Inflammation and the pathophysiology of work-related musculoskeletal disorders

Viktig studie om betennelse og hvordan det påvirker muskler og annet vev i kroppen. Nevner gangen i prosessen: repetitiv muskelsammentrekning, økning i betennelsesfaktorer for å reprere, manglende restitusjon, økning i fibrøst vev (arrvev), kompresjon på nerver, myalgi, økt temperament, osv. Nevner også hvordan betennelser påvirker psyken; depresjon, nedsatt seksuallyst, tilbaketrekning, smerter, m.m. IL-6 gir utmattelse.

Den beskriver hvordan cytokiner sprøytet inn i mus gir «sickness behaviour» og hyperalgesi (økt smertesensitivitet). Studien her forholder seg mest til betennelser som følge av repetitive bevegelser, men dette utsagnet vil også tilsi at kosthold som øker pro-inflammatoriske cytokiner kan bidra til hyperalgesi.

Results from several clinical and experimental studies indicate that tissue microtraumas occur as a consequence of performing repetitive and/or forceful tasks, and that this mechanical tissue injury leads to local and perhaps even systemic inflammation, followed by fibrotic and structural tissue changes.

We also propose a conceptual framework suggesting the potential roles that inflammation may play in these disorders, and how inflammation may contribute to pain, motor dysfunction, and to puzzling psychological symptoms that are often characteristic of patients with work-related MSDs.

Several recent clinical and experimental studies have been published indicating that inflammation plays a role in the development of tissue pathologies associated with these chronic disorders.

The US Department of Labor defines work-related MSDs as injuries or disorders of the muscles, nerves, tendons, joints, cartilage, and spinal discs associated with exposure to risk factors in the workplace. MSDs include sprains, strains, tears, back pain, soreness, pain, carpal tunnel syndrome, musculoskeletal system, or connective tissue diseases and disorders, when the event or exposure leading to the injury or illness is bodily reaction/bending, climbing, crawling, reaching, twisting; overexertion; or repetition (Bureau of Labor Statistics, 2005). Several risk factors are associated with the development or exacerbation of MSDs in the workplace, including physical, biomechanical, individual predisposition, and psychosocial conditions.

Psychosocial risk factors in the workplace also contribute to MSDs. These factors are associated with levels of workplace stress, such as job content and demands, job control, and social support (National Research Council, 2001). Non-workplace factors may also contribute to the development and exacerbation of MSDs, such as similar physical or high stress levels in the home. Certain past or present medical conditions also represent comorbid risk factors for MSDs (National Research Council, 2001).

Examples include past traumatic injury to the affected body part, systemic diseases that affect the musculoskeletal system, and diseases/disorders of the circulatory system. Women appear more susceptible than men to the development of MSDs, although this is highly industry-dependent. Advanced age or obesity may increase the impact of other risk factors on the severity of MSDs (National Research Council, 2001).

Musculotendinous injuries resulting from performing repetitive and/or forceful tasks are due to repeated overstretch, compression, friction, ischemia, and overexertion. We hypothesize that these injuries lead initially to an inflammatory response (Fig. 1). While the ultimate outcome of inflammation is to replace or repair injured tissues with healthy, regenerated tissue, Copstead and Banadki, 2000, when continued task performance is superimposed upon injured and inflamed tissue a vicious cycle of injury, chronic or systemic inflammation, fibrosis, and perhaps even tissue breakdown may occur. The end result is often pain and loss of motor function.

Schematic diagram showing three primary pathways hypothesized to lead to work-related musculoskeletal disorders caused by repetitive and/or forceful hand-intensive tasks: CNS reorganization (reviewed in Barr et al., 2004), tissue injury, or tissue reorganization.

Hirata et al. (2005) divided patients into symptom duration groups (<3, 4-7, 8-12, and >12 months).

  • Edematous changes were found in these tissues in patients of ❤ month duration.
  • Prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) were increased in patients of 4-7 month symptom duration,
  • while fibrotic changes were present in patients of longer symptom duration (>7 months).

PGE2 is a factor believed to cause vasodilation, edema, and enhancement of cytokines that induce synoviocyte proliferation, while VEGF is associated with endothelial and vascular smooth muscle cell proliferation during chronic inflammation. In Hirata’s study, both molecules peak in the intermediate phase (4-7 months) of CTS-induced tendosynovial changes and appear to contribute to tissue remodeling. Hirata postulates that since PGE2 is thought to regulate the production of several molecules, that it may regulate VEGF production in tenosynovium.

The increase in IL-6 is interesting. IL-6 has both inflammatory and anti-inflammatory properties, the latter primarily to suppress low-grade inflammation (Biffl et al., 1996). IL-6 is a tightly regulated cytokine normally not detectable in serum unless there is trauma, infection, or cellular stress, at which time IL-6 is an early cytokine responder. Pro-inflammatory effects of IL-6 include induction of cell growth and proliferation, and acute-phase responses, while its anti-inflammatory actions include inducing increases in serum IL-1 receptor antagonist and soluble TNF receptor (Biffl et al., 1996).

Trapezius muscle biopsies from male and female workers with either continuous or intermittent trapezius myalgia of at least 12 months duration show evidence of myopathic changes such as moth eaten and ragged, red type I muscle fibers, increased frequency of type II myofibers and atrophic myofibers consistent with muscle injury, and denervation/ischemic loss of muscle fibers, but no evidence of inflammation (Larsson et al., 2001). In contrast, Dennet and Fry (1988) examining the first dorsal interosseous muscle collected from 29 patients with painful chronic overuse syndrome found increased inflammatory cells as well as myopathic changes.

The first study, by Freeland et al. (2002) detected increased serum malondialdehyde, an indicator of cell stress, in patients with carpal tunnel syndrome, but no serum increases in PGE2, IL-1, or IL-6.

A recent study by Kuiper et al. (2005), examined serum for biomarkers of collagen synthesis and degradation (but not for biomarkers of injury or inflammation) in construction workers involved in heavy manual materials handling. Both collagen synthesis and degradation products were increased in workers involved in heavy manual tasks, although the overall ratio of synthesis to degradation products remained the same as in sedentary workers. Kuiper’s results suggest that tissues undergo adaptive growth responses that protect them from unresolved degradation.

In the third study, elevated plasma fibrinogen were present in subjects with low job control, linking perceived job stress with a biomarker of chronic inflammation (Clays et al., 2005).

a recently submitted study from our lab found increased pro-inflammatory cytokines in serum of patients with moderate and severe work-related MSD.

Archambault et al. (1997) observed hypercellularity, inflammatory cells, increased inflammatory cytokines, and increased mRNA of matrix molecules in the tendon by 6-8 weeks. When the kicking protocol was prolonged to 11 weeks, the inflammatory responses were apparently resolved. Instead, matrix reorganization processes, such as increased mRNA for collagen type III and matrix metalloproteinases, were observed (Archambault et al., 2001). Thus, in the higher demand kicking task, inflammation and tissue pathology were simultaneously present, while in the lower demand kicking task, inflammation preceeded matrix reorganization which may be a beneficial adaptive reorganization since no necrosis was observed.

In a series of studies, they report evidence of inflammation and angiogenesis (hypercellularity; increased COX-2 and VEGF mRNA) after 4 weeks of running at a rate of 17 m/min on a decline, 1 h/day for 5 days/week. These changes persisted through 16 weeks. They also found tendon thickening and reduced biomechanical tissue tolerance, changes that increased with continued exposure. Thus, repetitive tendon overuse is associated with inflammation. The tendon tissue is unable to launch a successful healing response due to continued use, and becomes fibrotic and structurally damaged.

These dose-dependent findings are similar to our recently submitted human study in which a systemic inflammatory mediator/marker response was greater in patients with moderate and severe MSD compared to mild.

In MSD, the primary causes of peripheral nerve trauma are over-stretch and compression of neuronal tissues during excursion (reviewed in Barr et al., 2004).

Animal models of chronic nerve constriction injury using ligatures show that chronic compression leads to an upregulation of intraneural inflammatory cytokines, fibrosis, Schwann cell death, axonal demyelination, and declines in electrophysiological function.
In our rat model, we found decreased nerve conduction velocity (NCV) in the median nerve at the wrist. By week 10 in HRLF rats, there was a small (9%) but significant decrease in NCV (Clark et al., 2003), demonstrating that nerve injury accumulates with continued task performance and leads to a clinically relevant loss of nerve function.

The association of motor behavioral changes with tissue changes in both our and Messner’s studies indicates that functional declines accompany tissue injury, inflammation and fibrosis/degeneration.

The psychoneuroimmunological effects of pro-inflammatory cytokines, specifically IL-1β, TNF-α, and IL-6, have been extensively studied in humans and in animal models over the past decade for their contribution to a constellation of physiological and behavioral responses known collectively as the “sickness behaviors”. This response includes fever, weakness, listlessness, hyperalgesia, allodynia, decreased social interaction and exploration, somnolence, decreased sexual activity, and decreased food and water intake (amply reviewed by Capuron and Dantzer, 2003Wieseler-Frank et al., 2005). Sickness behaviors can be induced by administration of exogenous cytokines to animals, whether the cytokines were injected peripherally or centrally. One mechanism of action, the immune-to-brain communication through activation of brain and spinal cord glial cells was reviewed by Wieseler-Frank et al. (2005). Activation of CNS glia and subsequent production of inflammatory cytokines can lead to hyperalgesia.

Cohen et al. (1997) have also speculated that the elevation of serum IL-6 produces fatigue, which then may be responsible for decreases in an individual’s ability to perform functionally. The possibility for patients with chronic inflammatory conditions to succumb to the depressive effects of local and systemic pro-inflammatory cytokines has implications in the management of overuse MSDs.

Symptoms of depression, anxiety, heightened job stress, more anger with their employer, higher pain ratings, greater reactivity to pain, enhanced feelings of being overwhelmed by pain, and low confidence in problem solving abilities have been reported in numerous epidemiological and clinical studies of patients with MSDs (Clays et al., 2005Gold et al., 2006Shaw et al., 2002).

We hypothesize that performance of repetitive and/or forceful tasks may induce MSDs through three primary pathways: (1) CNS reorganization, (2) tissue injury, and (3) tissue reorganization.

The extent of these changes is dependent on task exposure (duration and level). A systemic response may be stimulated by cytokines released into the blood stream by injured tissues and immune cells. Circulating cytokines can stimulate global responses such as widespread increase in macrophages, local and distant tissue sensitization, and perhaps the induction of sickness behaviors, depression or anxiety, as may cytokine elevation in peripheral nerve tissues.

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