Oxidant stress in asthma

Abstract

The inflammatory cells recruited to the asthmatic airways have an exceptional capability for producing ROS. Activated eosinophils, neutrophils, monocytes, and macrophages can generate superoxide (O₂ ^–) via the membrane associated NADPH-dependent complex. Subsequently, dismutation of O₂ ^– gives hydrogen peroxide (H₂O₂). O₂ ^– and H₂O₂ per se are moderate oxidants; however, both species are critical for the formation of potent cytotoxic radicals in biological systems through their interaction with other molecules. For example, hydroxyl radical (^•OH), a powerful and indiscriminate oxidant, can be produced from O₂ ^– and hypohalous acids (HOCl or HOBr). The latter component can be formed from H₂O₂ and a halide (Cl^– or Br^–) in a reaction catalysed by myeloperoxidase (MPO) provided by neutrophils and monocytes,1 or eosinophil peroxidase (EPO) from eosinophils.2 MPO preferably utilises Cl^– as a halide, whereas EPO uniquely prefers Br^–. Moreover, a recent study has shown that MPO and EPO can use nitrite (a major end product of nitric oxide (^•NO) metabolism) and H₂O₂ as substrates to promote formation of reactive nitrating intermediates.3 The oxidative injury caused by eosinophils can be substantial because the cells possess several times greater capacity to generate O₂ ^–and H₂O₂ than neutrophils,4 and the content of EPO in eosinophils is 2–4 times higher than the amount of MPO in neutrophils.5 Another example of a powerful oxidant and a nitrating radical is peroxynitrite (ONOO^–) produced from the reaction of O₂ ^– with^•NO.6This pathway may be involved in asthma because the concentration of ^•NO is increased in the asthmatic airways.7 In addition to the recruited inflammatory cells, the constitutive airway cells such as epithelial cells are also potential sources of ROS.8 Moreover, cells recovered from bronchoalveolar lavage (BAL) fluid and blood of asthmatic subjects have been shown to generate greater amounts of ROS at baseline and after stimulation ex vivo than in normal subjects, a feature which in some studies correlated with disease severity. This suggests that the biochemical milieu in asthma contains factors which prime oxidative pathways in vivo.9-14