Inhibition of Pulmonary Eosinophilia Does Not Necessarily Prevent the Airway Hyperresponsiveness Induced by Sephadex Beads

Abstract

Background: The Lewis rat among highly inbred strains exhibits significant airway hyperresponsiveness (AHR) following intravenous administration of Sephadex G-200 (Sephadex). The aim of this study was to investigate the association of Sephadex-induced AHR with changes in airway inflammation in Lewis rats. Methods: A suspension (0.5 mg/ml/rat) of Sephadex was intravenously administered to male Lewis rats on days 0, 2 and 5. Measurement of airway responsiveness to serotonin, bronchoalveolar lavage (BAL) and histological study were performed on day 2–11. Results: Significant AHR induced by Sephadex was recognized on day 2 (p < 0.05), and AHR reached a maximum on day 7 (p < 0.001). In the BAL study, eosinophils increased on day 2 (p < 0.01) with a peak on day 5 (p < 0.05). In the histological study, we found Sephadex beads trapped in small arteries of the lung and granulomatous arteritis on day 2 or later. Pulmonary granulomas, horseshoe-shaped multinuclear giant cells, eosinophils and goblet cell hyperplasia were observed on day 2, and the degree became intense on day 5–7. GCC-AP0341 (10 mg/kg, i.p. × 3) inhibited the recruitment of eosinophils in BAL fluid and in lung tissue, but it did not inhibit AHR. The compound also inhibited pulmonary granulomas and goblet cell hyperplasia. Conclusion: The mechanism of Sephadex-induced AHR may not be directly associated with inflammatory changes such as recruitment of eosinophils, pulmonary granulomas and hyperplasia of goblet cells in rats.

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

“…The increase in eosinophil influx to lung tissue was apparent 6 h after challenge and remained elevated at least 72 h after treatment in confirming previous reports (16,18,26,27). Our data also demonstrate an accumulation of T cells, including CD4 ϩ (helper) T cells, in lung tissue.…”

Matrix Metalloproteinase-9 Deficiency Impairs Cellular Infiltration and Bronchial Hyperresponsiveness during Allergen-Induced Airway Inflammation

“…21 The fact that MMP-9 Ϫ/Ϫ mice display lower AHR without any difference in the eosinophilic inflammation strongly supports previous observations showing that eosinophils are not essential for the development of AHR after allergen challenge. 16,[22][23][24][25][26] The significant decrease in lymphocyte counts in the BALF along with a failure to develop AHR in MMP-9 Ϫ/Ϫ mice further supports the previously suggested key role of lymphocytes in the AHR. Lymphocyte migration through basement membranes is likely to involve MMP-9 production.…”

Airway eosinophilia is not a requirement for allergen‐induced airway hyperresponsiveness

“…It is unlikely that the airway hyperresponsiveness observed in the mice with the low dose allergen exposure just resulted from an increased vascular permeability caused by the house dust mite aerosol since it was demonstrated that T cell‐mediated induction of airway hyperresponsiveness in mice is independent of changes in the pulmonary vascular permeability [ 29]. Increasing evidence accumulates indicating that the eosinophil is not a crucial link in the induction of allergen‐induced AHR [ 25, 30–35] although some investigators stressed the importance of the eosinophil [ 36]. Again, differences in the strains and in experimental conditions could be a contributing factor.…”