title: Pivotal role for alpha1-antichymotrypsin in skin repair.
abstract: α1-Antichymotrypsin (α1-ACT) is a specific inhibitor of leukocyte-derived chymotrypsin-like proteases with largely unknown functions in tissue repair. By examining human and murine skin wounds, we showed that following mechanical injury the physiological repair response is associated with an acute phase response of α1-ACT and the mouse homologue Spi-2, respectively. In both species, attenuated α1-ACT/Spi-2 activity and gene expression at the local wound site was associated with severe wound healing defects. Topical application of recombinant α1-ACT to wounds of diabetic mice rescued the impaired healing phenotype. LC-MS analysis of α1-ACT cleavage fragments identified a novel cleavage site within the reactive center loop and showed that neutrophil elastase was the predominant protease involved in unusual α1-ACT cleavage and inactivation in nonhealing human wounds. These results reveal critical functions for locally acting α1-ACT in the acute phase response following skin injury, provide mechanistic insight into its function during the repair response, and raise novel perspectives for its potential therapeutic value in inflammation-mediated tissue damage.
authors.affiliation: Department of Dermatology, University of Cologne, 50931 Cologne, Germany.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Hoffmann
authors.affiliation: Department of Dermatology, University of Cologne, 50931 Cologne, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Textoris
authors.affiliation: Biotech Development, Bayer HealthCare AG, 42117 Wuppertal, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Oehme
authors.affiliation: A&M Labor GmbH, 50126 Bergheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Klaassen
authors.affiliation: Baxter Innovation GmbH, 1020 Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Goppelt
authors.affiliation: A&M Labor GmbH, 50126 Bergheim, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Römer
authors.affiliation: Bayer Innovation GmbH, 40225 Düsseldorf, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Fugmann
authors.affiliation: Research Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212,; Vanderbilt University School of Medicine, Nashville, Tennessee 37240.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Davidson
authors.affiliation: ETH Zurich, Honggerberg, 8092 Zurich, Switzerland, and.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.affiliation: Department of Dermatology, University of Cologne, 50931 Cologne, Germany,; Center for Molecular Medicine Cologne, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.affiliation: Department of Dermatology, University of Cologne, 50931 Cologne, Germany,; Center for Molecular Medicine Cologne, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, 50674 Cologne, Germany. Electronic address: sabine.eming@uni-koeln.de.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
mesh_terms: D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000293:injuries / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; C516148:SERPINA3 protein, human; D015843:Serpins; C086598:lambda Spi-2; D019272:Leukocyte Elastase