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A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 29824Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and T-reg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and T-reg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the T-reg cell fraction was lower (p amp;lt; 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more T-reg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2016. Vol. 6, no 29824
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-130383DOI: 10.1038/srep29824ISI: 000379584000001PubMedID: 27405922OAI: oai:DiVA.org:liu-130383DiVA: diva2:952752
Note

Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2017-11-28
In thesis
1. Inflammation and tendon healing
Open this publication in new window or tab >>Inflammation and tendon healing
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.

The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.

First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.

In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations. 

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 45 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1583
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-142349 (URN)10.3384/diss.diva-142349 (DOI)9789176854716 (ISBN)
Public defence
2017-11-22, Belladonna, Campus US, Linköping, 13:00 (English)
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Supervisors
Available from: 2017-10-30 Created: 2017-10-30 Last updated: 2017-10-30Bibliographically approved

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Blomgran, ParmisBlomgran, RobertErnerudh, JanAspenberg, Per

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Division of Clinical SciencesFaculty of Medicine and Health SciencesDivision of Microbiology and Molecular MedicineDivision of Neuro and Inflammation ScienceDepartment of Clinical Immunology and Transfusion MedicineDepartment of Orthopaedics in Linköping
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