Oxidants in Acute and Chronic Lung Disease

Abstract

Oxidants play an important role in homeostatic function, but excessive oxidant generation has an adverse effect on health. The manipulation of Reactive Oxygen Species (ROS) can have a beneficial effect on various lung pathologies. However indiscriminate uses of anti-oxidant strategies have not demonstrated any consistent benefit and may be harmful. Here we propose that nuanced strategies are needed to modulate the oxidant system to obtain a beneficial result in the lung diseases such as Acute Lung Injury (ALI) and Chronic Obstructive Pulmonary Disease (COPD). We identify novel areas of lung oxidant responses that may yield fruitful therapies in the future.

Keywords: Acute lung injury; Chronic obstructive pulmonary disease; Oxidant stress; Oxidative phosphorylation; Reactive oxygen species.

Figure 1. Biochemistry of ROS

The first step in the formation of ROS is the gain of an electron by oxygen to form superoxide (O₂·⁻⁾, a reaction that is catalyzed by NADPH oxidase. Further addition of electrons, mediated by manganese and copper superoxide dismutases (Mn-SOD, Cu-SOD), generates other forms of ROS such as hydrogen peroxide (H₂O₂). H₂O₂ is converted to hydroxyl radical (.OH) catalysed by Fe³⁺ and Cu²⁺. Antioxidant systems in the lung include the catalase system and the glutathione system both of which are complementary systems to reduce H₂O₂ to water. In the glutathione reaction reduced glutathione (GSH) is converted to glutathione disulfide (GSSG).

Figure 2. Major oxidant systems in the lung

The mitochondria are a major source of ROS in the cell. ROS are generated as electrons constantly escape from the oxidative phosphorylation (OXPHOS) transport chain to generate superoxide. In the cytoplasm the NADPH oxidase (Nox) complex is another important source of ROS. The Nox complex is cluster of proteins that donate an electron from NADPH to molecular oxygen (O₂) to produce superoxide (O₂·⁻). The Nox system consists of 2 membrane bound subunits, gp⁹¹ phox and p²² phox. On stimulation the membrane bound units associate with a complex of Rac1, p⁶⁷ phox, p⁴⁰ phox and p⁴⁷ phox, which then can transfer electrons from NADPH to oxygen to form the superoxide.

Figure 3. Concept of ROS hormesis

Hormesis postulates that low doses of ROS are beneficial and have a physiologic role while increasing doses (yellow line) will cause toxicity. This is in contrast to the traditional view that all levels of ROS (dotted line) will have a harmful effect.

Figure 4. HO system

Heme oxygenase (HO) is an enzyme that catalyzes the degradation of heme in the body to produce biliverdin, iron and the gas carbon monoxide (CO). Biliverdin is the subsequently converted to bilirubin by biliverdin reductase. HO^-1 is a critical lung defense mechanism against oxidative stress and inflammation.