Neutrophil-mediated degradation of lung proteoglycans: Stimulation by tumor necrosis factor-α in sputum of patients with bronchiectasis

Abstract

Neutrophil-mediated degradation of bronchial matrix has been proposed as a pathogenetic factor in bronchiectasis. We hypothe-size that neutrophils, found in abundance in the bronchial lumens of patients with bronchiectasis, are capable of degrading lung matrix proteoglycans and that proinflammatory mediators in bronchial secretions of these patients can enhance the degradative action of neutrophils. We used rat bronchoalveolar proteoglycans entrapped in polyacrylamide gel beads as a substrate for test incubations with neutrophils from healthy volunteers and sputum sol from patients with idiopathic bronchiectasis. Coincubations with specimens of sputum sol and neutrophils showed proteoglycan degradation indices (PDIs) in excess of the sum of indices due to incubation with either heat-inactivated sputum sol or heat-inactivated neutrophils, suggesting sputum stimulation of the neutrophil response. Mediation of this stimulation by tumor necrosis factor (TNF)-α was suggested because (1) indices for the coincubations correlated with sputum levels of TNF-α and (2) an anti-TNF-α antibody completely attenuated the sputum-stimulated effect. Furthermore, recombinant human TNF-α required accompanying sputum sol to exert an enhancing effect on neutrophil-mediated proteoglycan degradation. Because neutrophil-mediated proteoglycan degradation in the coincubations was inhibited largely (90%) by Eglin C and much less so (8% to 20%) by ethylenediamine tetraacetic acid, we conclude that serine proteases secreted by neutrophils were mainly responsible for degradation of proteoglycans in the model matrix and that the secretion was stimulated by TNF-α in the presence of cofactors in the bronchial secretions of patients with bronchiectasis.