The present report describes the results of the first study that addresses the temporal relationships between local chemical mediators of inflammation and resolution in patients undergoing AAA repair. We focused on both lipid- and peptide-derived chemical mediators of interest and their relationship to well-appreciated pro-inflammatory mediators, including vasoactive eicosanoids and cytokines important to tissue repair [see and refs. 8
AAA is a relatively frequent disease (approximately 10 per 100,000 persons/year) [20
]. The most appropriate treatment of this disease is surgical repair. The overall post-operative mortality is between 3% and 7% [21
]. The pathophysiological basis for the disease is quite complex and includes chronic inflammation [24
]. The relatively high rate of complication and mortality after this surgery results from many different factors including older age, multiple comorbidities, and medications that treat the comorbidities; but one of the many reasons for the high rate of complications and mortality is the severe inflammatory response to surgical intervention associated with ischemia-reperfusion injury, either to tissues subjected directly to temporary ischemia followed by reperfusion (all organs and tissues distal to the aortic clamp), and/or injury to distant organs (such as the lungs, kidneys, and others) initiated by activated neutrophils and pro-inflammatory mediators released by reoxygenated tissues [6
]. Along with and apparently in response to the release of pro-inflammatory mediators, the formation and release of anti-inflammatory cytokines and mediators is also increased. The latter eventually leads to the inflammatory process to subside and/or resolve. Since it is now apparent from results of in vivo
experiments with laboratory animals that resolution is an active process that involves the newly uncovered local mediators, namely lipoxins and resolvins [7
], excessive inflammatory responses may arise from the loss of endogenous resolution programs, and can lead to the progression of a chronic inflammatory state [2
]. The complete resolution of acute inflammation is critically important in preventing tissue injury, auto-immunity, chronic inflammation, and the return to homeostasis. The AAA patients studied here gave mediator profiles that grouped into two main profiles denoted as group A and B. The profile, magnitude, and relationship between the local mediators monitored herein based on their known potent bioactions () suggests that those in the group A profile fit a pro-inflammatory status throughout the time course and those in group B displayed a pro-resolving mediator profile. These two broad categories may reflect an early resolver population and a delayed resolver population since all patients in both groups recovered. Future translational metabolomic studies are needed to relate these pathways and bioactive mediators to individual patient outcomes (vide infra
Recently, with samples from humans, Wu et al
. reported that the time course of resolution of streptococcal glomerulonephritis is accompanied by increased levels of lipoxin A4
and decreases in leukotrienes in peripheral blood and urine as the infection resolves [31
]. Also, Gilroy et al.
found that low-dose aspirin increased 15-epi-lipoxin-A4
(the aspirin-triggered form of lipoxin A4
) in skin blisters in humans, reducing the neutrophil infiltration [33
]. The mechanisms for the aspirin-triggered lipoxins as well as resolvins shorten the resolution time in many experimental animal models and include their ability to counterregulate cytokine formation and actions [14
]. Along these lines, tumor necrosis factor-α, which is well appreciated as a cytokine in inflammation and infection, has also recently been shown to play a pivotal role in postoperative cognitive decline [35
]. Since resolvins, in particular RvE1 and RvD1, counterregulate TNF-α formation and actions, the levels of resolvins may be critical in preventing surgery-induced cognitive decline. Also, recently, aspirin-triggered lipoxin and RvE1 were found to modulate smooth muscle phenotype, which can correlate with the degree and magnitude of atherosclerosis [36
]. These findings suggest that the temporal biosynthesis of these mediators following surgery and particularly following AAA repair can have an acute local impact as well as initiate long-range responses in AAA patients that are relevant to long-term effects of surgical intervention and tissue remodeling. Since lipoxins and resolvins can regulate growth factor responses [37
], it is likely that the ability of an individual to generate a pro-resolving profile can have a long-range impact on the outcome of AAA surgery. These findings are also consistent with published literature on LXA4
inhibition of VEGF and stimulation of IL-10 [38
]. Thus, in view of the present results, in order to enhance the endogenous profile, it is important to consider the nutritional availability of essential fatty acids such as arachidonic acid that can be converted to local mediators including the lipoxins and aspirin-triggered lipoxins, as well as the omega-3 essential fatty acids DHA and EPA, which can be converted to resolvins and protectins. The nutritional status upon surgery and the circulating and tissue levels of these fatty acids can have a far-reaching impact on the response to surgical intervention.
In the present study, in addition to monitoring the anti-inflammatory and pro-resolving mediators such as lipoxin A4
, its relationship to the aspirin-triggered epimer was also obtained. Along these lines, it is of interest to point out that the production of lipoxin A4
was recently documented in peripheral blood of women during parturition [39
]. Thus, lipoxin A4
levels could increase in peripheral blood during pregnancy; however, it is unlikely that any of the patients undergoing the AAA repair procedure in the present study was pregnant. Hence, the lipoxin A4
levels monitored were more likely to reflect the status of the surgical patient to be able to mount an endogenous anti-inflammatory cascade. Two widely used drugs, aspirin and the statins such as lovastatin, increase the production of 15-epi-LXA4
], which has a potent pro-resolving and anti-inflammatory action. Thus, the profiles obtained for 15-epilipoxin A4
documented in the present patients may serve as new means to gauge the ability of the AAA patients to completely resolve and to initiate repair. Along these lines, Gilroy et al.
recently identified and defined early resolvers and delayed resolvers as two phenotypes that emerge in healthy subjects challenged in a controlled experimental setting with an inflammatory stimulus [33
]. In these healthy subjects on cantharidin-challenge and skin blister formation, lipoxin A4
and 15-epilipoxin A4
time course of formation within blister exudates defined the early and delayed resolver phenotypes. Also, DiGennaro et al
. recently demonstrated in human AAA patients increased expression of leukotriene C4
synthesis and cysteinyl-leukotriene production in tissue samples from these patients [42
]. Together, these recent reports and results from the present emphasize the potential value for monitoring lipoxygenase pathway products and their temporal metabolomics in human samples obtained on challenge in experimental settings and/or in surgery to assess future outcomes associated with excessive leukotriene production and inflammation versus
pro-resolving mediators (e.g.
, resolvin, protectin), resolution, and the return to homeostasis.
The inflammatory processes associated with surgical AAA repair are relatively well-established [6
]. The processes critical in the resolution of inflammation as it concerns AAA repair have not been studied earlier. Therefore, it is reasonable to hypothesize from the present results that the knowledge of these mediators () and resolution potential in these patients should help to better understand the nature of inflammation and its timely resolution, and to serve as a basis for rational and effective future therapeutics that would improve the outcome of this disease and surgery. In order to test such possibilities, information concerning the time course of changes in pro-, anti-inflammatory mediators, and pro-resolving mediators as well as their relationships was obtained. The results herein thus suggest that surgical patients that have undergone AAA fall into two main groups of temporal profile(s) for local chemical mediator(s): those with an essentially pro-inflammatory profile such as patients in group A or a potential resolving profile as those profiles obtained and noted for patients in group B. Whether these translational metabolomic profiles of local mediators in inflammation and resolution can be used to determine patient outcomes and/or pinpoint their response to surgery or progress to recovery remains for future studies. Nonetheless, the present results identify chemical mediators and metabolomic pathway markers that show temporal changes on surgery and recovery in AAA patients. They also establish the feasibility of using lipidomic metabolomic profiles to gauge initial responses to surgical interventions and their potential outcomes. Together, these results suggest that enhancing the patient profile of endogenous anti-inflammatory and pro-resolving mediators may shorten recovery times, resolution, and improve outcomes in these patients.