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Multifunctional roles of plasmin in inflammation: Studies of animal models on rheumatoid arthritis, multiple sclerosis, wound healing and infection
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
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.

Place, publisher, year, edition, pages
2005. , 80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 936
Keyword [en]
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: urn:nbn:se:umu:diva-422OAI: oai:DiVA.org:umu-422DiVA: diva2:143429
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
List of papers
1. The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis.
Open this publication in new window or tab >>The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis.
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2005 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 166, no 3, 783-792 p.Article in journal (Refereed) Published
Abstract [en]

The plasminogen activator (PA) system has been proposed to have important roles in rheumatoid arthritis. Here we have used the autoimmune collagen type II (CII)-induced arthritis (CIA) model and mice deficient for urokinase-type PA (uPA) or plasminogen to investigate the role of the PA system for development of arthritis. Our data revealed that uPA-deficient mice have a lower severity and incidence of CIA than wild-type mice. Furthermore, although >80% of wild-type control mice developed CIA, we found that none of the 50 plasminogen-deficient littermates that were tested developed CIA within a 40-day period. Antibody generation after CII immunization as well as the binding of labeled anti-CII antibodies to the surface of cartilage were similar in wild-type and plasminogen-deficient mice. No sign of inflammation was seen when plasminogen-deficient mice were injected with a mixture of monoclonal antibodies against CII. However, after daily injections of human plasminogen, these mice developed arthritis within 5 days. Our finding that infiltration of inflammatory cells into the synovial joints was impaired in plasminogen-deficient mice suggests that uPA and plasminogen are important mediators of joint inflammation. Active plasmin is therefore essential for the induction of pathological inflammatory joint destruction in CIA.

Keyword
Animals, Antibodies; Monoclonal/chemistry, Arthritis/*immunology/pathology, Arthritis; Experimental/*immunology/pathology, Collagen Type II/*metabolism, Enzyme-Linked Immunosorbent Assay, Epitopes, Immunohistochemistry, Inflammation/*metabolism, Joints/*immunology, Mice, Mice; Inbred C57BL, Plasmin/*metabolism, Plasminogen/*metabolism/*physiology, Plasminogen Activators/*metabolism, Time Factors, Urinary Plasminogen Activator/*physiology
Identifiers
urn:nbn:se:umu:diva-6331 (URN)15743790 (PubMedID)
Available from: 2007-12-09 Created: 2007-12-09 Last updated: 2011-03-18Bibliographically approved
2. Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models.
Open this publication in new window or tab >>Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models.
2005 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 8, 2541-2548 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate the contrasting roles of plasminogen deficiency between models of collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA). METHODS: We developed a new animal model of arthritis, which we have called local injection-induced arthritis (LIA). In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen and is injected intraarticularly into the knee joint, with type II collagen (CII) to induce AIA. The severity of CIA, LIA, and AIA in wild-type and plasminogen-deficient mice was evaluated by clinical scoring or histologic grading. Necrosis was determined by histology and immunohistochemistry. RESULTS: After CII immunization alone, wild-type mice developed arthritis in most of the paws as well as in the knee joints, whereas plasminogen-deficient mice were totally resistant to the disease. Local knee injections of CII or saline slightly enhanced the severity of the knee arthritis in wild-type mice during a 60-day experimental period. Unexpectedly, the plasminogen-deficient mice also developed arthritis in joints that were injected with CII or saline. However, the arthritis was milder than that in their wild-type littermates. Sustained tissue necrosis was found only in the plasminogen-deficient mice after the local injection. CONCLUSION: Our data show that both the antigen and the joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This further indicates that CIA and AIA have distinct pathogenic mechanisms. The data also suggest that plasmin may be required for the induction of these arthritis models that are critically dependent on complement activation.

Keyword
Animals, Arthritis; Experimental/*metabolism/physiopathology, Arthritis; Rheumatoid/etiology/immunology/*metabolism/physiopathology, Collagen Type II/administration & dosage/immunology, Disease Models; Animal, Immunization, Injections; Intra-Articular, Knee Injuries/complications, Knee Joint, Mice, Mice; Inbred C57BL, Mice; Inbred DBA, Necrosis, Plasminogen/*deficiency, Severity of Illness Index, Sodium Chloride/administration & dosage, Synovial Membrane/pathology
Identifiers
urn:nbn:se:umu:diva-6330 (URN)10.1002/art.21229 (DOI)16052596 (PubMedID)
Available from: 2007-12-09 Created: 2007-12-09 Last updated: 2011-03-18Bibliographically approved
3. Plasmin does not play an essential role in experimental autoimmune encephalomyelitis
Open this publication in new window or tab >>Plasmin does not play an essential role in experimental autoimmune encephalomyelitis
(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-4370 (URN)
Available from: 2005-01-26 Created: 2005-01-26 Last updated: 2011-03-30Bibliographically approved
4. Plasmin/plasminogen is essential for the healing of tympanic membrane perforations.
Open this publication in new window or tab >>Plasmin/plasminogen is essential for the healing of tympanic membrane perforations.
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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.

Keyword
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:nbn:se:umu:diva-6327 (URN)10.1160/TH06-03-0168 (DOI)17003931 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-03-18Bibliographically approved
5. Spontaneous development of otitis media in plasminogen-deficient mice
Open this publication in new window or tab >>Spontaneous development of otitis media in plasminogen-deficient mice
2006 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 296, no 7, 501-509 p.Article in journal (Refereed) Published
Abstract [en]

Inflammatory conditions of the ear, otitis media, are one of the most common disease entities in children. In this study, the role of the plasminogen (plg)/plasmin system for the spontaneous development of chronic otitis media was investigated by the analysis of plg-deficient mice. Whereas essentially all of the wild-type control mice kept a healthy status of the middle ear, all the plg-deficient mice gradually developed chronic otitis media with various degrees of inflammatory changes during an 18-week observation period. Five bacterial strains were identified in materials obtained from the middle ear cavities of six plg-deficient mice. Morphological studies revealed the formation of an amorphous mass tissue and inflammatory changes in the middle ears of plg-deficient mice. Immunohistochemical studies further indicate a mass infiltration of neutrophils and macrophages as well as the presence of T and B cells in the middle ear mucosa of these mice. Extensive fibrin deposition and an abnormal keratin formation were also observed in the tympanic membrane, the middle ear cavity and external ear canal in these mice. These results suggest that plg plays an essential role in protecting against the spontaneous development of chronic otitis media. Our findings also suggest the possibility of using plg for clinical therapy of certain types of otitis media.

Keyword
Animals, B-Lymphocytes, Bacteria/classification/isolation & purification, Disease Models; Animal, Ear; External/chemistry, Ear; Middle/chemistry/microbiology/pathology, Fibrin/analysis, Hematologic Diseases/*complications, Immunohistochemistry, Keratins/analysis, Macrophages, Mice, Mice; Inbred C57BL, Mice; Inbred DBA, Mucous Membrane/microbiology/pathology, Neutrophil Infiltration, Otitis Media/*etiology, Plasminogen/*deficiency/*physiology, T-Lymphocytes, Tympanic Membrane/chemistry
Identifiers
urn:nbn:se:umu:diva-6328 (URN)10.1016/j.ijmm.2006.04.002 (DOI)16956791 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-03-18Bibliographically approved

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