Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets

Abstract

Asthma is a complex inflammatory disease characterized by airway inflammation and hyperresponsiveness. The mechanisms associated with the development and progression of asthma have been widely studied in multiple populations and animal models, and these have revealed involvement of various cell types and activation of intracellular signaling pathways that result in activation of inflammatory genes. Significant contributions of Toll-like-receptors (TLRs) and transcription factors such as NF-кB, have been reported as major contributors to inflammatory pathways. These have also recently been associated with mechanisms of oxidative biology. This is of important clinical significance as the observed inefficacy of current available treatments for severe asthma is widely attributed to oxidative stress. Therefore, targeting oxidizing molecules in conjunction with inflammatory mediators and transcription factors may present a novel therapeutic strategy for asthma. In this review, we summarize TLRs and NF-кB pathways in the context of exacerbation of asthma pathogenesis and oxidative biology, and we discuss the potential use of polyphenolic flavonoid compounds, known to target these pathways and possess antioxidant activity, as potential therapeutic agents for asthma.

Keywords: Asthma; Inflammation; NF-кB; Oxidative stress; Polyphenolic flavonoid compounds; Toll-like receptors.

Figure 1. Schematic of TLR signaling pathways

TLRs differentially recruit specific sets of TIR domain-containing adaptor molecules like MyD88, TRIF, TIRAP/MAL, or TRAM. The MyD88-dependent pathway is utilized by all TLRs except TLR3, where TLR1-2 dimers, TLR2-6 dimers, or TLR5 and TLR4 self-dimerization lead to the activation of NF-κB and MAPKs for the induction of inflammatory cytokine genes. TLR3 utilizes TRIF adapter molecules and leads to the activation of IRF3, NF-κB, and MAPKs for induction of type I IFNs and inflammatory cytokine genes.

Figure 2. Schematic of oxidative stress induced lung inflammation and role of IL-6 signaling pathways in conjunction with TLRs and NF-κB

Oxidative stress leads to the generation of lipid peroxidation products, ROS, free radicals in lung cell types. These oxidants can further mediate activation of downstream biochemical events including increased and altered TLR expression and activation in response to allergens. Oxidants and oxidative stress also impart direct effect on NF-κB as well as on the molecules of NF-κB pathway leading to the production of inflammatory factors and lung damage. (Adapted and modified from (Mishra, et al., 2016)).