Asthma, Rhinitis, Other Respiratory Diseases
Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia

https://doi.org/10.1016/S0091-6749(03)01889-XGet rights and content

Abstract

Background

Prostaglandin E2 (PGE2) is known to be produced within human airways, but it is not clear whether in airway diseases it can play a deleterious or a beneficial role. Recently it has been reported that PGE2 can enhance eosinophil survival in vitro.

Objective

To evaluate whether the concentrations of PGE2 in asthmatic airways correlate with the number of eosinophils and can be responsible for eosinophil-enhanced survival and to identify the cyclooxygenase isoform contributing to the synthesis of PGE2 by cells present in asthmatic airways.

Methods

Reversed-phase high-performance liquid chromatography and/or specific radioimmunoassay was used to measure PGE2 concentrations in induced sputum supernatants from 14 control and 30 asthmatic subjects. Correlations between concentrations of PGE2 and the number of eosinophils in induced sputum were evaluated. Expression of cyclooxygenase-2 (COX-2) in induced sputum cells was determined by immunocytochemistry, and the effect of COX-2 inhibition on PGE2 production was evaluated with the use of radiolabeled arachidonic acid. The effects on eosinophil apoptosis by PGE2 or induced sputum supernatants were studied by using peripheral blood eosinophils obtained by negative immunomagnetic selection.

Results

PGE2 concentrations resulted in elevated samples from asthmatic subjects and directly correlated with the percentage of eosinophils and the concentrations of eosinophilic cationic protein. Immunostaining for COX-2 showed enhanced expression in macrophages of asthmatic subjects when compared with control subjects, and the use of a specific COX-2 inhibitor provided evidence that PGE2 synthesis was the result of COX-2 enzymatic activity in asthma-induced sputum cells. Supernatant from induced sputum of asthmatic subjects with high eosinophil counts caused a decreased apoptosis of peripheral blood eosinophils when compared with control subjects, and immunoprecipitation of PGE2 significantly reverted this phenomenon, suggesting that PGE2 was present in biologically relevant concentrations in induced sputum.

Conclusions

The results obtained suggest that COX-2 expression in alveolar macrophages from asthmatic subjects may contribute to enhanced eosinophil survival through an increased PGE2 production. (J Allergy Clin Immunol 2003;112:709-16.)

Section snippets

Patients

The study included 14 control subjects and 30 patients with asthma. Control subjects (age median, 31; 25th to 75th percentiles, and 29 to 37 years) never had asthma, allergic diseases, or chronic bronchitis. All the subjects were lifelong nonsmokers, and their pulmonary functions were within the normal range.

Asthmatic subjects (median age, 38; 29 to 55 years) were diagnosed on the basis of criteria previously described in detail,11 and they had objective evidence of variable airflow obstruction

Study subjects

The median age of patients with asthma and of control subjects was not statistically different. FEV1 values of control subjects had a median of 101% of the predicted value (25th to 75th percentiles, 100 to 105). The median of FEV1 values for the asthmatic subjects resulted of 81% (72 to 94; P < .001). Fifteen untreated asthmatic subjects had a FEV1 value of <80%. Atopy was present in 11 asthmatic subjects (Table I).

Total and differential cell counts in induced sputum samples

The median volume of recovered supernatants resulted of 4.7 mL (3 to 8.4) in

Discussion

The results of this study showed that PGE2 concentrations in induced sputum samples of asthmatic subjects directly correlate with eosinophilic inflammation markers such as the concentration of ECP or the number of eosinophils present, pointing out a potential link between AA cyclooxygenase metabolites and eosinophilic infiltration and inflammation.

Recently, a subdivision of asthma phenotype based on the presence of high or low eosinophil infiltrate has been proposed21 suggesting that in

Acknowledgements

SC-58236 was kindly provided by Dr Peter Isakson, Searle, St Louis, Mo.

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