Oxygen-Mediated Molecular Mechanisms Involved in Intestinal Ischemia and Reperfusion Injury

The gastrointestinal tract is affected by multiple ailments that manifest with similar chemical, subcellular, and cellular changes, such as those in intestinal ischemia-reperfusion injury (IRI). The main chemical changes that are described under IRI conditions include the depletion of oxygen available for normal metabolism and the abundant production and increase in intracellular and extracellular concentrations of hydrogen peroxide and other reactive oxygen species (ROS). The enzymes causing this accumulation are xanthine dehydrogenase turning into xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, and nitric oxide synthase. The cellular changes revolve around an oxygen-sensing system that is responsive to varying oxygen levels, which has Hypoxia-Inducible Factors (HIFs) at its base. HIFs are transcription factors, the intracellular concentrations of which significantly increase under hypoxic conditions. Upon activation, they alter the expression of gene sets to ensure appropriate cellular adjustment to the hypoxic and IRI environment. Despite the primary regulation of the system involving oxygen, it is interconnected with multiple other subcellular and cellular functions. Thus, it represents a linchpin control mechanism of cellular adaptation. The effect of HIF activation in intestinal cells aims at preserving the structural integrity of the intestinal lining. The effect in different subtypes of leucocytes aims at immune system activation to protect against previously luminally located and subsequently invading pathogens and toxins. All in all, the HIF system is an integral part of cellular and tissue compensation against intestinal IRI.