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COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping. Linköping University, Faculty of Health Sciences.
2015 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 5, p. 534-540Article 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. Vol. 119, no 5, p. 534-540
Keywords [en]
tendon healing; COX-2; NSAIDs; mechanical stimulation; microdamage
National Category
Physiology Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-122063DOI: 10.1152/japplphysiol.00239.2015ISI: 000360694300013PubMedID: 26159755OAI: oai:DiVA.org:liu-122063DiVA, id: diva2:885310
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: 2019-02-11
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. p. 45
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)
Opponent
Supervisors
Available from: 2017-10-30 Created: 2017-10-30 Last updated: 2018-01-13Bibliographically approved
2. Tendon Healing: Mechanical Loading, Microdamage and Gene Expression
Open this publication in new window or tab >>Tendon Healing: Mechanical Loading, Microdamage and Gene Expression
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mechanical loading and the inflammatory response during tendon healing might be important for the healing process. Mechanical loading can improve the healing tendon but the mechanism is not fully understood. The aim of this thesis was to further clarify the effect of mechanical loading on tendon healing and how mechanical loading affects the inflammatory response during the healing process.

We used a rat Achilles tendon model to study healing. The rats were exposed to different degrees of loading by unloading methods such as paralysis of the calf muscles with Botox, tail suspension, and an orthosis (a boot). Full loading was achieved by free cage activity or treadmill walking. Microdamage in tendons, unloaded with Botox, was also investigated by needling. The healing tendons were evaluated in a materials testing machine (to analyze the mechanical properties), by gene expression analysis (microarray and PCR), or histology.

Our results show that moderate loading (unloading with Botox) improves the mechanical properties of healing tendons compared to minimal loading (unloading with Botox in combination with tail suspension or a boot), especially the material properties. In accordance to these findings, expression of extracellular matrix genes were also increased by moderate compared to minimal loading.

Full loading improved all mechanical properties and the expression of extracellular matrix genes was further increased compared to moderate loading. However, structural properties, such as the strength and the size of the healing tendon, were more affected by full loading. Full loading also affected the expression of inflammation-related genes during the early healing phase, 3 and 5 days after tendon injury, and increased the number of immune cells in the healing tendon tissue. Also microdamage of the healing tendon (detected by blood leakage) was increased by full loading compared to moderate loading during the early healing phase.

Induced microdamage by repeated needling in the healing tendon tissue increased the structural properties of the healing tendon. The gene expression after needling was similar to the gene expression after full loading.

The improvement of mechanical properties by loading in healing tendons was decreased by an anti-inflammatory drug called parecoxib, which decreases the production of prostaglandins by inhibiting COX-2 activity. The effect of parecoxib was reduced when loading was reduced but we could not confirm that the effect of parecoxib was related to the degree of loading. However, parecoxib abolished the stimulatory effect of microdamage.

In conclusion, these studies show that moderate loading improves the quality of the healing tendon whereas full loading also increases the quantity of the healing tendon tissue. Full loading creates microdamage and increases inflammation during the early healing phase. The strong effect of full loading on the structural properties might be due to microdamage. Indeed, the anti-inflammatory drug parecoxib seems to impair mechanical stimulation of healing tendons by reducing the response to microdamage.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 28
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1609
National Category
Biomaterials Science
Identifiers
urn:nbn:se:liu:diva-145281 (URN)10.3384/diss.diva-145281 (DOI)9789176853610 (ISBN)
Public defence
2018-03-26, Belladonna, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved

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Hammerman, MalinRamstedt, SandraAspenberg, Per

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