Cystic Fibrosis-Related Oxidative Stress and Intestinal Lipid Disorders

Abstract

Significance: Cystic fibrosis (CF) is the most common lethal genetic disorder in the Caucasian people. It is due to the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of the chromosome 7, which encodes for CFTR protein. The latter, an adenosine triphosphate binding cassette, is a transmembrane chloride channel that is also involved in glutathione transport. As glutathione/glutathione disulfide constitutes the most important pool of cellular redox systems, CFTR defects could thus disrupt the intracellular redox balance. Resulting multisystemic diseases are essentially characterized by a chronic respiratory failure, a pancreatic insufficiency, an essential fatty acid deficiency (EFAD), and inadequate levels of antioxidant vitamins. Recent Advances: The pathophysiology of CF is complex; however, several mechanisms are proposed, including oxidative stress (OxS) whose implication is recognized and has been clearly demonstrated in CF airways. Critical Issues: Little is known about OxS intrinsic triggers and its own involvement in intestinal lipid disorders. Despite the regular administration of pancreatic supplements, high-fat high-calorie diets, and antioxidant fat-soluble vitamins, there is a persistence of steatorrhea, EFAD, and harmful OxS. Intriguingly, several trials with elevated doses of antioxidant vitamins have not yielded significant improvements. Future Directions: The main sources and self-maintenance of OxS in CF should be clarified to improve treatment of patients. Therefore, this review will discuss the potential sources and study the mechanisms of OxS in the intestine, known to develop various complications, and its involvement in intestinal lipid disorders in CF patients. Antioxid. Redox Signal. 22, 614-631.

Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D 3 administration

“…Decreased plasma amino acids concentrations in CF patients with an acute pulmonary exacerbation is likely multifactorial, and may occur due to a decreased total body amino acid pool with skeletal muscle wasting, decreased protein intake associated with acute illness, decreased intestinal absorption, and/or increased amino acid utilization (3,39) Our results are consistent with a previous report on amino acid concentrations in CF patients aged 16 to 39 years during a pulmonary exacerbation (40). The lower concentration of oxoproline may reflect the known defects in glutathione redox balance (41) or arginine metabolism in CF (40). The elevations in creatinine, creatine, and glucose are consistent with the catabolic response and insulin resistance that occurs during infection and pulmonary exacerbation in CF (42,43), or may reflect renal changes or other dysregulation of metabolism.…”

Novel antioxidant therapy with the immediate precursor to glutathione, γ-glutamylcysteine (GGC), ameliorates LPS-induced cellular stress in anin vitrocystic fibrosis model

“…Peroxidation of membrane lipids can disturb the assembly of cell membranes, which inevitably will impact membrane permeability. Intestinal malabsorption of fat soluble vitamins, a characteristic of CF, causes deficiency of the major lipid membrane antioxidant, vitamin E, leading to excessive lipid peroxidation [5]. Further impairment of the membrane integrity is evident by dislocation of epithelial tight junction protein ZO-1 from the membrane to the cytosol and to the nucleus in CF epithelial cells [31].…”

“…Release of bacterial toxins, mostly derived from the persistent Pseudomonas aeruginosa infection, further provokes an exaggerated neutrophilic inflammatory response that produces additional ROS [6]. The uncontrolled production of ROS can be detrimental through the promotion of aberrant cell signalling responses and the oxidative modification of biomolecules leading to lipid peroxidation, protein oxidation and dysfunction, and DNA strand-breaks, that together can promote loss of viability of lung epithelial cells [5]. Under normal physiological conditions, ROS generation is controlled by various adaptive cellular stress responses including the transient formation of cytoplasmic stress granules (SGs), activation of autophagy and alterations to mitochondrial function.…”

“…Under normal physiological conditions, ROS generation is controlled by various adaptive cellular stress responses including the transient formation of cytoplasmic stress granules (SGs), activation of autophagy and alterations to mitochondrial function. ROS generation is balanced by several antioxidant defence systems, which include enzymes such as superoxide dismutase (SOD), catalase, peroxiredoxins (Prx) and glutathione peroxidases (GPXs), which employ the major intracellular reducing agent glutathione (GSH) as a substrate to detoxify ROS [5]. However, CF patients are characterised by GSH deficiency [4] meaning they are exposed to a chronic burden of elevated ROS that cannot be effectively mitigated.…”

Effects of low glycemic index/high-fat, high-calorie diet compared to the high-fat, high-calorie diet on glycemic control, lipid profile, and inflammatory markers in children and adolescence with cystic fibrosis: A study protocol for a randomized double-blind controlled clinical trial

“…Individuals with CF develop a wide spectrum of complications, of which, exocrine pancreatic dysfunction is one of the most common manifestations, found in 85% of patients [4]. This type of dysfunction leads to fat malabsorption and in turn results in fat-soluble vitamin inadequacy, malnutrition, and growth failure [5,6]. CF-related diabetes (CFRD) is another hallmark of CF manifestations which directly linked to increased morbidity and mortality of CF [7].…”