18 characteristic examples of inflammatory biomarkers in IBD, but as alluded to earlier, they are clinically deemed insufficient and carry their own limitations. In recent years, new, innovative and highly-sensitive techniques such as electrochemiluminescence (ECL) detection, inductively coupled plasma mass-spectrometry (ICP-MS) and high-throughput proximity extension assay (PEA) technology have become available and further optimized, enabling us to quantify the concentrations of circulating biomarkers in a highly sensitive, validated and efficient manner. Using these techniques, we have evaluated the utility of inflammatory biomarkers (cytokines, chemokines, markers for angiogenesis and vascular injury), and intestinal permeability (52Cr-EDTA, a non-radioactive, orally administered tracer for intestinal permeability) in relation to intestinal inflammatory disease activity in patients with IBD. Inflammatory biomarkers, or combinations thereof, may confer predictive value in relation to disease activity, in a similar way as CRP or FCal are used nowadays. Similarly, intestinal permeability may also be a potential biomarker for disease progression.33 Numerous intestinal permeability biomarkers have previously been studied, including orally administered tracers such as 51Cr-labeled ethylenediaminetetraacetic acid (51CrEDTA). However, the role of the latter radioactive tracer is not yet entirely clear as relatively small and heterogeneous cohorts of patients with IBD were used for evaluation.34-36 Recently, a new alternative tracer was developed, in which the 52Cr stable isotope was incorporated to create 52CrEDTA. Oxidative stress is another key pathophysiological process in IBD and is defined as an imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of physiological redox signalling.37 Oxidative stress is associated with reduced levels of serum free thiols (R-SH) since these compounds are rapidly oxidized by reactive oxygen species (ROS). Although the role of R-SH compounds had already been evaluated in a number of oxidative stress-mediated diseases38-40, their role in IBD was not yet thoroughly investigated. Therefore, this biomarker became of special interest, since oxidative stress may be a key therapeutic target in IBD, and related biomarkers may serve to reflect disease activity or therapeutic efficacy. Considering intestinal oxygen handling, the hypoxia-inducible factor (HIF) pathway may also be of particular interest, since it is a key player in intestinal homeostasis by modulating intestinal barrier and immune function.41,42 Under physiological circumstances, the intestinal mucosa is characterized by an oxygen gradient along the crypt-villus axis, with higher levels of oxygen towards the mucosa and lower levels towards the predominantly anaerobic intestinal lumen.43 In inflamed circumstances, this physiological hypoxia becomes more extensive and severe, culminating in pathophysiological hypoxia.44 To restore this pathophysiological state, HIF becomes transcriptionally active, and activates a number of target genes that counteract the resultant hypoxic state or oxidative stress.41 Activation of HIF also influences systemic and cellular iron homeostasis, and iron itself has a direct impact on regulating the transcriptional activity of HIF. As patients with IBD frequently suffer from impaired iron homeostasis, leading to iron deficiency and anaemia, it would be highly interesting to examine the interplay between iron and HIF pathway activation. Moreover, this could have potential clinical implications, as the HIF pathway is a potential therapeutic target to improve patients’ responsiveness to iron supplementation and decrease intestinal inflammation. Chapter 1
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