase in size (hypertrophy), and the number of goblet cells is increased (hyperplasia), becoming more dense in the peripheral airways, via a phenotypic conversion of nongoblet epithelial cells (metaplasia) (Rogers, 1994;Jackson, 2001). The increased ratio of goble...

Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD

“…In addition, LPS may play an important role in bacterial infection-induced exacerbations of COPD, which contribute to the progression of the disease [28]. Accordingly, in various animal models, inhalation of LPS was shown to induce pathological features of COPD, such as neutrophilia, goblet cell hyperplasia, airway fibrosis and emphysema [29][30][31][32]. In the present study, we present evidence that ACh plays a major role in the development of pulmonary inflammation as well as in airway remodelling.…”

Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury

“…PDE4 inhibition could explain this phenomenon by airway smooth muscle relaxation, modulation of the activity of pulmonary nerves and suppression of the activation of inflammatory cells, thus modulating the bronchomotor tone [1,33]. Additionally, LASSBio596 attenuated the alveolar collapse observed in the LPS group, suggesting that it might diminish the impairment of the surfactant system usually observed in injured lungs.…”

Animal models of chronic obstructive pulmonary disease

“…With chronic administration over several weeks, LPS instillation produces enlarged air spaces (Fig. 9B) and remodeled airways with thickened walls and increased goblet cells in the larger airways in mice, guinea pigs, and rats (40,142,147). In the guinea pig model (40), progressive exposures resulted in a decline in specific airway conductance and an increased duration of bronchoconstriction after exposure.…”