Redox balance in Cystic Fibrosis

Abstract

The homeostatic balance between oxidants and antioxidants in biological systems is known as redox balance, and is regulated by complex processes. Redox balance regulates many of the known cellular pathways and disease processes. The dysregulation of redox balance can lead to acute or long-term oxidative or reductive stresses that are associated with many of the abnormalities observed in cystic fibrosis (CF). Over the past 5 decades researchers have examined contributors to redox dysregulation, their molecular products, and their impact on ion transport, cell proliferation, inflammation, bacterial killing, and the metabolism of nucleic acids, proteins, and lipids in CF. CF patients exhibit elevated markers of oxidative stress when compared to non-CF healthy controls; however, whether the reported redox imbalance is sufficient to produce pathology has been controversial. In addition, comparisons between CF and non-CF disease controls have been lacking. To better understand the mechanisms which mediate the generation of oxidants and antioxidants in CF and the importance of their balance in effecting oxidative or reductive stress, we will review the determinants of redox balance in the blood, lumen, and cellular compartments. From the perspective of methodological application, we will focus on the approaches most often used to study oxidant and antioxidants in CF, including biochemical, proteomic, metabolomic, and lipidomic studies, with a discussion of the few transcriptomic analyses that predict changes in the expression of regulators of redox. Finally, we will discuss the utility of oxidants and antioxidants as biomarkers of disease and the use of antioxidant therapy in CF.

Importance of superoxide dismutases A and M for protection ofStaphylococcus aureusin the oxidative stressful environment of cystic fibrosis airways

“…The elevated expression of sodA , sodM , and other oxidative stress response genes in S. aureus located in CF airways compared with the housekeeping genes is most likely due to the presence of oxidative stress provoked by an antioxidants/oxidants imbalance (Ziady & Hansen, ) and the enormous accumulation of ROS‐generating PMNs (Konstan et al, ; Nordenfelt & Tapper, ) in the CF patients' lung. While the presence of oxidative stress can be proven by measuring the levels of the lipid peroxidation product and oxidative stress marker 8‐isoprostane (Antus, ), accumulation of PMNs can be detected by determining the concentration of the inflammatory host protein S100A8/A9, also termed “CF antigen,” which makes up to 40% of the cytoplasmic proteins in PMNs (Dorin et al, ; Roth et al, ).…”

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

“…Oxidative bursts are seen in many different organisms' response to bacterial infection [131][132][133][134], and high oxidative stress in cystic fibrosis patients has been well documented [135,136]. A correlation has been established between oxidative stress and strain diversity in P. aeruginosa [137].…”

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

“…Several other immune pathways have been reported to be dysregulated in individuals with CF. Among these pathways thought to be directly affected by a deficiency of CFTR are: decreased NO synthesis in the lower lung [39], altered STAT1 signaling that leads to NOS2 inactivation [40], an increased differentiation of T lymphocytes to the Th17 phenotype in CF patients [41], a decrease in efferocytosis [42], abnormal Nrf2 signaling that prevents proper anti-inflammatory and antioxidant responses [43], increased epithelial ER stress from a misfolded protein response [44], abnormal TLR5 responses [45], and increased MAPK and NFkB-dependent pathways [46]. Systemic and lung epithelial lining fluid glutathione deficiency has also been reported in CF [47,48], and is speculated to be due to the lack of CFTR-mediated GSH transport, although CFTR is poorly selective for glutathione [49].…”