Role of oxidative stress & transient receptor potential in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) affect millions of people worldwide and is known to be one of the leading causes of death. The highly sensitive airways protect themselves from irritants by cough and sneeze which propel endogenous and exogenous substances to minimize airway noxious effects. One noxious effect of these substances is activation of peripheral sensory nerve endings of nociceptor neurons innervating these airways lining thus transmitting dangerous signals from the environment to the central nervous system (CNS). Nociceptor neurons include transient receptor potential (TRP) ion channels, especially the vanilloid and ankyrin subfamilies, TRPV1/A1 which can be activated by noxious chemical challenges in models of airways disease. As oxidative stress may activate airways sensory neurons and contribute to COPD exacerbations we sought to review the role that TRP channel activation by oxidative signals may have on airway responses. i0 t would be prudent to target the TRP channels with antagonists and lower systemic oxidative stress with agents that can modulate TRP expression and boost the endogenous levels of antioxidants for treatment and management of COPD.

Fig. 1

Cigarette smoke is a complex mixture of thousands of chemical compounds including free radicles and oxidants. Cigarette smoke activates alveolar and bronchial epithelial cells (1) to elicit inflammatory responses leading to the release of cytokines and recruitment of neutrophils. Endogenous oxidants (2) and proteases (3) are generated from neutrophils and other phagocytic cells (macrophages) (4) increasing the oxidative burden in the lung. The lung has an efficient antioxidant (5) and anti-protease systems (6). The balance between the oxidants and the anti- oxidants is deranged by the exogenously and endogenously produced oxidants by the cigarette smoke leading to oxidative stress (7). Oxidative stress also contributes to mucus hypersecretion (8), apoptosis (9) and inflammation (10).

Fig. 2

(A). A typical TRP channel containing six conserved transmembrane segments (TM1 to TM6) with a pore-forming reentrant loop between TM5 and TM6. TM1 carrying 6 ARDs (Ankyrin repeat domains); (B). the TRP pore structure formed of four subunits, each with six highly putative transmembrane helices. The pore contains a selectivity filter, which dictates through its stereochemical and electrostatic properties what kind of molecules are allowed through the pore.

Fig. 3

A simplified schematic diagram illustrating mechanisms and cell types with transient receptor potential (TRP) expression which are thought to be involved in the pathogenesis of COPD. Inhaled exogenous pollutants enter lungs causing oxidative/nitrative stress, resulting in activation of various cell types alongwith TRP expression. ROS reactive oxygen species; ↑ increase; ↓ decrease; OH∙ hydroxyl radical; H₂O₂ hydrogen peroxide; TGF-β, transforming growth factor- β; ECM, extra cellular matrix; TRPCs, transient receptor potential canonical.