Serum and tissue cytokines and chemokines increase with repetitive upper extremity tasks

Abstract

We investigated inflammation in rats performing a low repetition, negligible force (LRNF) or high repetition, negligible force (HRNF) task of reaching and retrieving food pellets at target rates of two or four reaches/min for 2 h/day, for 6-8 weeks. Serum was assayed for 11 cytokines and chemokines; forelimb tissues for four cytokines. Macrophages were counted in forelimb tissues of LRNF rats to add to results from our previous studies of HRNF rats. In HRNF rats, serum IL-1a, IL-1b, TNFa, MIP2, MIP3a, and RANTES were elevated in weeks 6 and 8. In contrast, only MIP2 and MIP3a increased in serum of LRNF rats. In 8 week HRNF reach limb tissues, IL-1a, IL-1b, TNFa, and IL-10 increased in distal bones, IL-1a and -b in muscles, and TNFa in tendons. Only IL-10 increased in LRNF reach limb muscles in week 8. Serum IL-1a and MIP2 correlated with macrophages in LRNF loose connective tissues, serum MIP3a and MIP2 correlated negatively with grip strength, while serum TNFa, MIP3a, and MIP2 correlated positively with total number of reaches. Thus, several tissue and circulating cytokines/chemokines increase in an exposure dependent manner following short-term performance of repetitive reaching tasks and correlate with macrophage infiltration and decreasing grip strength. Keywords: cytokines; chemokines; macrophages; repetitive motion injury; WMSD Repetitive motion injuries (RMI) of the wrist and hand are painful, potentially disabling, and costly. Recent work suggests that RMIs induce injury in several tissue types in animal models, 1-6 as well as an early inflammatory response at the tissue level. 2,3,[7][8][9] Increases in four circulating inflammatory mediators, C-reactive protein, interleukin 1 beta (IL-1b), IL-6, and tumor necrosis factor alpha (TNFa) have also been shown to increase in patients with upper extremity overuse disorders. 10 The factors triggering underlying pathophysiological responses are still under investigation, which impedes progress toward their primary and secondary prevention.Using a rat model, we have reported that repetitive reaching causes injury and wide-spread increases in macrophage influx into musculotendinous tissues and peripheral nerves, extraneural fibrosis, decreased nerve conduction, and decreased grip strength. [2][3][4]7,9 The macrophage response is associated with increased inflammatory cytokines in the median nerve, 9 and increased serum IL-1a following HRNF task performance. 2 A variety of inflammatory mediators including cytokines and chemokines are released by injured cells and infiltrating macrophages. 9,11 Although serum cytokine and chemokine response patterns to exercise of varying intensities 12-15 and multiple organ trauma and fractures have been studied, [16][17][18] exposure to more chronic, lower levels of injury are not yet well characterized.Here, we examine several cytokines and chemokines in forelimb musculoskeletal tissues and serum to identify their response profiles, as well as potential cellular sources, after the performance of a voluntary repetitive ...

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“…In the repetitive rat model, localized inflammation occurs immediately in bone and joint tissues and remains elevated for 5 or 12 weeks, depending on the level of inducing injury 27 . The inflammatory response was matched by exposure-dependent structural changes in the skeletal tissues, such as adaptive bone remodelling with performance of a low-force task but degradative bone and cartilage changes with a highforce task 27,28 . When ibuprofen treatment, at anti-inflammatory levels, was administered early during the inflammatory period, a reduction in inflammatory cytokines was observed in the loaded joint tissues 27 .…”

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“…Evidence of tissue injury was paralleled by inlammatory responses, such as increased pro-inlammatory cytokines in lexor digitorum muscles and tendons [30][31][32]39], and increased macrophages in the median nerve at the level of the wrist (Figure 3A, B). Elevated levels of key pro-inlammatory cytokines, IL-1beta, and TNF-alpha were also observed in serum of rats that had performed a HRHF task for 12 weeks (12-week HRHF rats) ( Figure 3D, E).…”

“…Those suggested maximum limits are indicated in Table 1. 4. An operant rat model of WMSD Several animal models have been developed to study WMSDs and have shown that repetitive hand activities induce sensorimotor dysfunction [27][28][29][30][31][32][33]. A model developed in our laboratory is a unique operant rat model of voluntary reaching and grasping (Figure 1; [7,34]).…”

“…A model developed in our laboratory is a unique operant rat model of voluntary reaching and grasping (Figure 1; [7,34]). Using this model, we are able to examine the efects of voluntary performance of repetitive low or high demand tasks on sensorimotor performance and musculoskeletal tissues [7,30,35]. This model is nonsurgical and involves performance of voluntary repetitive tasks to induce mechanical loading of forearm tissues.…”

“…Using this rat model, we have observed early exposure-dependent changes (duration and task level) in inlammatory responses in the form of increased macrophages and inlammatory cytokines in soft tissues involved in performing the repetitive task [7,30,32,35,36]. The greatest responses were observed in rats performing a high-repetition high-force (HRHF) task for 6-12 weeks, compared to lower demand tasks.…”