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Subacromial “bursitis” is a significant source of shoulder pain in patients with rotator cuff tear. The nature of the inflammatory processes in the subacromial bursal tissue is controversial and incompletely investigated. Macroscopically, subacromial bursa of patients with rotator cuff dysfunction have thickened walls, tears, and are erythematous. Histological studies, however, showed predominantly fibrovascular tissue with an inconsistent degree of synovial hyperplasia, fibrosis, and, usually, minimal “inflammatory cell infiltrate”.1 To characterise the nature of the processes in the subacromial bursa of painful shoulders we aimed at determining which cytokines and which isoforms of nitric oxide synthases (NOSs) are expressed in patients with rotator cuff tear.
Cytokines have key roles in the induction and effector phases of all immune and inflammatory responses.2 Cytokines are also key molecules in soft tissue response to injury and wound healing.3-5 Nitric oxide, a free radical produced by NOSs, is another potent stimulator and mediator of biological processes, including immune and inflammatory responses, as well as wound healing6 and tendon healing.7 ,8
Seventeen patients with shoulder symptoms due to rotator cuff tear were included in the study (table 1). Subacromial bursal samples were collected at open surgery and total RNA was extracted from the tissue samples. The mRNA expression of interleukin 1β (IL1β), IL6, IL8, tumour necrosis factor (TNFα), and granulocyte macrophage colony stimulating factor (GM-CSF), as well as inducible, endothelial, and neuronal isoforms of nitric oxide synthase (iNOS, eNOS, and nNOS) were examined by semiquantitative reverse transcriptase-polymerase chain reaction. Densitometry readings were standardised against the housekeeping gene β-actin. Data were compared using Spearman rank order correlation test.
There was a consistent pattern of cytokine mRNA expression in the subacromial bursal samples. All 17 samples expressed IL6, IL8, and 15 out of 17 expressed GM-CSF as well, but there was no detectable mRNA expression for IL1β, and only in one sample for TNFα. Positive, significant correlations were found between IL6 and GM-CSF (rs =0.7, p<0.05), and IL6 and IL8 (rs =0.5, p<0.05), demonstrating a concomitant expression of these cytokines.
iNOS and eNOS mRNA expression was detected in all samples, while nNOS was found in five out of 17 samples (fig 1). Significant correlation was found between the mRNA expression of eNOS and IL8 (rs =0.7, p<0.05). This study was unable to detect correlations between the expression levels of cytokines or NOS isoforms and patient age, duration of symptoms, and shoulder pain scores.
In systemic immune response, proinflammatory cytokines tend to increase together. A temporal sequential expression of cytokines has been reported during wound healing. IL1 and TNF are expressed mainly in the early (inflammatory and proliferative) phase of wound healing,5 whereas IL6 levels are highest at a later (revascularisation) stage.4 Increase in IL6 and decrease in IL1 levels have been reported in cultured human tendon fibroblasts subjected to repetitive motion.3 It may be, therefore, that the pattern of cytokine expression, which we observed in the subacromial bursae, may reflect a dominance of reparative processes, or a response to altered mechanical stimuli rather than inflammatory or destructive processes.
In joint cartilage, production of NO has generally been implicated as a pathogenetic factor. However, increased local NO production seems to be essential for normal tissue healing.6 The expression of NOS isoforms in the subacromial bursa is a new finding and generates interesting questions.
The molecular events involved in the subacromial space are likely to be complex. Whether induction or inhibition of certain cytokines and NOS isoforms impairs or enhances the overall healing processes remains to be answered.
This study was supported in part by St George Private Hospital/Health Care of Australia and The St George Hospital/South Eastern Sydney Area Health Service.