The Effect of Cigarette Smoke-derived Oxidants on the Inflammatory Response of the Lung

Abstract

The inhalation of cigarette smoke triggers a marked cellular influx in the lung and this inflammation is believed to play a central role in the development of smoke-related lung diseases such as asthma and COPD. Studies demonstrate that smoke-derived oxidants are a major factor in this inflammatory reaction to cigarette smoke. These oxidants can overwhelm the lung's antioxidant defenses and they can up regulate inflammation by a number of mechanisms. Free radicals directly stimulate the production of chemotactic compounds such as 8-isoprostane. In addition, smoke-derived oxidants can activate several intracellular signaling cascades including NF-κB, MAPK and AP-1. This transcriptional activation induces the expression of cytokines and intracellular adhesion molecules that facilitates the trafficking of neutrophils, macrophages and lymphocytes into the lung. Moreover, oxidants can promote chromatin remodeling that facilitates the expression of proinflammatory genes by stimulating the acetylation of histone residues in the nucleosome. This leads to conformational changes that enhance expression by rendering the gene more accessible to binding to transcriptional factors. Thus, the oxidant-antioxidant imbalance generated by cigarette smoke can promote inflammation which is critical to the functional decline that occurs in both asthma and COPD patients. Future research is needed to better define the effects of smoke-derived oxidants on lung inflammation and to determine the most efficacious strategies for generating significant antioxidant protection in the lung.

Keywords: Asthma; Emphysema; Induction; Inflammation; Regulation; Transcription.

Figure 1. The Effect of Smoke-derived Oxidants on MAPK Signaling

Oxidants present in cigarette smoke can induce the dimerization of the EGF receptor [arrow]. This stimulates the phosphorylation and activation of Ras, Raf and MEKK. MEKK phosphorylates and activates MAPK proteins. Oxidants can maintain MAPK proteins in their activated state by inactivating MKPs [blocked arrow]. The stimulate MAPK proteins can activate c-Jun and promote AP-1 signaling as well as acting on numerous other transcriptional factors. This leads to the induction of genes that promote the influx of inflammatory cells in the lung.

Figure 2. The Effect of Smoke-derived Oxidants on NF-κB Signaling

Reactive oxygen species in cigarette smoke activate IKK while inactivating IκB Phosphatase. This has the effect of phosphorylating IκB and targeting it for proteasomal degradation. In addition, smoke-derived oxidants stimulate PTK which then phosphorylates p65 and enhances its binding to DNA. NF-κB signaling increases the expression of numerous proinflammatory genes.