Fourteen Brown-Norway rats were pretreated with physiological saline (n = 7) or 500 μg Sephadex (n = 7) intratracheally. 24 h later, a bronchial provocation test was performed under pentobarbital anaesthesia using increasing doses of acetylcholine aerosol and the degree of bronchospasm was measured using a modified Konzett-Rössler method. Subsequently, leucocyte counts were determined in the bronchoalveolar lavage fluid (BALF), BALF cells were differentiated, and the chemiluminescence of the BALF leucocytes were measured. Finally, the lungs were removed and histologically examined. The cell count in the BALF was significantly (p < 0.05) increased in the animals pretreated with Sephadex compared to those in the saline group (mean value ± SEM: 0.38 ± 0.07 vs. 0.15 ± 0.02 × 10⁶/ml). This difference was also reflected in the chemiluminescence measurements (2.51 ± 0.53 vs. 0.20 ± 0.03 × 10⁶ counts/0.5 ml). In the Sephadex-treated animals there was also a significant increase in the absolute number of neutrophil (0.040 ± 0.010 vs. 0.011 ± 0.002 × 10⁶/ml) and, in particular, eosinophil granulocytes (0.188 ± 0.055 vs. 0.003 ± 0.001 × 10⁶/ml) in the total leucocytes of the BALF. Lung histology showed massive perialveolar and peribronchial oedema and granulomatous infiltrates, primarily with eosinophils, after intratracheal application of Sephadex; these findings were not observed in the saline group. None of these changes in the rats pretreated with Sephadex manifested themselves in increased bronchial reactivity to acetylcholine aerosol. It is uncertain if the Sephadex-induced increase in the eosinophil count is accompanied by an activation of this cell population, which appears to be of importance for the occurrence of bronchial hyperreactivity. It is clear from this animal model that the presence of inflammatory cells in the BALF and lung tissue of rats does not in itself result in increased reactivity of the airways.

In the first part of this review the important role played by the bronchial hyperreactivity caused by chronic bronchopulmonary inflammation in asthma is described. Deliberately, more emphasis is placed on the role of pro-inflammatory eosinophils, alveolar macrophages, lymphocytes and platelets rather than on mast cells and neutrophils or the numerous mediators. The reason for this is that, on account of the large number of mediators and their multitude of functions and interactions in asthma, antagonism of a specific mediator will probably not be clinically relevant for optimally effective curative treatment of asthma. Inhibition of the infiltration and activation of pro-inflammatory cells is likely to be a more successful approach. In the second part, various animal models of bronchial hyperreactivity, which could be suitable for testing anti-asthmatic drugs, are discussed. Most animal models pay too little attention to chronic bronchopulmonary inflammation as the cause of bronchial hyperreactivity in asthma. In various models the bronchial hyperreactivity is provoked by a single mediator and this leads to selection of specific antagonists which are unlikely to be of clinical benefit. Rats appear to have certain advantages over guinea-pigs as experimental animals for bronchial hyperreactivity.

Activation and generation of inflammatory mediators by different leukocytes may be important in the pathogenesis of airway hyperreactivity. We studied the effect of active sensitization with ovalbumin as antigen and i.v. treatment with Sephadex particles on bronchial reactivity (BR) in rats and its possible relation to leukocyte infiltration (LI) and activation (LA) in bronchoalveolar lavage (BAL). A marked BR to aerosols of serotonin (5-HT) and ovalbumin was found in Sephadex treated animals but not in control animals. In parallel to this a marked increase in BAL cell count from Sephadex-treated animals compared to controls was seen. This increase in BAL cell count corresponded with a clear augmentation of spontaneous, buffer-induced and C3Z-induced, luminol-amplified CL. We deduce that detection of CL of BAL cells from rats might be used for studying inflammatory mechanisms which lead to a hyperreactive bronchus.

A thrombin-like proteinase (THROLP) was detected colorimetrically as the main proteolytic activity (PROA) in bronchoalveolar lavage fluid (BALF) 4 and 24 h after ovalbumin aerosol (OVA) challenge of actively immunized rats. Other proinflammatory parameters increased also significantly in BALF, like chemiluminescence of leukocytes (1 h), protein and cell number (24 h after challenge). In parallel, increased bronchoconstrictions against 5-HT aerosols are detected 24 h post OVA challenge. THROLP is an indicator for plasma leakage, activation of the clotting reaction and the protracted inflammation in the airways, which induced bronchial hyperreactivity.

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