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

Neutrophil-mediated degradation of bronchial matrix has been proposed as a pathogenetic factor in bronchiectasis. We hypothesize that neutrophils, fou nd in abundance in the bronchial lumens of patients with bronchiectasis, ar e capable of degrading lung matrix proteoglycans and that proinflammatory m ediators in bronchial secretions of these patients can enhance the degradat ive action of neutrophils. We used rat bronchoalveolar proteoglycans entrap ped in polyacrylamide gel beads as a substrate for test incubations with ne utrophils from healthy volunteers and sputum sol from patients with idiopat hic bronchiectasis. Coincubations with specimens of sputum sol and neutroph ils showed proteoglycan degradation indices (PDIs) in excess of the sum of indices due to incubation with either heat-inactivated sputum sol or heat-i nactivated neutrophils, suggesting sputum stimulation of the neutrophil res ponse. Mediation of this stimulation by tumor necrosis factor (TNF)-alpha. was suggested because (1) indices for the coincubations correlated with spu tum levels of TNF-alpha and (2) an anti-TNF-alpha antibody completely atten uated the sputum-stimulated effect. Furthermore, recombinant human TNF-alph a required accompanying sputum sol to exert an enhancing effect on neutroph il-mediated proteoglycan degradation. Because neutrophil-mediated proteogly can degradation in the coincubations was inhibited largely (90%) by Eglin C and much less so (8% to 20%) by ethylenediamine tetraacetic acid, we concl ude that serine proteases secreted by neutrophils were mainly responsible f or degradation of proteoglycans in the model matrix and that the secretion was stimulated by TNF-alpha in the presence of cofactors in the bronchial s ecretions of patients with bronchiectasis.