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Plasminogen in periodontitis and wound repair
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The plasminogen activator (PA) system plays a critical role in many physiological and pathological processes, such as fibrinolysis, extracellular matrix (ECM) degradation, wound healing, inflammation, and cancer. The key component of the PA system is plasmin, a broad-spectrum serine protease that is derived from its inactive form, plasminogen. The first aim of this thesis research was to determine the role of plasminogen in periodontitis, an inflammatory oral disease. The second aim was to explore the molecular mechanism by which plasminogen contributes to wound healing in the skin. Finally, the third aim was to investigate the possibility of using plasminogen as a treatment for skin wounds, especially for chronic wounds, such as diabetic wounds.

Periodontitis is an oral disease that involves a bacterial infection, the inflammation of the periodontium, and the degradation of gum tissue and alveolar bone. This disease is irreversible and, in severe cases, can lead to loss of teeth due to the degradation of the periodontal ligament and alveolar bone. To study the effects of the PA system on oral health, we monitored the development of periodontitis in plasminogen-deficient mice and plasminogen activator-deficient mice. In control wild-type mice, periodontitis did not occur. However, in plasminogen-deficient mice, periodontitis developed rapidly within 20 weeks after birth. The morphological studies of plasminogen-deficient mice showed the detachment of gingival tissues, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. Immunohistochemical staining showed the massive infiltration of neutrophils into the periodontal tissues. Interestingly, doubly deficient mice lacking both tissue-type plasminogen activator (tPA) and urokinase-type PA (uPA) developed periodontitis at a similar rate as the plasminogen-deficient mice, but mice lacking only tPA or uPA remained healthy. The intravenous injection of human plasminogen for 10 days into plasminogen-deficient mice led to the absorption of necrotic tissue, the diminution of inflammation, and the full regeneration of gum tissues. Notably, there was also partial re-growth of degraded alveolar bone.

The wound healing process consists of three overlapping phases: inflammatory, proliferative, and remodeling. It has been postulated that the PA system plays an integral role in this process, and a lack of plasminogen leads to delayed wound healing in mice. To study the role of the PA system in wound healing, we monitored the responses of wild-type, plasminogen-deficient and diabetic mice to incision and burn wounds. We found that in addition to being delayed, the wound healing process in plasminogen-deficient mice was only superficial in nature. The plasminogen-deficient mice were unable to clear the provisional matrix after the formation of granulation tissue, and an extensive fibrin deposition. In addition, persistent inflammation was still present subcutaneously in these mice 60 days after introduction of the wound.

The essential role of plasminogen in burn and incision wounds healing was further confirmed by reconstitution experiments. Both intravenous and subcutaneous administrations of human plasminogen to plasminogen-deficient mice led to a restored healing rate and wound maturation that was comparable to those of wild-type mice. We also demonstrated that plasminogen supplementation of plasminogen to wild-type and diabetic mice significantly improved the healing of cutaneous wounds. Plasminogen levels were not only temporally increased during the inflammation phase but also spatially concentrated at the site of the wound. The wound-specific accumulation of plasminogen after systemic supplementation is mainly due to the transportation of plasminogen by neutrophils and macrophages. Furthermore, the increased expression of interleukin 6 and the enhanced phosphorylation of STAT3 were observed in the wound after plasminogen treatment. These data indicate that plasminogen acts as a key pro-inflammatory regulator. It enhances pro-inflammatory cytokines and activates intracellular signaling events during wound healing.

Taken together, the data obtained during the course of this project indicate that plasminogen is crucial for oral health in mice. We also demonstrate that supplementation of plasminogen to mice with periodontitis results in healing of gum tissues and significant re-growth of alveolar bone. Therefore, plasminogen may be a new drug that will be competitive to currently used oral health-related procedures, such as implantations and surgeries. Furthermore, we demonstrate for the first time that, in addition to its role in extracellular matrix degradation, plasminogen is a key pro-inflammatory factor that accumulates at the wound and potentiates the early inflammatory response during wound healing. Based on our findings, we propose the administration of plasminogen as a novel therapeutic strategy for the treatment of different types of wounds, including chronic diabetic wounds.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2013. , 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1549
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-63818ISBN: 978-91-7459-547-5 (print)OAI: oai:DiVA.org:umu-63818DiVA: diva2:583716
Public defence
2013-02-01, N450, Naturvetarhuset, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2013-01-11 Created: 2013-01-08 Last updated: 2013-01-11Bibliographically approved
List of papers
1. Plasmin is essential in preventing periodontitis in mice
Open this publication in new window or tab >>Plasmin is essential in preventing periodontitis in mice
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2011 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 2, 819-828 p.Article in journal (Refereed) Published
Abstract [en]

Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue- and urokinase-type plasminogen activators, developed periodontal disease similar to that in Pig-deficient mice; however, mice lacking only tissue- or urokinase-type plasminogen activator remained healthy. Supplementation by injection of Pig-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Pig-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases. (Am J Pathol 2011, 179:819-828; DOI: 10.1016/j.ajpath.2011.05.003)

Keyword
disease ligneous periodontitis; activator gene-function; osteoblast-like cells; deficient mice; macrophage activation; mediated proteolysis; tissue regeneration; growth; bone; conjunctivitis
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-51497 (URN)10.1016/j.ajpath.2011.05.003 (DOI)000298307200028 ()
Available from: 2012-01-23 Created: 2012-01-23 Last updated: 2017-12-08Bibliographically approved
2. Plasminogen is essential for the healing of cutaneous wounds
Open this publication in new window or tab >>Plasminogen is essential for the healing of cutaneous wounds
(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 plg-deficient 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 plg-deficient 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 re-epithelization in 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 granulation tissue 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 wild type 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 Cell and Molecular Biology
Research subject
biomedicinsk laboratorievetenskap
Identifiers
urn:nbn:se:umu:diva-63817 (URN)
Available from: 2013-01-08 Created: 2013-01-08 Last updated: 2013-01-11Bibliographically approved
3. 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, 5879-5887 p.Article 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)

Place, publisher, year, edition, pages
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 from: 2012-09-07 Created: 2012-09-06 Last updated: 2017-12-07Bibliographically approved

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