Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD

<p>Abstract</p> <p>Background</p> <p>Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium. We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis.</p> <p>Methods</p> <p>We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers.</p> <p>Results</p> <p>We observed that TGF-α was mainly shed by ADAM17 in PBECs from all groups. Interestingly, IL-8 production occurred independently from ADAM17 and TGF-α shedding, but was significantly inhibited by broad-spectrum metalloproteinase inhibitor TAPI-2. CSE did not induce ADAM17-dependent TGF-α shedding, while it slightly augmented the production of IL-8. This was accompanied by reduced endogenous inhibitor of metalloproteinase (TIMP)-3 levels, suggesting that CSE does not directly but rather indirectly alter activity of ADAM17 through the regulation of its endogenous inhibitor. Furthermore, whereas baseline TGF-α shedding was lower in COPD PBECs, the early release of IL-8 (likely due to its shedding) was higher in PBECs from COPD than healthy smokers. Importantly, this was accompanied by lower TIMP-2 levels in COPD PBECs, while baseline TIMP-3 levels were similar between groups.</p> <p>Conclusions</p> <p>Our data indicate that IL-8 secretion is regulated independently from ADAM17 activity and TGF-α shedding and that particularly its early release is differentially regulated in PBECs from COPD and healthy smokers. Since TIMP-2-sensitive metalloproteinases could potentially contribute to IL-8 release, these may be interesting targets to further investigate novel therapeutic strategies in COPD.</p

SHIP1 and the negative control of mast cell/basophil activation by supra-optimal antigen concentrations

IgE-mediated, antigen-triggered activation of mast cells and basophils often results in bell-shaped dose-response curves for the release of various pro-inflammatory mediators. The degree of suppression of mediator release observed following supra-optimal stimulation varies widely for different allergens as well as for different experimental agents that cause crosslinking of high-affinity IgE receptors (Fc?RI) on these cells. While the reasons for these differences have not yet been resolved it has become increasingly apparent that supra-optimal stimulation in many cases causes a shift in the balance of stimulatory and inhibitory signal transduction mechanisms arising from Fc?RI triggering. In particular, the lipid phosphatase SHIP1 has been shown to be centrally involved in explaining the bell-shaped phenomena in both mast cells and basophils in different species and appears to play a fundamental role in limiting the IgE responsiveness of these allergic effector cells. Elucidating the nature of this inhibitory signaling pathway may provide crucial knowledge in order to optimize desensitization strategies in the treatment of allergic diseases

Hamstring injury prevention and implementation

Currently, effective hamstring injury prevention is primarily based on exercise strategies. The FIFA 11+ is a general strength and conditioning programme that has been shown to reduce injuries in football, including hamstring injuries. Many hamstring injury prevention studies have shown that eccentric hamstring strength training can reduce the risk of sustaining a hamstring injury, with a particular emphasis in the literature on the Nordic hamstring exercise. However, exercise-based prevention can only be effective when adhered to. Meticulous planning, a gradual increase of eccentric training loads for each individual athlete and stimulating adherence through knowledge transfer are key components to make hamstring injury prevention work in a practical setting. So far, evidence from studies that have investigated stretching and plyometric interventions indicate that these interventions do not seem to be effective at reducing hamstring injuries. Research on other types of preventive strategies, such as running drills, core stability training and sports-specific training, is currently insufficient, and the value of these approaches in hamstring injury prevention remains unclear. This chapter aims to provide a detailed understanding of the available evidence for hamstring injury prevention and the practical considerations around implementing these prevention strategies