The role of elastase as an inflammatory stimulus in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a debilitating disease that as of yet has no cure and therapy is limited to symptomatic relief. A major risk factor for the development of COPD is smoking, although the disease does have some component of genetic predisposition. In excess of £500 million funding per year is required to accommodate the needs of COPD patients and approximately 27, 000 deaths per year in the UK can be attributed to COPD. COPD is comprised of three conditions-chronic bronchitis, bronchiolitis and emphysema and these will be present in the COPD patient to varying degrees.

It is well accepted that COPD is a disease characterised by increases in inflammation and as such inflammatory stimuli, such as cigarette smoke and lipopolysaccharide (LPS) from bacterial cell walls, have been associated with disease development and progression. Consequently, there are associated increases in inflammatory cytokines such as TNF? in the COPD patient. Although inflammation plays a major role in the pathogenesis of COPD there are other factors to consider such as proteolytic damage caused by disturbances in the proteinase/anti-proteinase balance. This is of particular importance in emphysema where increases in neutrophil elastase concentration results in the destruction of elastin fibres which results in a decrease in lung function. Elastase is also known to contribute to the mucus hypersecretion associated with chronic bronchitis. The proteolytic actions of elastase are well characterised but there is gathering evidence to suggest that it may also be able to act as an inflammatory stimulus, thereby increasing its role in the pathogenesis of COPD.

This study has utilised a human lung explant model to investigate whether elastase can initiate an inflammatory response; concentrations of the pro-inflammatory cytokine TNF? and the anti-inflammatory cytokine IL-10 in the culture supernatant have been investigated as part of this. Data from this model (n=36) has shown that elastase can significantly increase both TNF? and IL-10 compared to control. Elastase stimulation, for 24hrs, caused the release of 30.1±8.0pg TNF?/mg tissue and 3.1±0.5pg IL-10/mg tissue. This response is comparable to that produced by LPS. We have also found that elastase can induce a Th2 type response from the parenchymal explants, with increases in IL-4, IL-5 and IL-13.

The inflammatory response detailed in this study appears to be unique to elastase and cannot be reproduced with other serine proteinases, such as trypsin and chymotrypsin, or a cysteine proteinase, papain. Our data has also shown that the proteolytic activity of elastase can be inhibited by an elastase-specific inhibitor, elastatinal, and by doing so attenuates the TNF? response; elastase stimulation alone produced 127.5±72.1pg/mg tissue, whereas with the inhibitor this production dropped to 40.4±9.0pg/mg tissue.

As of yet, the exact mechanism by which elastase induces inflammation is unknown but we have investigated the relationship between elastase and two candidate receptors-proteinase-activated receptor (PAR)-2 and Toll-like receptor (TLR)-4. Although elastase stimulation does not appear to alter the gross amount of these receptors present in the parenchyma, we have found that those patients with mild to moderate COPD tend to have greater levels of both PAR-2 and TLR-4. We have also utilised synthetic activating peptides for PAR-2 and in comparison to elastase stimulation it is suggested that elastase may cause its inflammatory and Th2 effects via distinct pathways.

More information

Identifiers

Catalogue record

Export record