EQUINE VETERINARY EDUCATION / AE / SEPTEMBER 2017


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Healthy a) b)


Subacute c)


Chronic


Fig 1: Typical microscopic appearance of healthy and diseased equine superficial digital flexor tendons. Longitudinal histology sections are stained with Haematoxylin and Eosin. a) The section from a 12-year-old horse with a healthy SDFT shows regular arrangement of parallel orientated collagen fibrils and clearly defined regions of interfasicular matrix (purple linear regions between pink stained collagen bundles). b) The section from a 12-year-old horse with subacute SDFT injury (3–6 weeks post injury) shows marked cellular infiltration, increased vascularity, areas of haemorrhage and marked disorganisation of the tendon extracullular matrix.


c) Chronic injured SDFT (>3 months post injury) from a 7-year-old horse shows increased cellularity and poor organisation of collagen fibrils compared with healthy tendon. Scale bar = 200 lm.


TABLE 1: Terminology used to describe inflammation pathways Term


Function


DAMP (damage associated molecular patterns)


PAMP (pathogen associated molecular patterns)


IFN activation pathway (interferon)


NFjB activation pathway (nuclear factor kappa-light- chain-enhancer of activated B cells)


STAT-6 pathway


Molecules that can initiate and perpetuate a noninfectious inflammatory immune response


Molecules that can initiate and perpetuate an infectious inflammatory immune response


Interferon signalling genes and proteins are released in response to inflammation. IFNc is the main pro-inflammatory cytokine associated with this activation pathway


A transcription factor involved in cellular stress responses and regulates immune responses to inflammation and infection. Lipopolysaccharide (LPS) is an example of a proinflammatory mediator acting via this pathway


STAT-6 pathways play a central role in exerting IL-13/IL-4 mediated biological responses involved in chronic inflammation and tissue repair


GCR pathway glucocorticoid receptor


Glucocorticoid receptor pathways influence monocyte adherence, phagocytosis and apoptosis in tissue repair


samples from patients who remained persistently painful 2– 4 years after surgical treatment compared with those whose symptoms had resolved. Notably, tendon samples from asymptomatic patients after treatment showed significantly increased expression of genes associated with tissue repair and resolving inflammation including CD206 and ALOX15 compared with persistently painful patients, suggesting these pathways may moderate tendon pain (Dakin et al. 2015).


Inflammation triggers resolution


Inflammation stimulates a series of events broadly termed ‘resolution’ that promote restoration of the damaged tissue to its normal state (Serhan et al. 1984, 2008; Serhan and Chiang 2002). Studies have shown that inflammation does not simply ‘fizzle out’ and that resolution is a highly orchestrated and active process that regulates the duration and magnitude of the inflammatory response. A repertoire of proresolving mediators are concerned with the timely resolution of inflammation to prevent prolonged or inappropriate tissue damage (Serhan and Chiang 2002, 2008). These ‘stop’ signals for inflammation include limiting further recruitment of inflammatory cells, promoting phagocytosis of apoptotic cells and facilitating egress of inflammatory cells from the injured site (Ortega-Gomez et al. 2013).


Mechanisms for sustaining chronic inflammation


proteins induced by STAT-6 and glucocorticoid receptor activation in advanced stage disease (Dakin et al. 2015). This transition in inflammation activation signature with established disease has striking parallels to tendinopathy in the equine SDFT (Dakin et al. 2012b). Little is known of how tendon inflammation signatures


change after treatment. To investigate this, shoulder tendon biopsies from human patients were studied to investigate if differences in inflammation pathways occurred between


Chronic inflammation is thought to develop due to dysregulated or inadequate resolution of inflammation (Gilroy et al. 2004; Lawrence and Gilroy 2007). Whilst resolution has been well characterised in experimental rodent models, it is not well studied in inflammatory musculoskeletal diseases. However, levels of the proresolving protein FPR2/ALX were found to be increased in samples of early stage equine tendinopathy compared with normal tendons (Dakin et al. 2012b). This observation is further supported in samples from diseased shoulder tendons in man, whereby increased expression of proresolving proteins occurred in early stage tendon disease (Dakin et al. 2015). Collectively, these studies suggest that diseased equine and human tendons mount a


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