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Inflammation and tendon healing
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
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: urn:nbn:se:liu:diva-142349DOI: 10.3384/diss.diva-142349ISBN: 9789176854716 (print)OAI: oai:DiVA.org:liu-142349DiVA: diva2:1153309
Public defence
2017-11-22, Belladonna, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2017-10-30 Created: 2017-10-30 Last updated: 2017-10-30Bibliographically approved
List of papers
1. A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
Open this publication in new window or tab >>A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 29824Article in journal (Refereed) Published
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
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-130383 (URN)10.1038/srep29824 (DOI)000379584000001 ()27405922 (PubMedID)
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: 2017-10-30
2. Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
Open this publication in new window or tab >>Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
2017 (English)In: Muscles, ligaments and Tendons journal, ISSN 2240-4554, Vol. 7, no 2, 223-229 p.Article in journal (Refereed) Published
Abstract [en]

Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations.Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10.Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point.Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells.

Place, publisher, year, edition, pages
Rome, Italy: CIC Edizioni Internazionali, 2017
Keyword
tendon healing; NSAID; inflammation; rat model; flow cytometry
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-142352 (URN)
Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2017-10-30
3. Systemic corticosteroids improve tendon healing when given after the early inflammatory phase
Open this publication in new window or tab >>Systemic corticosteroids improve tendon healing when given after the early inflammatory phase
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 12468Article in journal (Refereed) Published
Abstract [en]

Inflammation initiates tendon healing and then normally resolves more or less completely. Unresolved inflammation might disturb the remodeling process. We hypothesized that suppression of inflammation during the early remodeling phase by systemic dexamethasone treatment can improve healing. 36 rats underwent Achilles tendon transection and were randomized to dexamethasone or saline on days 0-4 after surgery (early inflammatory phase), and euthanasia day 7. Another 54 rats received injections days 5-9 (early remodeling phase) and were euthanized day 12 for mechanical, histological and flow cytometric evaluation. Dexamethasone treatment days 0-4 reduced the cross-sectional area, peak force and stiffness by day 7 to less than half (p amp;lt; 0.001 for all), while material properties (peak stress and elastic modulus) were not significantly affected. In contrast, dexamethasone treatment days 5-9 increased peak force by 39% (p = 0.002) and stiffness by 58% (p amp;lt; 0.001). The cross-sectional area was reduced by 42% (p amp;lt; 0.001). Peak stress and elastic modulus were more than doubled (p amp;lt; 0.001 for both). Semi-quantitative histology at day 12 showed that late dexamethasone treatment improved collagen alignment, and flow cytometry revealed reduced numbers of CD8a(+) cytotoxic T cells in the tendon callus. These results suggest that downregulation of lingering inflammation during the early remodeling phase can improve healing.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Biomaterials Science
Identifiers
urn:nbn:se:liu:diva-142175 (URN)10.1038/s41598-017-12657-0 (DOI)000412032600034 ()28963482 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; Ostergotland county (ALF)

Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-11-16
4. COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
Open this publication in new window or tab >>COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
2015 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 5, 534-540 p.Article in journal (Refereed) Published
Abstract [en]

Early tendon healing can be stimulated by mechanical loading and inhibited by cyclooxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs). Therefore, we investigated if impairment of tendon healing by a COX-2 inhibitor (parecoxib) is related to loading. Because loading might infer microdamage, which also stimulates healing, we also investigated if this effect is inhibited by parecoxib. The Achilles tendon was transected in 114 rats. Three degrees of loading were used: full loading, partial unloading, and unloading (no unloading, Botox injections in the plantar flexor muscles, or Botox in combination with tail suspension). For each loading condition, the rats received either parecoxib or saline. In a second experiment, rats were unloaded with Botox, and the tendon was subjected to microdamage by needling combined with either saline or parecoxib. Mechanical testing day 7 showed that there was a significant interaction between loading and parecoxib for peak force at failure (P less than 0.01). However, logarithmic values showed no significant interaction, meaning that we could not exclude that the inhibitory effect of parecoxib was proportionate to the degree of loading. Microbleeding was common in the healing tissue, suggesting that loading caused microdamage. Needling increased peak force at failure (P less than 0.01), and this effect of microdamage was almost abolished by parecoxib (P less than 0.01). Taken together, this suggests that COX-2 inhibition impairs the positive effects of mechanical loading during tendon healing, mainly by reducing the response to microdamage.

Place, publisher, year, edition, pages
AMER PHYSIOLOGICAL SOC, 2015
Keyword
tendon healing; COX-2; NSAIDs; mechanical stimulation; microdamage
National Category
Physiology Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-122063 (URN)10.1152/japplphysiol.00239.2015 (DOI)000360694300013 ()26159755 (PubMedID)
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: 2015-12-18 Created: 2015-10-19 Last updated: 2017-10-30

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