Effects of inhaled eotaxin on airway function and inflammatory cell influx in sensitised and non-sensitised guinea pigs.

Eotaxin is a chemokine that has high potency and selectivity as a chemoattractant agent for eosinophils, signalling exclusively through the CCR3 receptor. Eotaxin is upregulated in the lungs within 3 h of antigen challenge, levels peak at 6 h in lung tissue and bronchoalveolar (BAL) fluid, and fall within 12 h of exposure. This study aimed to look at the effect(s) of eotaxin inhalation on airway function in guinea pigs, to determine if the expected inflammatory cell (eosinophil) infiltration could induce airway hyperreactivity (AHR) and a bronchoconstrictor response equivalent to the late asthmatic response (LAR) seen after antigen challenge. Animals were sensitised with 100 microg/ml OA with a dose on days 1 and 5. Airway responses to inhaled eotaxin (10 or 20 microg/ml) were determined by whole body plethysmography as the change in specific airway conductance (sGaw). Inhaled histamine (1mM) was used to investigate AHR, and cell influx was determined by BAL. Senitised animals exposed to 10 microg/ml eotaxin did not reveal a bronchoconstrictor response or AHR and cellular infiltration to the lungs was not evident 24 h after exposure. Both sensitised and non-sensitised animals exposed to 20 microg/ml eotaxin however revealed a significant bronchoconstrictor response 6h post-challenge, with reductions in sGaw of -27.0+/-6.6% and -32.3+/-6.8%, respectively. Both groups also displayed a bronchoconstrictor response to inhaled histamine 24h after exposure, indicating AHR, and a significant increase in both total and differential cell counts. Sensitised animals, however, revealed a significant increase in cell influx compared to non-sensitised animals. Nebulised eotaxin can reveal a LAR, AHR to inhaled histamine, and cellular infiltration to the lungs, possibly via the mobilisation of eosinophils from the bone marrow, and their subsequent recruitment to the airways.

Elastolytic activity and alveolar epithelial type-1 cell damage after chronic LPS inhalation: effects of dexamethasone and rolipram.

This study investigated whether a correlation between leukocyte-derived elastolytic activity, alveolar epithelial type-1 cell damage, and leukocyte infiltration of the airways existed in guinea-pigs chronically exposed to inhaled lipopolysaccharide (LPS). The airway pathology of this model, notably the neutrophilia, resembles chronic obstructive pulmonary disease (COPD). The effect of the corticosteroid, dexamethasone, or the phosphodiesterase-4 (PDE4)-inhibitor, rolipram, on these features was studied. Conscious guinea-pigs were exposed for 1 h to single or repeated (nine) doses of LPS (30 microg ml(-1)). Dexamethasone (20 mg kg(-1), ip) or rolipram (1 mg kg(-1), ip) was administered 24 and 0.5 h before the first exposure and daily thereafter. Bronchoalveolar lavage fluid (BALF) was removed and elastolytic activity determined as the elastase-like release of Congo Red from impregnated elastin. The presence of the specific epithelial cell type-1 protein (40-42 kDa) RT1(40) in BALF was identified by Western blotting using a rat monoclonal antibody and semi-quantified by dot-blot analysis. The antibody was found to identify guinea-pig RT1(40). BALF inflammatory cells, particularly neutrophils and macrophages, and elastolytic activity were increased in chronic LPS-exposed guinea-pigs, the latter by 90%. Chronic LPS exposure also increased (10.5-fold) RT1(40) levels, indicating significant alveolar epithelial type-1 cell damage. Dexamethasone or rolipram treatment reduced the influx of inflammatory cells, the elastolytic activity (by 40% and 38%, respectively), and RT1(40) levels (by 50% and 57%, respectively). In conclusion, chronic LPS-exposed guinea-pigs, like COPD, exhibit elastolytic lung damage. This was prevented by a PDE4 inhibitor and supports their development for suppressing this leukocyte-mediated pathology.