title: Maintenance of α(1)-antitrypsin activity by means of co-application of hypochlorous acid-scavengers in vitro and in the supernatant of polymorphonuclear leukocytes: as a basis for a new drug delivery approach.
abstract: Tissue destruction, pain and loss of function in chronically inflamed tissues can result from noxious agents released from myeloperoxidase (MPO) and its highly reactive product hypochlorous acid (HOCl) or proteases such as neutrophil elastase (NE). Currently there exists a high demand for medications that provide gentle treatments, free from side effects inherent in those prescribed today. One method to circumvent side effects is through the use of locally applied drug delivery. In contrast to systemic therapy, the main advantages of transport systems are the low dosages of drug with a time-controlled delivery. The aim of this study was to ascertain interactions of NE and its inhibitor α(1)-antitrypsin (AT), the influence of hypochlorous acid (HOCl), as well as its scavengers, in order to define an effective mixture of drugs acting in a synergistic way which can be applied by means of drug delivery systems. These investigations determine the effective amounts of AT/HOCl-scavengers that drug mixtures need for delivery under inflammatory conditions in order to prevent tissue damage. AT was shown to inhibit NE in a dose-dependent manner, whereas a physiological concentration of 1.14 µM AT caused a significant NE inhibition (78%, pH 7.5). The concomitant existence of MPO/HOCl inactivated AT in a dose-dependent manner as well. To regain AT efficacy, HOCl-scavengers, such as L-methionine, α-aminosalicylic acid and cefoperazone were additionally applied. Finally, AT was assembled as surface layer onto layer-by-layer biopolymer-coated microcarriers and carrier phagocytosis by polymorphonuclear leukocytes could be shown.
authors.affiliation: Institute of Medical Physics and Biophysics, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Schönberg
authors.forename: Uta
authors.initials: U
authors.lastname: Reibetanz
authors.forename: Sophie
authors.initials: S
authors.lastname: Rathmann
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lessig
mesh_terms: D010131:Aminosalicylic Acid / Q000008:administration & dosage; D001704:Biopolymers / Q000737:chemistry*; D002438:Cefoperazone / Q000008:administration & dosage; D002470:Cell Survival; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D003102:Colloids / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006997:Hypochlorous Acid / Q000737:chemistry; D007249:Inflammation; D019272:Leukocyte Elastase / Q000737:chemistry*; D008715:Methionine / Q000008:administration & dosage; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000166:cytology; D010447:Peptide Hydrolases / Q000737:chemistry; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding; D013499:Surface Properties; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D001704:Biopolymers; D020099:Coated Materials, Biocompatible; D003102:Colloids; D004337:Drug Carriers; D000515:alpha 1-Antitrypsin; D010131:Aminosalicylic Acid; D006997:Hypochlorous Acid; D002438:Cefoperazone; D008715:Methionine; D009195:Peroxidase; D010447:Peptide Hydrolases; D019272:Leukocyte Elastase
keywords: chronic inflammation; human neutrophil elastase; hypochlorous acid; microcarrier; myeloperoxidase; α1-antitrypsin