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Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, e51303- p.Article in journal (Refereed) Published
Abstract [en]

Mice deficient in plasminogen, the precursor of plasmin, show completely arrested healing of tympanic membrane (TM) perforations, indicating that plasmin plays an essential role in TM healing. The activation of plasminogen to plasmin is performed by two plasminogen activators (PAs), urokinase-type PA (uPA) and tissue-type PA (tPA). To elucidate the functional roles of PAs in the healing of TM perforations, we investigated the phenotypes of single gene-deficient mice lacking uPA (uPA(-/-)) or tPA (tPA(-/-)) after TM perforation. Delayed healing of TM perforations was observed in uPA(-/-) mice but not tPA(-/-) mice. The migration of keratinocytes was clearly delayed and seemed to be misoriented in uPA(-/-) mice. Furthermore, fibrin deposition and the inflammatory response were persistent in these mice. Our findings demonstrate that uPA plays a role in the healing of TM perforations. The observed phenotypes in uPA(-/-) mice are most likely due to the reduced generation of plasmin.

Place, publisher, year, edition, pages
Public library of science , 2012. Vol. 7, no 12, e51303- p.
Keyword [en]
receptor; upa; keratinocytes; system; gene; model
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-64176DOI: 10.1371/journal.pone.0051303ISI: 000312064100090PubMedID: 23236466OAI: oai:DiVA.org:umu-64176DiVA: diva2:589306
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Plasminogen: a novel inflammatory regulator that promotes wound healing
Open this publication in new window or tab >>Plasminogen: a novel inflammatory regulator that promotes wound healing
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The plasminogen activator (PA) system has been shown to be intimately involved in wound healing. However, the role of this system in the initiation and resolution of inflammation during healing process remained to be determined. The aims of this thesis were to investigate the molecular mechanism underlying the interaction between the PA system and the inflammatory system during wound healing and to explore the therapeutic potential of plasminogen in various wound-healing models.

The role of plasminogen in the inflammatory phase of the healing process of acute and diabetic wounds was studied first. Our data showed that administration of additional plasminogen to wild-type mice accelerates the healing of acute wounds. After injury, both endogenous and exogenous plasminogen are bound to inflammatory cells and are transported to the wound site, which leads to activation of inflammatory cells. In diabetic db/db mice, wound-specific accumulation of plasminogen does not take place and the inflammatory response is impaired. However, when additional plasminogen is injected, plasminogen accumulates in the wound, the inflammatory response is enhanced, the signal transduction cascade is activated and the healing rate is significantly increased. These results indicate that administration of plasminogen may be a novel therapeutic strategy to treat different types of wounds, especially chronic wounds in diabetes.

The role of plasminogen at the later stage of wound healing was also studied in plasminogen-deficient mice. Our data showed that even if re-epithelialization is achieved in these mice, a prolonged inflammatory phase with abundant neutrophil accumulation and persistent fibrin deposition is observed at the wound site. These results indicate that plasminogen is also essential for the later phases of wound healing by clearing fibrin and resolving inflammation.

The functional role of two physiological PAs during wound healing was further studied in a tympanic membrane (TM) wound-healing model. Our data showed that the healing process was clearly delayed in urokinase-type PA (uPA)-deficient mice but not in tissue-type PA (tPA)-deficient mice. Less pronounced keratinocyte migration, abundant neutrophil accumulation and persistent fibrin deposition were observed in uPA-deficient mice. These results indicate that uPA plays a central role in the generation of plasmin during the healing of TM perforations.

Finally the therapeutic potential of plasminogen in the TM wound-healing model was studied. Our data showed that local injection of plasminogen restores the ability to heal TM perforations in plasminogen-deficient mice in a dose-dependent manner. Plasminogen supplementation also potentiates healing of acute TM perforations in wild-type mice, independent of the administration method used. A single local injection of plasminogen in plasminogen-deficient mice can initiate healing of chronic TM perforations resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. Three plasminogen injections lead to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer that can start to reorganize and further mature to its normal appearance. In conclusion, our results suggest that plasminogen is a promising drug candidate for the treatment of chronic TM perforations in humans. 

Taken together, our data indicate that plasminogen is a novel inflammatory regulator that promotes wound healing.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2013. 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1575
Keyword
Plasminogen, inflammation, wound healing, diabetic wounds, tympanic membrane perforations
National Category
Basic Medicine Otorhinolaryngology Dermatology and Venereal Diseases Endocrinology and Diabetes
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-68755 (URN)978-91-7459-651-9 (ISBN)
Public defence
2013-05-24, KB3A9, KBC-huset, Umeå University, Umeå, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2013-05-03 Created: 2013-04-25 Last updated: 2013-05-21Bibliographically approved

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