In community-dwelling older persons, randomly selected from the general population, we found a positive and significant association between UA and inflammatory markers, such as WBC, neutrophil count, C-reactive protein, IL-6, IL-1ra, IL-18, and TNF-α. These associations were independent of multiple potential confounders, and in most cases remained statistically significant after restricting the analysis to subjects within the normal UA levels. Moreover, across the UA quintiles, we found a progressive increase in the percentage of subjects with abnormally high levels of IL-6 and CRP, which are considered solid markers of inflammation in clinical practice. These findings suggest that the relationship between UA and inflammatory markers is linear across the entire range of UA and that such a relationship may be clinically relevant even in subjects with UA within the normal range. However, the nature of such a relationship remains unknown.
Although several studies have found that higher UA is an independent risk factor for CVD and mortality in subjects with cardiovascular risk profile and a negative prognostic factor for survival in heart failure patients, it is still controversial whether high UA is a compensatory attempt to counteract increased oxidative stress, an independent cause of CVD, or just a condition associated with other well-established risk factors such as hypertension, diabetes, and an accelerated clinical evolution of the disease.13–17
Allopurinol, a xanthine oxidase (XO) inhibitor, has been shown to improve contractile capacity and myocardial efficiency both in CHF patients and in experimental models.36–41
Furthermore, in post-myocardial infarction primary angioplasty and aorto-coronary bypass surgery, allopurinol reduced the oxidative damage related to reperfusion and increased immediate and late left ventricular contractility.42,43
It has been suggested that these beneficial effects of allopurinol are mediated by XO inhibition or radical scavenger properties or both. However, an additional protective contribution due to the UA reduction may not be excluded.
Some authors suggested that high UA levels may promote the development and the progression of arteriolosclerosis,26
or hypertensive organ damage,45
perhaps by exerting a deleterious effect on endothelial function.10
Recently, an intrinsic negative effect of UA on the arterial wall has been demonstrated in hyperuricemic subjects,46
but this finding was not confirmed in healthy and relatively young subjects exposed to UA infusion.47
However, building on the finding that excess mortality risk attributable to UA is particularly evident in women,9,16,48
and subjects with pre-existing CVD,51,52
and considering that immunosenescence is less pronounced in women than in men53
and that aging and CVD are both characterized by a proinflammatory state,19,54,55
we imply that UA may contribute to mortality through proinflammatory mechanisms. Indeed, a significant association between high UA levels and inflammatory markers has been demonstrated in subjects affected by heart failure.22,23
By demonstrating a positive association between UA and several pro-inflammatory markers our study adds to this evidence. Interestingly, the association between UA and inflammation was found in large sample representative of the general population and was not limited to subjects with hyperuricemia. Actually, a significant linear trend was also detected within the UA ‘normal range’. These findings suggest that UA is not only a marker of catabolic rate but also might be actively involved in systemic inflammation, which is an important component of the causal pathway leading to hypertension, vascular diseases, and renal failure.10
Given the epidemiological nature of our observations, whether UA is a marker of pro-inflammatory state or causes inflammation ‘per se
’ remains uncertain. However, considerable pre-clinical data support the latter hypothesis. Soluble UA activates the proliferation of rat vascular smooth muscle cells, stimulates the pro-inflammatory response and up-regulates the cyclo-oxygenase-2 activity and vascular C-reactive protein.10,25,56
Human mononuclear cells exposed to UA increase their production of IL-1β, IL-6, and TNF-α,10
whereas neutrophils release proinflammatory proteins.57
Overall, these findings support the idea that UA may negatively impact the health status, perhaps by activating a complex vicious cycle involving inflammatory and oxidative related mechanisms. Briefly, in inflammatory related diseases chronic hypoxia causes cellular damage that upregulates the XO enzyme, leading to parallel increase of UA and free radicals production,58
resulting into endothelial dysfunction.59
Cytokines (TNF-α, IL-1, and IFN-γ) may increase the UA production through the enhancement of XO activity, the ROS-mediated cell damage,60
and the promotion of apoptosis.61
In support to this hypothesis, UA released from cytoplasm into local tissue microenvironments may boost the proinflammatory immune responses, even when its concentration is within normal physiological limits.24
The pathogenetic relevance of this vicious cycle in the clinical evolution of CVD is likely to be particularly important in the presence of predisposing conditions, such as old age or high burden of comorbidity.
The main strength of this study is that the InCHIANTI project is especially suited to address the association between UA levels and multiple cytokines, because they were systematically measured in all participants, together with information about major confounders.
Potential limitations of the study should be considered as well. First, because of the cross-sectional nature of our data, a casual pathway from UA to inflammation is suggested but not definitively proven by our findings. Indeed, a possible mechanism of reverse causality is supported by some pre-clinical data and may account for the UA–inflammation–UA vicious cycle described previously.60
In addition, we could only measure circulating UA, which is only a weak reflection of tissue deposits.
In spite of this limitation, our findings may have significant clinical and speculative implications. The increased level of inflammatory markers as well the progressively higher percentage of subjects with abnormally elevated inflammatory markers across the UA levels suggest that UA might contribute to the proinflammatory state that characterizes many chronic diseases typical in old age. This hypothesis would have to be tested in future clinical studies.