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Egelrud, Torbjörn
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Publications (10 of 13) Show all publications
Palmér, R., Mäenpää, J., Jauhiainen, A., Larsson, B., Mo, J., Russell, M., . . . Gardiner, P. (2018). Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects. Clinical Pharmacology and Therapeutics, 104(6), 1155-1164
Open this publication in new window or tab >>Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects
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2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 6, p. 1155-1164Article in journal (Refereed) Published
Abstract [en]

Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions. Several dose-dependent, possibly DPP1-related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-154935 (URN)10.1002/cpt.1053 (DOI)000449645100015 ()29484635 (PubMedID)
Funder
AstraZeneca
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-05-16Bibliographically approved
Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M. & Egelrud, T. (2008). Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. Journal of Investigative Dermatology, 128(1), 18-25
Open this publication in new window or tab >>Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases
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2008 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 128, no 1, p. 18-25Article in journal (Refereed) Published
Abstract [en]

Proteinase-activated receptor-2 (PAR2) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR2 is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR2 is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand. The endogenous activators of PAR2 on keratinocytes have not been identified as of yet. Potential candidates are kallikrein-related peptidases (KLKs) expressed by epidermal cells. Therefore, the ability of four human skin-derived KLKs was examined with regard to their capacity to activate PAR2 in vitro. PAR2 cleavage was followed by immunofluorescence analysis and functional activation by measurements of changes in intracellular calcium levels. We found that KLK5 and KLK14, but neither KLK7 nor KLK8, induced PAR2 signalling. We conclude that certain, but not all, epidermal KLKs are capable of activating PAR2. We could also show the coexpression of KLK14 and PAR2 receptor in inflammatory skin disorders. These in vitro results suggest that KLKs may take part in PAR2 activation in the epidermis and thereby in PAR2-mediated inflammatory responses, including epidermal barrier repair and pruritus. The role of KLKs in PAR2 activation in vivo remains to be elucidated.

Place, publisher, year, edition, pages
Elsevier, 2008
Identifiers
urn:nbn:se:umu:diva-7000 (URN)10.1038/sj.jid.5700965 (DOI)000251613600005 ()17625593 (PubMedID)
Available from: 2008-01-02 Created: 2008-01-02 Last updated: 2019-07-08Bibliographically approved
Egelrud, T. (2007). Atopic dermatitis: a skin barrier disease.. Acta Dermato-Venereologica, 87(6), 482-3
Open this publication in new window or tab >>Atopic dermatitis: a skin barrier disease.
2007 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 87, no 6, p. 482-3Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-7039 (URN)doi:10.2340/00015555-0356 (DOI)17989883 (PubMedID)
Available from: 2008-01-03 Created: 2008-01-03 Last updated: 2018-06-09Bibliographically approved
Stefansson, K., Brattsand, M., Ny, A., Glas, B. & Egelrud, T. (2006). Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum.. Biological chemistry (Print), 387(6), 761-768
Open this publication in new window or tab >>Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum.
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2006 (English)In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 387, no 6, p. 761-768Article in journal (Refereed) Published
Keywords
Epidermis/*enzymology, Humans, Kallikreins/analysis/isolation & purification/*metabolism, Serine Endopeptidases/metabolism, Skin Physiology, Sweat Glands/enzymology, Trypsin/*metabolism
Identifiers
urn:nbn:se:umu:diva-6060 (URN)doi:10.1515/BC.2006.095 (DOI)16800737 (PubMedID)
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2018-06-09Bibliographically approved
Hachem, J.-P., Wagberg, F., Schmuth, M., Crumrine, D., Lissens, W., Jayakumar, A., . . . Elias, P. M. (2006). Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. Journal of Investigative Dermatology, 126(7), 1609-21
Open this publication in new window or tab >>Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome
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2006 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 126, no 7, p. 1609-21Article in journal (Refereed) Published
Keywords
Abnormalities; Multiple/*genetics, Adolescent, Adult, Animals, Carrier Proteins/*genetics/physiology, Cell Membrane Permeability/physiology, Child, Dermatitis; Atopic/*genetics/*pathology, Desmocollins, Desmoglein 1/physiology, Desmosomes/physiology/ultrastructure, Enzyme Activation, Epidermis/chemistry/pathology, Gene Expression Regulation, Hair Follicle/*abnormalities/physiopathology, Humans, Ichthyosis; Lamellar/*genetics/*pathology, Kallikreins/analysis, Membrane Glycoproteins/physiology, Mice, Mice; Transgenic, Mutation, Phenotype, Proteinase Inhibitory Proteins; Secretory, Serine Endopeptidases/*metabolism, Severity of Illness Index, Syndrome
Identifiers
urn:nbn:se:umu:diva-6741 (URN)10.1038/sj.jid.5700288 (DOI)16601670 (PubMedID)
Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2018-06-09Bibliographically approved
Brattsand, M., Stefansson, K., Lundh, C., Haasum, Y. & Egelrud, T. (2005). A proteolytic cascade of kallikreins in the stratum corneum. Journal of Investigative Dermatology, 124(1), 198-203
Open this publication in new window or tab >>A proteolytic cascade of kallikreins in the stratum corneum
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2005 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 124, no 1, p. 198-203Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3178 (URN)10.1111/j.0022-202X.2004.23547.x (DOI)
Available from: 2008-05-12 Created: 2008-05-12 Last updated: 2018-06-09Bibliographically approved
Egelrud, T., Brattsand, M., Kreutzmann, P., Walden, M., Vitzithum, K., Marx, U. C., . . . Mägert, H. J. (2005). hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6.. British Journal of Dermatology, 153(6), 1200-1203
Open this publication in new window or tab >>hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6.
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2005 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 153, no 6, p. 1200-1203Article in journal (Refereed) Published
Keywords
Carrier Proteins/*pharmacology, Dose-Response Relationship; Drug, Humans, Kallikreins, Plasmin/antagonists & inhibitors, Proteinase Inhibitory Proteins; Secretory, Serine Endopeptidases/*chemistry, Serine Proteinase Inhibitors/*pharmacology, Skin/*enzymology, Skin Diseases/enzymology
Identifiers
urn:nbn:se:umu:diva-7016 (URN)doi:10.1111/j.1365-2133.2005.06834.x (DOI)16307658 (PubMedID)
Available from: 2008-01-02 Created: 2008-01-02 Last updated: 2018-06-09Bibliographically approved
Caubet, C., Jonca, N., Brattsand, M., Guerrin, M., Bernard, D., Schmidt, R., . . . Serre, G. (2004). Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.. Journal of Investigative Dermatology, 122(5), 1235-1244
Open this publication in new window or tab >>Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.
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2004 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 122, no 5, p. 1235-1244Article in journal (Refereed) Published
Keywords
Antibody Specificity, Cadherins/immunology/metabolism, Cells; Cultured, Desmocollins, Desmoglein 1, Desmosomes/*enzymology, Epidermis/*metabolism, Gene Expression, Glycoproteins/immunology/*metabolism, Glycosylation, Humans, Hydrogen-Ion Concentration, Kallikreins/genetics/*metabolism, Kidney/cytology, Membrane Glycoproteins/immunology/metabolism, Oligosaccharides/metabolism/pharmacology, Recombinant Proteins/genetics/metabolism, Serine Endopeptidases/genetics/*metabolism
Identifiers
urn:nbn:se:umu:diva-7017 (URN)doi:10.1111/j.0022-202X.2004.22512.x (DOI)15140227 (PubMedID)
Available from: 2008-01-02 Created: 2008-01-02 Last updated: 2018-06-09Bibliographically approved
Ekholm, I. E., Brattsand, M. & Egelrud, T. (2000). Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process?. Journal of Investigative Dermatology, 114(1), 56-63
Open this publication in new window or tab >>Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process?
2000 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 114, no 1, p. 56-63Article in journal (Refereed) Published
Abstract [en]

Stratum corneum chymotryptic enzyme may be important in desquamation. It has also been suggested that other proteases, especially stratum corneum tryptic enzyme, may be involved. Stratum corneum tryptic enzyme has been purified and its cDNA has been cloned. Results from expression analyses indicate that stratum corneum tryptic enzyme is as skin specific as stratum corneum chymotryptic enzyme. In this work we have produced and characterized antibodies specific for stratum corneum tryptic enzyme. We have also by means of biochemical, immunochemical, and immunohistochemical methods performed studies on stratum corneum tryptic enzyme in normal human epidermis. Antibodies against bacterial recombinant stratum corneum tryptic enzyme were produced and purified by affinity chromatography. Two types of antibodies were obtained: one reacting only with pro-stratum corneum tryptic enzyme and one specific for the catalytically active part of stratum corneum tryptic enzyme. Immunohistochemistry with the antibodies reacting with pro-stratum corneum tryptic enzyme showed a staining pattern similar to stratum corneum chymotryptic enzyme-specific antibodies, i.e., the expression was confined to cornifying epithelia with a need of desquamation-like processes. Extracts of tape strips with superficial human stratum corneum were found to contain precursors as well as active forms of stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme. The enzymes had maximal activity at pH 8, but both had considerable activity also at pH 5.5. The results were compatible for a role of stratum corneum tryptic enzyme in desquamation. Stratum corneum tryptic enzyme may act in concert with stratum corneum chymotryptic enzyme and/or function as a stratum corneum chymotryptic enzyme-activating enzyme. The presence in normal superficial stratum corneum of precursors as well as of active forms of stratum corneum chymotryptic enzyme and stratum corneum tryptic enzyme, and the activity of both enzymes over a broad range of pH-values, suggest some possible ways by which the desquamation may be regulated.

Place, publisher, year, edition, pages
Nature Publishing Group, 2000
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-82017 (URN)10.1046/j.1523-1747.2000.00820.x (DOI)10620116 (PubMedID)
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2018-06-08Bibliographically approved
Bäckman, A., Strandén, P., Brattsand, M., Hansson, L. & Egelrud, T. (1999). Molecular cloning and tissue expression of the murine analog to human stratum corneum chymotryptic enzyme. Journal of Investigative Dermatology, 113(2), 152-5
Open this publication in new window or tab >>Molecular cloning and tissue expression of the murine analog to human stratum corneum chymotryptic enzyme
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1999 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 113, no 2, p. 152-5Article in journal (Refereed) Published
Abstract [en]

Human stratum corneum chymotryptic enzyme (SCCE) may play a central part in epidermal homeostasis. Its proposed function is to catalyze the degradation of intercellular structures, including desmosomes, in the stratum corneum as part of the desquamation process. In order to facilitate physiologic and pathophysiologic studies on SCCE we have looked for the corresponding murine enzyme. A cDNA obtained by reverse transcription-polymerase chain reaction with total RNA prepared from mouse tails as starting material was cloned, and the expression of the corresponding mRNA studied. The murine cDNA showed 77% homology to human SCCE cDNA. It had an open-reading frame encoding a protein comprising 249 amino acids with 82% amino acid sequence homology to human SCCE including the conserved sequences of the catalytic traid of mammalian serine proteases. The murine protein was deduced to have a 21 amino acid signal peptide and a four amino acid propeptide ending with a tryptic cleavage site, followed by a sequence motif identical to the N-terminal amino acid sequence of native active human SCCE. As in human SCCE the P2 position of the propeptide was occupied by an acidic amino acid residue, and the position corresponding to the suggested bottom of the primary substrate specificity pouch occupied by an asparagine residue. Analyses of mouse tissues by reverse transcriptase-polymerase chain reaction showed high expression in the skin, low expression in lung, kidney, brain, heart, and spleen, and no expression in liver or skeletal muscle. In situ hybridization of mouse skin showed expression in high suprabasal keratinocytes and in the luminal parts of hair follicles. Our results strongly suggest that we have cloned the murine analog of human SCCE cDNA.

Place, publisher, year, edition, pages
Nature Publishing Group, 1999
Keywords
desquamation, serine protease
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-82019 (URN)10.1046/j.1523-1747.1999.00662.x (DOI)000081855900002 ()10469296 (PubMedID)
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2018-06-08Bibliographically approved
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