Evaluation of immunomodulatory mediators in chronic obstructive pulmonary disease and cardiovascular disease
Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are among the leading causes of mortality and poor health burden in the world. Both COPD and CVD often co-exist, due to shared risk factors and common pathophysiological pathways. There is an unmet need for effective therapeutics in COPD, given that there has been a paucity of therapeutic progress over the last decades and currently very few therapeutics have been proven to improve survival in COPD. To this end, addressing cardiovascular risk and evaluating cardiovascular therapeutics in people with COPD is an attractive prospect to reduce mortality and morbidity in this patient group. Furthermore, there is an urgent need to improve understanding of immunomodulatory mediators that may have potential as therapeutics targets in both COPD and CVD, and thus health outcomes in COPD and CVD. This thesis evaluated two distinct immunomodulatory pathways, which are of interest therapeutically in both COPD and CVD. Firstly, the Interleukin-33 (IL-33)/ST2 axis and secondly, specialised pro-resolving mediators (SPMs), specifically the specialised pro-resolving mediator Resolvin D1. Additionally, data pertaining to the anti-platelet drug aspirin in people with COPD was evaluated. The reason for this was to evaluate if aspirin may have therapeutic benefit in COPD. Given aspirin’s mechanism of actions not only as an anti-inflammatory anti-platelet therapeutics but also possible enhancement of endogenous production of specialised resolution mediators, it is helpful to evaluate patient level data relating to aspirin use and outcomes. Firstly, a systematic review and meta-analysis of published human studies of the IL-33/ST2 axis across the spectrum of human cardiovascular disease was undertaken. The role of IL-33 in CVD is unclear with both ameliorative and harmful effects reported, and circulating ST2 is a biomarker in CVD. The review included 77 studies and 62075 participants. The main findings were that incremental increases in circulating ST2 levels were associated with increased risk of all-cause mortality and cardiovascular events in populations with cardiovascular disease. IL-33 levels were found to be lower in heart failure, coronary artery disease and acute coronary syndrome patient groups, compared to controls, with the opposite being observed in stroke patients. The results of this analysis have been published in PLOS One. Secondly, levels of immunomodulatory mediators were measured in serum samples COPD patients and controls, specifically the specialised pro-resolving mediator Resolvin D1. Specialised pro-resolving mediators (SPMs) are metabolites of polyunsaturated fatty acids and are responsible for resolution after acute inflammatory events. There are several families of SPMs, including lipoxins, protectins, maresins and resolvins which are derived from different polyunsaturated fatty acids and are released at different times during the course of inflammation resolution. Of these SPM families, Resolvin D1 has been most extensively investigated in COPD pathogenesis and is thought to be dysregulated in COPD. Resolvin D1 levels were measured using enzyme linked immunosorbent assays in serum samples from 86 stable COPD patients, 140 COPD patients with recorded exacerbations at baseline and 146 healthy controls, to evaluate the differences in circulating levels between the groups. Resolvin D1 levels were significantly lower in stable COPD patients compared with COPD patients with exacerbations at baseline, which suggests potentially dysregulated resolution pathways in COPD. The finding that samples from patients who had reported acute exacerbations at baseline had higher Resolvin D1 levels than in stable COPD patients suggests that it plays an essential role in the natural resolution of inflammation in COPD. Lastly, aspirin use has in some observational studies showed encouraging data that it was associated with reduced exacerbation rates. Therefore, work was undertaken to evaluate aspirin use at baseline for its association with health outcomes in COPD populations, in a comprehensive statistical analysis of two large high quality clinical trial datasets (SUMMIT trial n=16485, IMPACT trial n=10355), which included patients with both moderate (SUMMIT) and severe COPD (IMPACT) respectively, and those with a history/risk of cardiovascular disease (SUMMIT). The patient level data from both trials were obtained and patient level analysis performed. The analysis showed that aspirin use was associated with increased risk of mortality [SUMMIT hazard ratio 1.15 (1.00-1.33), p=0.048] fully adjusted for known and possible confounders, exacerbations and cardiovascular events (including myocardial infarction and stroke) over follow up of 52 weeks (IMPACT) and median 1.8 years (SUMMIT) respectively. In summary, the IL-33 has potential as a therapeutic target and biomarker across the range of human cardiovascular disease although further studies with larger sample sizes are needed. Whilst IL-33 levels were lower in patients than in controls for several cardiovascular diseases, further investigation is needed to explain the contradictory findings in stroke patients. Resolvin D1 is dysregulated in stable COPD patients and has potential in future treatment regimens. The results of the Resolvin D1 study led to an ongoing clinical study which measures changes in patient Resolvin D1 levels over time, following a COPD exacerbation. While previous observational studies had suggested aspirin use was associated with reduced mortality risk and exacerbations in COPD patients, the findings of this extensive analysis suggest that aspirin use is associated with increased mortality risk and exacerbations, and should not presently be indicated for treating COPD patients. Future work would include assessing IL-33 and ST2 receptor expression in tissue samples from CVD patients which could identify any disruptions to this pathway. Additionally, levels of SPMs including resolvins need to be measured in COPD patients at set time points after an exacerbation, to identify changes in the trajectory of SPM levels. Finally, a randomised control trial of aspirin in COPD patients would be useful to evaluate the effect of aspirin use on patient exacerbations and all-cause mortality.
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