Proteolytic Activity of Human Neutrophil Elastase and Porcine Pancreatic Trypsin Causes Bronchial Secretory Cell Metaplasia in Hamsters

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Abstract
The authors wished to determine whether secretory cell metaplasia (SCM) induced in the bronchi of hamsters by human neutrophil elastase (HNE) was enzy-matically mediated. We also wished to determine whether SCM could be induced by a proteolytic enzyme devoid of elastolytic activity. Accordingly, groups of weight-matched hamsters were given a single intratracheal instillation of 0.5 ml of saline solution containing one of the following: 300 μg of HNE purified from blood neutro-phils, n = 14; 300 μg of HNE inactivated with Suc-Ala-Ala-Pro-Val chloromethyl ketone (CMK), n = 10; 500 μg of porcine pancreatic trypsin treated with CMK to eliminate residual active elastase, n = 10; 500 μg of trypsin inactivated by tosyl lysine chloromethyl ketone, n = 10; 2 μg CMK, n = 10; and saline alone, n = 10. Seven untreated animals served as additional controls. Twenty-one days post treatment, 5–6 μm paraffin-embedded sections, from the left lung hilar region, stained by Alcian blue and periodic acid-Schiff reaction were graded on a five-point scale for determination of the secretory cell index, which reflects SCM. Both elastase and trypsin produced severe SCM: mean±SEM secretory cell indices were 2.96 ± 0.11 and 2.72 ± 0.19, respectively, compared with values of 0.90 ± 0.35 for the untreated group and 0.93 ± 0.46 for the saline group (p < .05). The secretory cell indices of the groups treated with inactivated elastase or trypsin were comparable to those of the salinetreated and untreated groups. These data establish that induction of secretory cell metaplasia in hamster bronchi by serine proteases requires proteolytic but not elasto-lytic activity. If both elastase and trypsin share a common target molecule for the production of SCM, then proteolytic alteration of this molecule is not dependent on hydrolysis of one specific peptide bond.