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Fallah, M. (2018). Plasminogen: a pleiotropic inflammatory regulator in radiation-induced wound formation and wound repair. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Plasminogen: a pleiotropic inflammatory regulator in radiation-induced wound formation and wound repair
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The plasminogen activator (PA) system plays important roles in many physiological and pathological processes, including inflammation and wound healing. Plasmin, the central component of the PA system, is a broad-spectrum serine protease that is derived from its inactive precursor form, plasminogen. The first aim of this thesis was to study the role of plasminogen in the formation of radiation-induced wounds, which are an inflammatory side effect of radiotherapy. The second aim was to investigate the molecular mechanisms behind the potentiating effect of plasminogen in the healing of radiation-induced wounds. The third aim was to explore the therapeutic potential of plasminogen in the healing of radiation-induced wounds.

Radiation therapy in cancer patients is often limited by side effects such as radiation-induced skin damage (radiodermatitis). The mechanisms behind the formation of radiodermatitis are not fully elucidated, and there are no effective preventive therapies for clinical use. In this study, we show that irradiation of skin in WT (wild-type) mice induces plasminogen accumulation, which is followed by activation of TGF-β (transforming growth factor-beta) signaling and the development of inflammation that leads to skin damage. However, plasminogen-deficient mice and mice lacking PAs were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreases radiodermatitis in WT mice and prevented radiodermatitis in heterozygous mice. Thus, plasmin is required for the formation of radiodermatitis, and inhibition of plasminogen activation might be a novel treatment strategy to reduce or prevent radiodermatitis in patients undergoing radiotherapy.

Wound healing consists of partially overlapping inflammatory, proliferation, and tissue remodeling phases, and failure to terminate inflammation leads to the formation of chronic wounds. Previous studies by our group have shown that plasminogen is transported to acute wounds by inflammatory cells where it potentiates inflammation and enhances wound healing. Here, we report that plasminogen-deficient mice, which have delayed wound healing, have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialization, indicating inefficient debridement and chronic inflammation. The delayed formation of granulation tissue suggests that fibroblast function is also impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for the resolution of inflammation and the activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing capacity that is comparable to that in WT mice. Therefore, plasminogen might be an important future therapeutic agent for treatment of wounds.

In radiation-induced wounds, inflammation often cannot resolve and the wounds become chronic and fibrotic. Currently, there is no gold standard for the treatment of radiation-induced wounds. In this study, we have shown that radiation-induced wounds treated with plasminogen healed faster than placebo-treated wounds, had diminished inflammation and granulation tissue formation, and had enhanced re-epithelialization and collagen maturation. Transcriptome analysis showed that plasminogen has a pleiotropic effect on gene expression during wound healing, influencing the expression of 33 genes out of the 84 genes studied. In particular, plasminogen decreased the expression of 11 pro-inflammatory genes early in the healing process. Later, plasminogen decreased WNT (Wingless/Integrated) and TGF-β signaling, as well as the expression of 5 growth factors and 13 factors involved in granulation tissue formation. From the genes downregulated by plasminogen, 19 genes are known to be involved in fibrosis. These results show that in radiation-induced wounds with excessive inflammation and tissue formation plasminogen is able to direct the healing process to a normal outcome without the risk for developing fibrosis. This makes plasminogen an attractive drug candidate for treating radiodermatitis in cancer patients. Taken together, our results indicate that plasminogen is a pleiotropic inflammatory regulator involved in radiation-induced wound formation as well as in wound repair.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2018. p. 45
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1994
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-152952 (URN)978-91-7601-968-9 (ISBN)
Public defence
2018-11-23, Stora hörsalen (KBE303), KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2018-11-02 Created: 2018-10-31 Last updated: 2018-11-16Bibliographically approved
Fallah, M., Shen, Y., Brodén, J., Bäckman, A., Lundskog, B., Johansson, M., . . . Ny, T. (2018). Plasminogen activation is required for the development of radiation-induced dermatitis. Cell Death and Disease, 9(11), Article ID 1051.
Open this publication in new window or tab >>Plasminogen activation is required for the development of radiation-induced dermatitis
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2018 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 9, no 11, article id 1051Article in journal (Refereed) Published
Abstract [en]

Skin damage caused by radiation therapy (radiodermatitis) is a severe side effect of radiotherapy in cancer patients, and there is currently a lack of effective strategies to prevent or treat such skin damage. In this work, we show with several lines of evidence that plasminogen, a pro-inflammatory factor, is key for the development of radiodermatitis. After skin irradiation in wild type (plg+/+) mice, the plasminogen level increased in the radiated area, leading to severe skin damage such as ulcer formation. However, plasminogen-deficient (plg−/−) mice and mice lacking plasminogen activators were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreased radiodermatitis in plg+/+ mice and prevented radiodermatitis in plg+/ mice. Together with studies at the molecular level, we report that plasmin is required for the induction of inflammation after irradiation that leads to radiodermatitis, and we propose that inhibition of plasminogen activation can be a novel treatment strategy to reduce and prevent the occurrence of radiodermatitis in patients.

 

 

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Inflammation, plasminogen, radiation-induced dermatitis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-152950 (URN)10.1038/s41419-018-1106-8 (DOI)000447324600005 ()30323258 (PubMedID)
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2018-11-01Bibliographically approved
Mendoza-Garcia, P., Hugosson, F., Fallah, M., Higgins, M. L., Iwasaki, Y., Pfeifer, K., . . . Palmer, R. H. (2017). The Zic family homologue Odd-paired regulates Alk expression in Drosophila. PLoS Genetics, 13(4), Article ID e1006617.
Open this publication in new window or tab >>The Zic family homologue Odd-paired regulates Alk expression in Drosophila
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006617Article in journal (Refereed) Published
Abstract [en]

The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression. Further characterization identifies evolutionarily conserved Opa-binding cis-regulatory motifs in one of the Alk associated enhancer elements. Employing Alk reporter lines as well as CRISPR/Cas9-mediated removal of regulatory elements in the Alk locus, we show modulation of Alk expression by Opa in the embryonic AS, epidermis and VM. In addition, we identify enhancer elements that integrate input from additional TFs, such as Binou (Bin) and Bagpipe (Bap), to regulate VM expression of Alk in a combinatorial manner. Taken together, our data show that the Opa zinc finger TF is a novel regulator of embryonic Alk expression.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-137009 (URN)10.1371/journal.pgen.1006617 (DOI)000402549200004 ()
Available from: 2017-06-29 Created: 2017-06-29 Last updated: 2019-09-18Bibliographically approved
Sulniute, R., Shen, Y., Guo, Y.-Z., Fallah, M., Ahlskog, N., Ny, L., . . . Ny, T. (2016). Plasminogen is a critical regulator of cutaneous wound healing. Thrombosis and Haemostasis, 115(5), 1001-1009
Open this publication in new window or tab >>Plasminogen is a critical regulator of cutaneous wound healing
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2016 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 115, no 5, p. 1001-1009Article in journal (Refereed) Published
Abstract [en]

Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completion of wound healing and is a known reason for formation of chronic wounds. Previous studies have shown that wound closure is delayed in plasminogen deficient mice, and a role for plasminogen in dissection of extracellular matrix was suggested. However, our finding that plasminogen is transported to the wound by inflammatory cells early during the healing process, where it potentiates inflammation, indicates that plasminogen may also have other roles in the wound healing process. Here we report that plasminogen-deficient mice have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialisation, indicating inefficient debridement and chronic inflammation. Delayed formation of granulation tissue suggests that fibroblast function is impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for subsequent steps, including resolution of inflammation and activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing process that is comparable to that in wild-type mice. Besides of being an activator of the inflammatory phase during wound healing, plasminogen is also required for the subsequent termination of inflammation. Based on these results, we propose that plasminogen may be an important future therapeutic agent for wound treatment.

Keywords
Plasminogen, wound healing, inflammation
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-121571 (URN)10.1160/TH15-08-0653 (DOI)000375372400015 ()
Available from: 2016-06-30 Created: 2016-06-03 Last updated: 2018-10-31Bibliographically approved
Moonens, K., Gideonsson, P., Subedi, S., Bugaytsova, J., Romao, E., Mendez, M., . . . Remaut, H. (2016). Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. Cell Host and Microbe, 19(1), 55-66
Open this publication in new window or tab >>Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
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2016 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 19, no 1, p. 55-66Article in journal (Refereed) Published
Abstract [en]

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-117839 (URN)10.1016/j.chom.2015.12.004 (DOI)000369839900010 ()26764597 (PubMedID)
Available from: 2016-04-04 Created: 2016-03-04 Last updated: 2018-06-07Bibliographically approved
Popichenko, D., Hugosson, F., Sjögren, C., Dogru, M., Yamazaki, Y., Wolfstetter, G., . . . Palmer, R. H. (2013). Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in the Drosophila visceral mesoderm. Development, 140(15), 3156-3166
Open this publication in new window or tab >>Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in the Drosophila visceral mesoderm
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2013 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 140, no 15, p. 3156-3166Article in journal (Refereed) Published
Abstract [en]

The Jelly belly (Jeb)/Anaplastic Lymphoma Kinase (Alk) signalling pathway regulates myoblast fusion in the circular visceral mesoderm (VM) of Drosophila embryos via specification of founder cells. However, only a limited number of target molecules for this pathway are described. We have investigated the role of the Lame Duck (Lmd) transcription factor in VM development in relationship to Jeb/Alk signal transduction. We show that Alk signalling negatively regulates Lmd activity post-transcriptionally through the MEK/MAPK (ERK) cascade resulting in a relocalisation of Lmd protein from the nucleus to cytoplasm. It has previously been shown that downregulation of Lmd protein is necessary for the correct specification of founder cells. In the visceral mesoderm of lmd mutant embryos, fusion-competent myoblasts seem to be converted to 'founder-like' cells that are still able to build a gut musculature even in the absence of fusion. The ability of Alk signalling to downregulate Lmd protein requires the N-terminal 140 amino acids, as a Lmd(141-866) mutant remains nuclear in the presence of active ALK and is able to drive robust expression of the Lmd downstream target Vrp1 in the developing VM. Our results suggest that Lmd is a target of Jeb/Alk signalling in the VM of Drosophila embryos.

Keywords
Lmd, Alk, Jeb, Drosophila, Visceral muscle, Founder cell, Fusion competent myoblast
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-79229 (URN)10.1242/dev.094466 (DOI)000321864900009 ()
Available from: 2013-09-16 Created: 2013-08-13 Last updated: 2018-06-08Bibliographically approved
Fallah, M., Viklund, E., Shen, Y., Bäckman, A., Lundskog, B., Johansson, M., . . . Ny, T.Plasminogen enhances the healing of radiation-induced wounds via decreased expression of pro-inflammatory and pro-fibrotic factors.
Open this publication in new window or tab >>Plasminogen enhances the healing of radiation-induced wounds via decreased expression of pro-inflammatory and pro-fibrotic factors
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-152951 (URN)
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2018-11-01
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2430-1636

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