title: Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects.
abstract: There is increasing evidence that antiproteases are able to affect the inflammatory response. To further examine this question, we administered human alpha-1-antitrypsin (alpha1AT) or a synthetic metalloprotease inhibitor (RS113456) to C57 mice followed by a single intratracheal dose of quartz, a dust that evokes a marked, lasting, polymorphonuclear leukocyte (PMN) infiltrate. At 2 hours after dust administration, both antiproteases completely suppressed silica-induced PMN influx into the lung and macrophage inflammatory protein-2 (MIP-2)/monocyte chemotactic protein-1 (MCP-1) (neutrophil/macrophage chemoattractant) gene expression, partially suppressed nuclear transcription factor kappaB (NF-kappaB) translocation, and increased inhibitor of NF-kappaB (IkappaB) levels. By 24 hours, PMN influx and connective tissue breakdown measured as lavage desmosine or hydroxyproline were still at, or close to, control levels after antiprotease treatment, and increases in NF-kappaB translocation and MIP-2/MCP-1 gene expression were variably suppressed. At both time points, neither agent prevented silica-induced increases in amount of whole lung MIP-2 or MCP-1 protein, but both did prevent increases in whole lung intercellular adhesion molecule-1 (ICAM-1) at 24 hours. Inactivating the alpha1AT by oxidation to the point that it no longer possessed antiproteolytic properties did not affect its ability to suppress inflammation. Both antiproteases also prevented the silica-induced acute inflammatory response in mice with knocked out genes for macrophage metalloelastase (MME -/-), mice that develop inflammation, but not connective tissue breakdown, and the pattern of alpha1AT breakdown fragments was identical in control and MME -/- animals. These findings suggest that, in this model of acute PMN mediated inflammation, a serine protease inhibitor and a metalloprotease inhibitor have similar anti-inflammatory properties, that inflammation is not mediated by proteolysis with generation of chemotactic matrix fragments, and that classic antiproteolysis (complexing of protease to antiprotease) probably does not play a role in suppression of inflammation. The antiproteolytic effects of these agents do not seem to be mediated by protection of endogenous alpha1AT.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. achurg@interchange.ubc.ca
authors.forename: A
authors.initials: A
authors.lastname: Churg
authors.forename: J
authors.initials: J
authors.lastname: Dai
authors.forename: K
authors.initials: K
authors.lastname: Zay
authors.forename: A
authors.initials: A
authors.lastname: Karsan
authors.forename: R
authors.initials: R
authors.lastname: Hendricks
authors.forename: C
authors.initials: C
authors.lastname: Yee
authors.forename: R
authors.initials: R
authors.lastname: Martin
authors.forename: R
authors.initials: R
authors.lastname: MacKenzie
authors.forename: C
authors.initials: C
authors.lastname: Xie
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Shapiro
authors.forename: J L
authors.initials: JL
authors.lastname: Wright
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054426:Chemokine CXCL2; D051550:I-kappa B Kinase; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012822:Silicon Dioxide; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D015846:Monokines; D016328:NF-kappa B; D011714:Pyrans; D012333:RNA, Messenger; C113899:RS 113456; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D018799:Intercellular Adhesion Molecule-1; D012822:Silicon Dioxide; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12