title: Elastase-coupled beads as a tool for characterizing localized alveolar tissue destruction associated with the onset of emphysema.
abstract: Intratracheal elastase challenge of laboratory animals has long been established as a model for observing the physiological and morphological changes that result from alveolar destruction, the hallmark of emphysema. However, instillation of elastase suspended in buffer results in widespread inflammation and variable emphysematous lesions, which has made the identification of specific cellular and molecular events associated with the onset of emphysema difficult to define. Here we establish a bead-based elastase delivery system that induces localized tissue destruction, a key event in the initiation of emphysema. Elastase was coupled to bisacrylamide beads, which were shown to retain enzymatic activity prior to intratracheal administration in mice. C57BL/6 mice were given a single dose of 40,000 beads, which became distributed throughout the small airways and parenchyma of the lung. Elastase-coupled beads resulted in a quantifiable loss of alveolar tissue immediately surrounding the beads, an effect that was not observed with beads that lacked protein altogether or with beads containing elastase inactivated by an irreversible inhibitor. Furthermore, beads bound with active elastase elicited local recruitment of mononuclear cells, including macrophages, and polymorphonuclear neutrophils to the site of bead deposition, a feature consistent with the cellular infiltration observed following conventional solubilized elastase challenges. This work identifies a novel bead-based enzyme delivery system that also extends the elastase model of emphysema to permit the characterization of mechanisms that drive alveolar surface area loss following elastin degradation in focal emphysematous lesions.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21231, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Craig
authors.forename: A L
authors.initials: AL
authors.lastname: Scott
authors.forename: W
authors.initials: W
authors.lastname: Mitzner
mesh_terms: D020106:Acrylamide / Q000737:chemistry*; D000818:Animals; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000138:chemical synthesis; D004646:Emphysema / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase / Q000008:administration & dosage* / Q000737:chemistry; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D004337:Drug Carriers; D020106:Acrylamide; D010196:Pancreatic Elastase
keywords: beads; elastase; emphysema; inflammation
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