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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, pages
Umeå: Umeå University, 2013. 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1575
Keyword [en]
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)oai:DiVA.org:umu-68755 (OAI)diva2:617977 (DiVA)
Public defence
2013-05-24, KB3A9, KBC-huset, Umeå University, Umeå, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from2013-05-03 Created:2013-04-25 Last updated:2013-05-21Bibliographically approved
List of papers
1. Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds
Open this publication in new window or tab >>Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds
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2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 119, no 24, 5879-5887Article in journal (Refereed) Published
Abstract [en]

Despite decades of research on wound healing, effective biologic agents for the treatment of chronic wounds, especially diabetic wounds, are still lacking. In the present study, we report that the inert plasma protein plasminogen (plg) acts as a key regulatory molecule that potentiates wound healing in mice. Early in the healing process, plg bound to inflammatory cells is transported to the wound area, where the level of plg is increased locally, leading to the induction of cytokines and intracellular signaling events and to a potentiation of the early inflammatory response. Systemic administration of additional plg not only accelerates the healing of acute burn wounds in wild-type mice, but also improves the healing of chronic diabetic wounds in a mouse model of diabetes. Our results suggest that the administration of plg may be a novel therapeutic strategy to treat many different types of wounds, especially chronic wounds such as those caused by diabetes. (Blood. 2012; 119(24):5879-5887)

Publisher, range
Washington, USA: American society of hematology, 2012
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-58921 (URN)10.1182/blood-2012-01-407825 (DOI)000307396500041 ()
Available from2012-09-07 Created:2012-09-06 Last updated:2013-05-06Bibliographically approved
2. Plasminogen is a critical regulator of cutaneous wound healing
Open this publication in new window or tab >>Plasminogen is a critical regulator of cutaneous wound healing
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Wound healing is a well-orchestrated, complex process leading to the repair of injured tissues. Two major proteolytic systems, the matrix metalloproteases and the plasminogen activator system, are involved in this process. The lack of plasminogen (plg) has previously been reported to cause a delay in wound closure in mice, and to be complemented by matrix metalloproteases. However, our previous finding that tympanic membrane perforations in plgdeficient mice do not heal indicated that plg has more important function in wound healing than previously regarded. In later studies, we have found that plg accumulates in the wound early during the healing process and potentiates the inflammatory response and the healing. In the present study, we have used incision and burn wound models in wild-type and plgdeficient mice to further investigate the role of plg in the later phases of the healing process, including its role after re-epithelization. In addition to the earlier observed delay of wound reepithelizationin plg-deficient mice, we have found that the tissue remodeling processes that take place after re-epithelization is also impaired in these mice. By morphological and immunohistochemical analyses, we found that plg-deficient mice had delayed granulationtissue formation, and were unable to clear the provisional matrix. Extensive fibrin deposition and persistent neutrophil infiltration even at day 60 post-wounding indicate that the inflammation was present subcutaneously in plg-deficient mice even at later time points. Importantly, intravenous or subcutaneous supplementation of plg-deficient mice by human plg led to a restored healing rate, and a healing pattern that was comparable to that in wildtype mice. Therefore, in addition to its important function in early stages of cutaneous wound healing, plg is also crucial for later phases, by clearing fibrin deposits and resolving inflammation after full re-epithelization of the wound. Our results suggest that plg may be a potential therapeutic agent for improving the healing of different types of skin wounds.

Keyword
plasminogen, wound, healing, skin
National Category
Basic Medicine Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-68761 (URN)
Funder
Swedish Research Council
Available from2013-04-25 Created:2013-04-25 Last updated:2013-05-06Bibliographically approved
3. Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations
Open this publication in new window or tab >>Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations
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2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 12, e51303-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.

Publisher, range
Public library of science, 2012
Keyword
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:nbn:se:umu:diva-64176 (URN)10.1371/journal.pone.0051303 (DOI)000312064100090 ()23236466 (PubMedID)
Available from2013-01-17 Created:2013-01-17 Last updated:2014-06-10Bibliographically approved
4. Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice
Open this publication in new window or tab >>Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice
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2014 (English)In: Journal of Translational Medicine, ISSN 1479-5876, Vol. 12, Article Number: 5-Article in journal (Refereed) Published
Abstract [en]

Background: Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. Traditionally, these perforations must be surgically closed, which is costly and time consuming. Therefore, there is a need for simpler therapeutic strategies. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that accelerates cutaneous wound healing in mice. We have also shown that the healing of TM perforations is completely arrested in plg-deficient (plg(-/-)) mice and that these mice develop chronic TM perforations. In the present study, we investigated the therapeutic potential of local plg injection in acute and chronic TM perforation mice models. Methods: Plg(-/-) mice and wild-type mice were subjected to standardized TM perforations followed by local injection of plg into the soft tissue surrounding the TM. TM perforations with chronic characteristics were induced by leaving TM perforations in plg(-/-) mice untreated for 9 days before treatment. The healing process was observed through otomicroscope and finally confirmed by immunostaining. The quality of TM healing was evaluated based on the morphology of the TM. Result: Daily local injections of plg into the soft tissue surrounding the TM restored the ability to heal TM perforations in plg(-/-) mice in a dose-dependent manner, and potentiated the healing rate and quality in wild-type mice. A single local injection of plg initiated the healing of the chronic-like TM perforations in these mice, resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. However, three plg injections led to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer. Conclusion: Our data suggests that plg is a promising drug candidate for the treatment of chronic TM perforations in humans.

Publisher, range
BioMed Central, 2014
Keyword
Plasminogen, wound healing, tympanic membrane perforations
National Category
Basic Medicine Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-68759 (URN)10.1186/1479-5876-12-5 (DOI)
Funder
Swedish Research Council
Available from2013-04-25 Created:2013-04-25 Last updated:2014-02-24Bibliographically approved

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