Protease‐antiprotease imbalance in the pathogensis of emphysema and chronic bronchial injury: A potential target for drug development

Abstract

The hypothesis that emphysema might be caused by an imbalance between proteases and antiproteases in the lungs arose shortly after the discovery of the premature and familial occurrence of emphysema in persons with hornozygous alpha-I-protease inhibitor deficiency. Experimental evidence for support of this hypothesis has come from experimental induction of emphysema in animals by proteases. The ability of proteases to induce emphysema is proportional to their elastolytic potency. The importance of elastin degradation as a cause of the development of emphysema has also come from experiments of genetic models in which elastin crosslinking is prevented. The neutrophilis believed to be the most likely source of elastase in the induction of the emphysema of smokers. Alpha-lprotease inhibitor is the most important antiprotease. Alpha-1-antiprotease is susceptible to oxidative inactivation by cigarette smoke or by endogenous oxidants. Oxidants from cigarette smoke may also interfere with proper elastin repair. Serine proteases have also been shown to produce secretory cell metaplasia in the central intrapulmonary bronchi of hamsters. The discovery of secretory leukoprotease inhibitor in sputum and its production 236Snider by bronchial secretory cells raises the possibility that secretory cell metaplasia in humans may also be caused by an imbalance between proteases and antiproteases. Although evidence for the validity of the proteaselantiprotease hypothesis of the phogenesis of emphysema and chronic bronchitis in human smokers is still indirect, the development of supplemental antiprotease therapy seems rational for the prevention of progression of these diseases in persons who are unable to stop smoking.

Protection of Rat Lung from Elastase-lnduced Elastic Fiber Degradation in vitro and from Emphysema in vivo by a Trifluoroacetylpeptide Anilide Inhibitor

“…E C 3.4.21.37), a serine protease abundant ly released by the azurophilic granules o f polymorphonu clear neutrophils [2] during inflammatory processes. In pathological circumstances, an imbalance between H N E and di-proteinase inhibitor, the primary physiological plasmatic inhibitor o f this elastase [3], is considered to be one o f the major causes for chronic inflammatory diseases such as pulmonary emphysema and chronic bronchial injury [4], Considerable efforts have been made to design lowmolecular-weight synthetic inhibitors o f H N E as drugs for the elastase-induced diseases [5]. The design o f several peptidic inhibitors has been based on the structural requirements o f the binding sites o f H N E for its peptidic substrates.…”

Stereoselective Synthesis of Peptidyl Trifluoromethyl Alcohols and Ketones: Inhibitory Potency Against Human Leucocyte Elastase, Cathepsin G, Porcine Pancreatic Elastase and HIV-1 Protease

“…The breakdown of the extracellular matrix by HLE is usually prevented by a1 -proteinase inhibitor, the primary physiological plasmatic inhibitor of this elastase (Travis & Salvesen 1983). However, genetic or functional deficiencies of al -proteinase inhibitor can occur and are considered to be responsible for inflammatory diseases such as pulmonary emphysema and chronic bronchial injury (Snider 1987).…”

Σύνθεση Χαρακτηρισμός Και Ενζυματικές Μελέτες Αναστολέων Μεταλλοενζύμων

“…Η αλκοολική αφυδρογονάση π.χ. περιέχει ένα καταλυτικό και ένα δομικό άτομο ψευδαργύρου^1 4 ). Η αντικατάσταση καταλυτικών ή ρυθμιστικών ατόμων ψευδαργύρου με άλλα μέταλλα επηρεάζει σημαντικά την καταλυτική δράση ενώ η αντικατάσταση δομικών ή μη καταλυτικών ατόμων ψευδαργύρου δεν επιφέρει σημαντικές μεταβολές στην καταλυτική δράση των ενζύμων.…”

“…Ετσι, το δικαρβοξυλικό παράγωγο[3] με ΚρΟ,04ηΜ έγινε γνωστό ως enalaprilat. Προβλήματα στην απορρόφηση του από το στόμα, οδήγησαν στη σύνθεση του αιθυλεστέρα[4] ο οποίος με in vivo υδρόλυση μετατρέπεται στον αναστολέα[3]. Ο αναστολέας |4[ είναι γνωστός ως enalapril και χρησιμοποιήθηκε ως αντιυπερτασικό φάρμακο καθώς και για την αντιμετώπιση της συμφορητικής καρδιακής ανεπάρκειας.…”

“…Οπως φαίνεται στον Πίνακα 6.6, η τιμή k C at/K m ενώ μειώνεται σταδιακά από το εννεαπεπτίδιο στο πενταπεπτίδιο, παραμένει εντούτοις πάντα υψηλή ως μέγεθος. Από το πενταπεπτίδιο στο τετραπεπτίδιο όμως, παρατηρείται πτώση της τιμής k ca t/K m της τάξης του ΙΟ4 . Η μελέτη αυτών των αποτελεσμάτων οδηγεί στο συμπέρασμα ότι το βέλτιστο μήκος υποστρώματος της αστασίνης πρέπει να περιλαμβάνει επτά ή και περισσότερα αμινοξέα και ασφαλώς όχι λιγότερα των πέντε.…”