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Plasmin/plasminogen is essential for the healing of tympanic membrane perforations.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
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2006 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 96, no 4, 512-519 p.Article in journal (Refereed) Published
Abstract [en]

Plasminogen has been proposed to play an important role in different tissue remodeling processes such as wound healing and tissue regeneration after injuries. The healing of tympanic membrane perforations is a well-organized chain of inflammatory events, with an initial invasion of inflammatory cells followed by reparative and restoration phases. Here we show that the healing of tympanic membrane perforations is completely arrested in plasminogen-deficient mice, with no signs of any healing even 143 days after perforation. Inflammatory cells were recruited to the wounded area, but there were no signs of tissue debridement. In addition, removal of fibrin, keratinocyte migration and in-growth of connective tissue were impaired. This contrasts with skin wound healing, where studies have shown that, although the healing process is delayed, it reaches completion in all plasminogen-deficient mice. Our finding that keratinocyte migration and re-epithelialization were completely arrested in plasminogen-deficient mice indicates that plasminogen/plasmin plays a more profound role in the healing of tympanic membrane perforations than in the healing of other epithelial wounds.

Place, publisher, year, edition, pages
2006. Vol. 96, no 4, 512-519 p.
Keyword [en]
Animals, Cell Proliferation, Fibrin/metabolism, Keratinocytes/metabolism/pathology, Keratins/metabolism, Macrophages/immunology, Male, Mice, Mice; Inbred C57BL, Mice; Inbred DBA, Mice; Knockout, Neutrophil Infiltration, Neutrophils/immunology, Plasmin/*metabolism, Plasminogen/genetics/*metabolism/pharmacology, Time Factors, Tympanic Membrane Perforation/immunology/*metabolism/pathology, Wound Healing/drug effects
Identifiers
URN: urn:nbn:se:umu:diva-6327DOI: 10.1160/TH06-03-0168PubMedID: 17003931OAI: oai:DiVA.org:umu-6327DiVA: diva2:145996
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-03-18Bibliographically approved
In thesis
1. The effects of plasminogen deficiency on the healing of tympanic membrane perforations
Open this publication in new window or tab >>The effects of plasminogen deficiency on the healing of tympanic membrane perforations
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The healing of tympanic membrane (TM) perforations is a complex wound healing process including inflammation, migration of keratinocytes and tissue remodelling. Most TM perforations in human heal spontaneously, however some perforations become chronic, and the reason to why is still largely unknown. In cutaneous wound healing plasminogen (plg) has been shown to play an important role. Plg is converted into the protease plasmin regulated by two plasminogen activators (PA), urokinase type PA (uPA) and tissue-type PA (tPA).

The aim of the present thesis was to evaluate the role of plg in healing of TM perforations, both in vivo and in vitro. The main objectives were to determine the healing capacity of the TM, the involvement of keratinocytes, fibrin(ogen) and inflammatory cells in the healing process. The studies were performed in plg deficient and uPA deficient mice, with littermate wild type (wt) mice as controls

It was shown that myringotomies of the TMs in plg deficient mice still remained open 143 days following a perforation. The wound area was characterized by an abundant recruitment and accumulation of inflammatory cells; mainly macrophages and neutrophils, an arrested keratinocyte migration and a fibrin deposition covering the surface of the TM. The TM perforations in the wt mice all healed within 11 days. Interestingly, the myringotomies of the plg deficient mice could be closed by reconstitution with systemic injections of plg, whereas injections of PBS had no affect on the healing.

To characterize mechanisms involved in the development of persistent TM perforations in plg deficient mice after a myringotomy the early inflammatory response during the first 48 hours was studied. The recruitment and accumulation of inflammatory cells in the perforated TMs was found to be similar between the plg deficient and the wt mice.

Myringotomized TMs in uPA deficient mice healed similar to perforations of wt controls. Neither did the keratinocyte migration nor the occurrence of inflammatory cells differ between these genotypes.

In the in vitro experiments TMs from plg deficient and wt mice, were dissected out, perforated and cultured in absence or surplus of plg. A decrease in perforation size was seen in all groups regardless of genotype or amount of plg in the medium.

In conclusion, the present studies show:

• Plg is essential for the healing of TM perforations in mice.

• The altered healing process after a myringotomy in plg deficient mice involves a disturbed keratinocyte migration, a massive deposition of fibrin and an abundant accumulation of inflammatory cells in the wound area.

• Plasminogen deficiency does not alter the early inflammatory response, following a myringotomy.

• Deficiency of uPA does not influence the healing of TM perforations.

• During in vitro conditions healing of TM perforations is initiated irrespectively of genotype of the explant (plg deficient or wt) or supply of plg.

The increased knowledge of the involvement of plg in the healing of TM perforations may open therapeutical possibilities in the treatment of chronic TM perforations in humans.

Place, publisher, year, edition, pages
Umeå: Klinisk vetenskap, 2007. 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1090
Keyword
tympanic membrane, macrophages, neutrophils, fibrin(ogen), inflammation, keratinocyte migration, wound healing, uPA, tPA, in vitro
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-1100 (URN)978-91-7264-276-8 (ISBN)
Public defence
2007-05-18, Sal D, Tandläkarhögskolan (Dallashuset), Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2011-04-08Bibliographically approved
2. Multifunctional roles of plasmin in inflammation: Studies of animal models on rheumatoid arthritis, multiple sclerosis, wound healing and infection
Open this publication in new window or tab >>Multifunctional roles of plasmin in inflammation: Studies of animal models on rheumatoid arthritis, multiple sclerosis, wound healing and infection
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Plasmin has been suggested to be involved in degradation of extracellular matrix (ECM) and tissue remodeling during a number of physiological and pathological processes. The aims of this thesis were to study the functional roles of plasmin during pathological inflammation in autoimmune and nonautoimmune disease models of rheumatoid arthritis (RA), multiple sclerosis (MS), wound healing and infection. In order to explain the obtained results in our functional studies as well as some previous results on the functional roles of plasmin during different tissue remodeling processes, I propose that there is a functional correlation between absence of plasmin and an inability to activate complement.

The role of plasminogen during autoimmune collagen type II-induced arthritis (CIA) was studied first. The data revealed that whereas 83% of wild-type (plg+/+) mice developed CIA, none of the plasminogendeficient (plg-/-) mice got arthritis within a 40-day period. When plg+/+ mice were injected with a mixture of monoclonal antibodies against collagen type II they developed arthritis within a 5-day period, whereas no arthritis could be seen in plg-/- mice, although these mice had normal binding of antibody to the cartilage surface. These data suggest that plasmin plays an essential role in the step between antibody binding and inflammatory cell infiltration during CIA, probably during the step of complement activation. When plg+/+ and plg-/- mice were injected intra-articularly with collagen type II or 0.9% NaCl following CIA induction, plg-/- mice developed typical CIA, but the disease was less severe than in the plg+/+ mice and restricted to the injected joints. Sustained tissue necrosis was found only in the plg-/- mice after the local injection. When the antigen-induced arthritis (AIA) model was used, plg-/- mice developed a much more severe arthritis than the plg+/+ mice. These results indicate that different forms of pathogenesis exist for CIA and AIA, and further emphasize the importance of trauma in the induction of CIA in plg-/- mice.

We further investigated the role of plasmin in experimental autoimmune encephalomyelitis (EAE), which is an autoimmune disease model for MS. During a 2-month period, the severity, incidence, mean onset day, mean maximal score and mean accumulative score of EAE were essentially identical in plg-/- and plg+/+ mice of B10.Q background. Histopathological studies revealed similar levels of inflammation and demyelination in plg-/- and plg+/+ mice. These data indicate that plasmin does not play an essential role in the development of EAE. The findings that plasmin is essential for the development of CIA but not needed for the development of EAE suggest that plasmin may play a pivotal role in autoimmune diseases where complement activation is critically involved in the pathogenesis.

The role of plasmin was also studied in a tympanic membrane (TM) wound healing model. After TM perforations were performed, the plg+/+ TMs had all healed by day 11, whereas TM healing was completely arrested in plg-/- mice even as late as day 143. Immunohistochemical studies revealed a disturbed inflammation and tissue remodeling pattern in plg-/- mice. These data indicate that plasmin plays a central role in the healing of TM perforations.

The involvement of plasminogen in ear infections was also investigated in plg-/- mice. During an 18-week experimental period, spontaneous otitis media (OM) was essentially developed in all of the plg-/- mice, whereas all of the plg+/+ mice kept a normal TM status. Positive bacterial growth was found in 5 out of 6 plg-/- mice, but only in 1 out of 6 plg+/+ mice. Immunohistochemical studies showed an accumulation of inflammatory cells, fibrin and also other extracellular matrix in the middle-ear cavity and the external-ear canal of plg-/- mice. These results show a spontaneous development of OM in plg-/- mice, but not in plg+/+ controls, suggesting that plasmin plays a critical role in the defense mechanisms during ear infections. Taken together, plasmin appears to play essential roles during autoimmune and non-autoimmune diseases in which complement activation is critical in the pathogenesis.

Publisher
80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 936
Keyword
Plasmin, complement, inflammation, wound healing, infection, autoimmune disease, non-autoimmune disease, rheumatoid arthritis, multiple sclerosis, tympanic membrane, otitis media
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-422 (URN)
Public defence
2005-02-10, hörsal KB3A9, KBC-huset, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Available from: 2005-01-26 Created: 2005-01-26 Last updated: 2009-11-18Bibliographically approved

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Li, JinanNy, Tor

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