title: Secretory leukocyte proteinase inhibitor and elafin are resistant to degradation by MMP-8.
abstract: The naturally occurring neutrophil elastase inhibitors, alpha1-proteinase inhibitor (alpha1PI), secretory leukocyte proteinase inhibitor (SLPI), and elafin, are potential therapeutic agents in the treatment of neutrophil-mediated lung disease. However alpha1PI has been shown to be susceptible to inactivation by matrix metalloproteinases (MMPs) released by neutrophils, particularly neutrophil collagenase (MMP-8). The aim of this study was to determine if SLPI and elafin are similarly susceptible to degradation by this neutrophil-specific MMP. The effect of MMP-8 on SLPI and elafin was assessed by determining the neutrophil elastase inhibitory capacity (NEIC) and electrophoretic protein profile of both inhibitors following exposure to purified MMP-8. As a positive control, the effect of MMP-8 alpha1PI was assessed in parallel. Although treatment of alpha1PI with MMP-8 resulted in a significant decrease in its NEIC (P = .025), no similar decrease was observed with SLPI or elatin. Electrophoretic analysis confirmed digestion of alpha1PI by MMP-8 but no digestion of either SLPI or elafin was observed. These results demonstrate that SLPI and elafin are resistant to proteolytic inactivation by MMP-8, a property that may enhance their therapeutic application in neutrophil-mediated inflammatory lung disease.
authors.affiliation: Department of Medicine and Therapeutics, University College Dublin, Ireland. pajo@freenetname.co.uk
authors.forename: M T
authors.initials: MT
authors.lastname: Henry
authors.forename: K
authors.initials: K
authors.lastname: McMahon
authors.forename: C
authors.initials: C
authors.lastname: Costello
authors.forename: M X
authors.initials: MX
authors.lastname: Fitzgerald
authors.forename: C M
authors.initials: CM
authors.lastname: O'Connor
mesh_terms: D006801:Humans; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism* / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology; D010084:Oxidation-Reduction; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000378:metabolism*; D053481:Secretory Leukocyte Peptidase Inhibitor; D013183:Sputum / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D020784:Matrix Metalloproteinase 8