Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing.
Identifieur interne : 001927 ( Ncbi/Checkpoint ); précédent : 001926; suivant : 001928Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing.
Auteurs : I. Hsu [Canada] ; L G Parkinson [Canada] ; Y. Shen [Canada] ; A. Toro [Canada] ; T. Brown [Canada] ; H. Zhao [Canada] ; R C Bleackley [Canada] ; D J Granville [Canada]Source :
- Cell death & disease [ 2041-4889 ] ; 2014.
English descriptors
- KwdEn :
- Acute-Phase Proteins (genetics), Acute-Phase Proteins (metabolism), Animals, Cell Differentiation, Cell Proliferation, Collagen (metabolism), Diabetes Mellitus, Experimental (enzymology), Diabetes Mellitus, Experimental (genetics), Diabetes Mellitus, Experimental (metabolism), Diabetes Mellitus, Experimental (physiopathology), Disease Models, Animal, Extracellular Matrix (metabolism), Granzymes (metabolism), Humans, Male, Mice, Mice, Inbred C57BL, Serpins (genetics), Serpins (metabolism), Skin (blood supply), Skin (injuries), Skin (metabolism), Skin (physiopathology), Wound Healing.
- MESH :
- chemical , genetics : Acute-Phase Proteins, Serpins.
- chemical , metabolism : Acute-Phase Proteins, Collagen, Granzymes, Serpins.
- blood supply : Skin.
- enzymology : Diabetes Mellitus, Experimental.
- genetics : Diabetes Mellitus, Experimental.
- injuries : Skin.
- metabolism : Diabetes Mellitus, Experimental, Extracellular Matrix, Skin.
- physiopathology : Diabetes Mellitus, Experimental, Skin.
- Animals, Cell Differentiation, Cell Proliferation, Disease Models, Animal, Humans, Male, Mice, Mice, Inbred C57BL, Wound Healing.
Abstract
Chronic, non-healing wounds are a major complication of diabetes and are characterized by chronic inflammation and excessive protease activity. Although once thought to function primarily as a pro-apoptotic serine protease, granzyme B (GzmB) can also accumulate in the extracellular matrix (ECM) during chronic inflammation and cleave ECM proteins that are essential for proper wound healing, including fibronectin. We hypothesized that GzmB contributes to the pathogenesis of impaired diabetic wound healing through excessive ECM degradation. In the present study, the murine serine protease inhibitor, serpina3n (SA3N), was administered to excisional wounds created on the dorsum of genetically induced type-II diabetic mice. Wound closure was monitored and skin wound samples were collected for analyses. Wound closure, including both re-epithelialization and contraction, were significantly increased in SA3N-treated wounds. Histological and immunohistochemical analyses of SA3N-treated wounds revealed a more mature, proliferative granulation tissue phenotype as indicated by increased cell proliferation, vascularization, fibroblast maturation and differentiation, and collagen deposition. Skin homogenates from SA3N-treated wounds also exhibited greater levels of full-length intact fibronectin compared with that of vehicle wounds. In addition, GzmB-induced detachment of mouse embryonic fibroblasts correlated with a rounded and clustered phenotype that was prevented by SA3N. In summary, topical administration of SA3N accelerated wound healing. Our findings suggest that GzmB contributes to the pathogenesis of diabetic wound healing through the proteolytic cleavage of fibronectin that is essential for normal wound closure, and that SA3N promotes granulation tissue maturation and collagen deposition.
DOI: 10.1038/cddis.2014.423
PubMed: 25299783
Affiliations:
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Hsu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Parkinson, L G" sort="Parkinson, L G" uniqKey="Parkinson L" first="L G" last="Parkinson">L G Parkinson</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Shen, Y" sort="Shen, Y" uniqKey="Shen Y" first="Y" last="Shen">Y. 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Brown</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Zhao, H" sort="Zhao, H" uniqKey="Zhao H" first="H" last="Zhao">H. Zhao</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Bleackley, R C" sort="Bleackley, R C" uniqKey="Bleackley R" first="R C" last="Bleackley">R C Bleackley</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, University of Alberta, Edmonton, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Granville, D J" sort="Granville, D J" uniqKey="Granville D" first="D J" last="Granville">D J Granville</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:25299783</idno><idno type="pmid">25299783</idno><idno type="doi">10.1038/cddis.2014.423</idno><idno type="wicri:Area/PubMed/Corpus">000663</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000663</idno><idno type="wicri:Area/PubMed/Curation">000663</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000663</idno><idno type="wicri:Area/PubMed/Checkpoint">000663</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000663</idno><idno type="wicri:Area/Ncbi/Merge">001927</idno><idno type="wicri:Area/Ncbi/Curation">001927</idno><idno type="wicri:Area/Ncbi/Checkpoint">001927</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing.</title><author><name sortKey="Hsu, I" sort="Hsu, I" uniqKey="Hsu I" first="I" last="Hsu">I. Hsu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Parkinson, L G" sort="Parkinson, L G" uniqKey="Parkinson L" first="L G" last="Parkinson">L G Parkinson</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Shen, Y" sort="Shen, Y" uniqKey="Shen Y" first="Y" last="Shen">Y. Shen</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Toro, A" sort="Toro, A" uniqKey="Toro A" first="A" last="Toro">A. Toro</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Brown, T" sort="Brown, T" uniqKey="Brown T" first="T" last="Brown">T. Brown</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Zhao, H" sort="Zhao, H" uniqKey="Zhao H" first="H" last="Zhao">H. Zhao</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Bleackley, R C" sort="Bleackley, R C" uniqKey="Bleackley R" first="R C" last="Bleackley">R C Bleackley</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, University of Alberta, Edmonton, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Granville, D J" sort="Granville, D J" uniqKey="Granville D" first="D J" last="Granville">D J Granville</name><affiliation wicri:level="1"><nlm:affiliation>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada [2] Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cell death & disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acute-Phase Proteins (genetics)</term><term>Acute-Phase Proteins (metabolism)</term><term>Animals</term><term>Cell Differentiation</term><term>Cell Proliferation</term><term>Collagen (metabolism)</term><term>Diabetes Mellitus, Experimental (enzymology)</term><term>Diabetes Mellitus, Experimental (genetics)</term><term>Diabetes Mellitus, Experimental (metabolism)</term><term>Diabetes Mellitus, Experimental (physiopathology)</term><term>Disease Models, Animal</term><term>Extracellular Matrix (metabolism)</term><term>Granzymes (metabolism)</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Serpins (genetics)</term><term>Serpins (metabolism)</term><term>Skin (blood supply)</term><term>Skin (injuries)</term><term>Skin (metabolism)</term><term>Skin (physiopathology)</term><term>Wound Healing</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Acute-Phase Proteins</term><term>Serpins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Acute-Phase Proteins</term><term>Collagen</term><term>Granzymes</term><term>Serpins</term></keywords><keywords scheme="MESH" qualifier="blood supply" xml:lang="en"><term>Skin</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Diabetes Mellitus, Experimental</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Diabetes Mellitus, Experimental</term></keywords><keywords scheme="MESH" qualifier="injuries" xml:lang="en"><term>Skin</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Diabetes Mellitus, Experimental</term><term>Extracellular Matrix</term><term>Skin</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Diabetes Mellitus, Experimental</term><term>Skin</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Differentiation</term><term>Cell Proliferation</term><term>Disease Models, Animal</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Wound Healing</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Chronic, non-healing wounds are a major complication of diabetes and are characterized by chronic inflammation and excessive protease activity. Although once thought to function primarily as a pro-apoptotic serine protease, granzyme B (GzmB) can also accumulate in the extracellular matrix (ECM) during chronic inflammation and cleave ECM proteins that are essential for proper wound healing, including fibronectin. We hypothesized that GzmB contributes to the pathogenesis of impaired diabetic wound healing through excessive ECM degradation. In the present study, the murine serine protease inhibitor, serpina3n (SA3N), was administered to excisional wounds created on the dorsum of genetically induced type-II diabetic mice. Wound closure was monitored and skin wound samples were collected for analyses. Wound closure, including both re-epithelialization and contraction, were significantly increased in SA3N-treated wounds. Histological and immunohistochemical analyses of SA3N-treated wounds revealed a more mature, proliferative granulation tissue phenotype as indicated by increased cell proliferation, vascularization, fibroblast maturation and differentiation, and collagen deposition. Skin homogenates from SA3N-treated wounds also exhibited greater levels of full-length intact fibronectin compared with that of vehicle wounds. In addition, GzmB-induced detachment of mouse embryonic fibroblasts correlated with a rounded and clustered phenotype that was prevented by SA3N. In summary, topical administration of SA3N accelerated wound healing. Our findings suggest that GzmB contributes to the pathogenesis of diabetic wound healing through the proteolytic cleavage of fibronectin that is essential for normal wound closure, and that SA3N promotes granulation tissue maturation and collagen deposition.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Hsu, I" sort="Hsu, I" uniqKey="Hsu I" first="I" last="Hsu">I. Hsu</name></noRegion><name sortKey="Bleackley, R C" sort="Bleackley, R C" uniqKey="Bleackley R" first="R C" last="Bleackley">R C Bleackley</name><name sortKey="Brown, T" sort="Brown, T" uniqKey="Brown T" first="T" last="Brown">T. Brown</name><name sortKey="Granville, D J" sort="Granville, D J" uniqKey="Granville D" first="D J" last="Granville">D J Granville</name><name sortKey="Parkinson, L G" sort="Parkinson, L G" uniqKey="Parkinson L" first="L G" last="Parkinson">L G Parkinson</name><name sortKey="Shen, Y" sort="Shen, Y" uniqKey="Shen Y" first="Y" last="Shen">Y. Shen</name><name sortKey="Toro, A" sort="Toro, A" uniqKey="Toro A" first="A" last="Toro">A. Toro</name><name sortKey="Zhao, H" sort="Zhao, H" uniqKey="Zhao H" first="H" last="Zhao">H. Zhao</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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