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Proteinet plasminogen kan ge bot åt kroniska sår. Avhandling. Umeå. Yue Shen

Var 20 sekund förlorar någon en fot eller ett ben på grund av fotsår som inte läker. Enligt Yue Shen, doktorand vid institutionen för medicinsk biokemi och biofysik, Umeå universitet, kan proteinet plasminogen bli ett nytt läkemedel för kronisk sårbehandling, vilket i sin tur kan förändra livet för miljontals patienter.


Diabetiska sår är den allvarligaste typen av kroniska sår som i hög grad försämrar livskvaliteten för drabbade patienter och som orsakar en enorm börda på vårdsystemet.
I världen finns det över 350 miljoner diabetespatienter och cirka 20 procent av dem utvecklar diabetiska fotsår som ofta inte läker, vilket slutligen leder till amputation.

Reglering av inflammation

I den avhandling som Yue Shen har skrivit vid institutionen för medicinsk biokemi och biofysik, samt Företagsforskarskolan vid Umeå universitet, visar han att plasminogen, ett välkänt plasmaprotein, fungerar som en viktig molekyl för reglering av inflammation. Proteinet kan i sin tur användas för att behandla olika typer av kroniska sår, inklusive diabetiska sår.

Injiceras runt såren

Yue Shen har bland annat visat att halterna av plasminogen normalt ökar dramatiskt i och runt sår. Det leder till minskad inflammation, vilket krävs för läkning.
I diabetiska sår som inte läker, ökar dock inte nivån av plasminogen, vilket gör att inflammationen inte heller dämpas. Yue Shen har också visat att läkningsprocessen startar när plasminogen injiceras runt diabetiska sår, vilket gör att såren så småningom kan läka helt.

Miljontals drabbade

Baserat på dessa resultat planerar Yue Shen nu att genomföra en kontrollerad klinisk studie med humanplasminogen för behandling av kroniska sår hos människor. Slutmålet är att utveckla plasminogen till ett läkemedel för sårbehandling.
– Resultaten ökar inte bara vår förståelse när det gäller plasminogen som molekyl och dess roll under sårläkningsprocessen, utan ger också hopp till miljontals desperata patienter som drabbats av kroniska sår, säger Yue Shen.

Källa: Pressmeddelande från Umeå universitet
Bild: Umeå universitet

Länk till avhandlingen med klickbart alla delarbetena

http://umu.diva-portal.org/smash/record.jsf?pid=diva2:617977

 

Author:
Shen, Yue (Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics) (Företagsforskarskolan, Industrial Doctoral School)
Title:
Plasminogen: a novel inflammatory regulator that promotes wound healing
Department:
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics
Publication type:
Doctoral thesis, comprehensive summary (Other academic)
Language:
English
Place of publ.: Umeå Publisher: Umeå University
Pages:
58
Series:
Umeå University medical dissertations, ISSN 0346-6612; 1575
Year of publ.:
2013
URI:
urn:nbn:se:umu:diva-68755
Permanent link:
http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-68755
ISBN:
978-91-7459-651-9
Subject category:
Basic Medicine
Otorhinolaryngology
Dermatology and Venereal Diseases
Endocrinology and Diabetes
Research subject:
Medical Biochemistry
Keywords(en) :
Plasminogen, inflammation, wound healing, diabetic wounds, tympanic membrane perforations
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.

 

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