Redox Control of Asthma: Molecular Mechanisms and Therapeutic Opportunities

Abstract

An imbalance in reducing and oxidizing (redox) systems favoring a more oxidative environment is present in asthma and linked to the pathophysiology of the defining symptoms and signs including airflow limitation, hyper-reactivity, and airway remodeling. High levels of hydrogen peroxide, nitric oxide ((*)NO), and 15-F(2t)-isoprostane in exhaled breath, and excessive oxidative protein products in lung epithelial lining fluid, peripheral blood, and urine provide abundant evidence for pathologic oxidizing processes in asthma. Parallel studies document loss of reducing potential by nonenzymatic and enzymatic antioxidants. The essential first line antioxidant enzymes superoxide dismutases (SOD) and catalase are reduced in asthma as compared to healthy individuals, with lowest levels in those patients with the most severe asthma. Loss of SOD and catalase activity is related to oxidative modifications of the enzymes, while other antioxidant gene polymorphisms are linked to susceptibility to develop asthma. Monitoring of exhaled (*)NO has entered clinical practice because it is useful to optimize asthma care, and a wide array of other biochemical oxidative and nitrative biomarkers are currently being evaluated for asthma monitoring and phenotyping. Novel therapeutic strategies that target correction of redox abnormalities show promise for the treatment of asthma.

Catalase C-262T Gene Variant in Patients with Bronchial Asthma

“…Experimental studies showed that catalase activity is up to 50% lower in bronchoalveolar lavage of asthmatic lungs compared to healthy controls, which is considered to be the result of protein oxidative modification and not the decreased amount of enzyme (1,8). Moreover, erythrocytes of the asthmatic children showed decreased catalase activity compared to healthy children (9).…”

“…Lungs are prone to damage caused by reactive oxygen species (ROS) due to the large surface that is directly exposed to high oxygen pressure and different irritants. Moreover, the lungs are exposed to microbes and the process of their elimination in order to keep airways sterile results in higher ROS production (1). High ROS levels, caused by increased ROS production or/and decreased antioxidant cellular capacity, results in oxidative stress which subsequently induces direct or indirect ROS-mediated damage of lipids, proteins and nucleic acids (2).…”

“…However, catalase may be released into the extracellular environment where it has the potential to function as antioxidant and regulator of cell survival (4). Catalase is especially active in the presence of high concentrations of H2O2, but in a prolonged oxidative stress its activity notably decreases due to the oxidation of NADP to NADP+ (1).…”

Нозоспецифічні Особливості Редокс-Процесів При Бронхіальній Астмі Та Хронічній Обструктивній Хворобі Легень

“…У больных с атопической формой БА в выдыхаемом воздухе идентифицируется концентрация NO в среднем в 3 раза выше, чем у здоровых людей. Повышенная генерация монооксида азота обусловлена активаци-ей транскрипции гена iNOS эпителиоцитов респи-раторного и усилением катаболического распада S-нитрозоглутатиона (GSNO) как пула хранения NO в легочной ткани [5]. GSNO является физио-логическим субстратом для глутатионзависимой формальдегид-дегидрогеназы (алкогольдегидро-геназы III класса), которая получила название GSNO-редуктазы (GSNOR).…”

“…Снижение активности каталазы не сопряжено с уменьшением молекулярного представительства данного фермента. По-видимому, снижение актив-ности каталазы обусловлено нарушением соотно-шения хлорирования и нитрования тирозиновых остатков протеина каталазы [5]. Интересно, что у больных БА процессы хлорирования в 20 раз актив-нее, чем нитрования тирозиновых остатков проте-инов.…”