Oxidative stress induced by cigarette smoke components augments endogenous heme‐oxygenase‐1 levels in dendritic cells and promotes neutrophilic chemokine generation.

Abstract

Little is known about the role of dendritic cells [DCs] in emphysema, a disease characterized by prominent neutrophilic airway inflammation. We hypothesized that lung DCs participate in the pathogenesis of emphysema by producing chemotactic factors that recruit neutrophils to the lung. Cigarette smoke extract (CSE 0.5–2%) generated from 1RF4 Kentucky research cigarettes dose‐dependently induced interleukin‐8 [IL‐8] production from both immature and maturing DCs. Although relatively high nicotine concentrations induced IL‐8 production in vitro, nicotine concentrations equivalent to those obtained in CSE or in the blood of smokers failed to induce IL‐8 release from DCs. The antioxidant n‐acetyl cysteine [NAC] completely suppressed IL‐8 generation by CSE‐activated DCs. Using a cigarette smoking chamber, we observed that cigarette smoking enhanced the production of the murine IL‐8 homologs keratinocyte‐derived chemokine [KC] and macrophage inflammatory protein‐2 [MIP‐2] by both LPS and CD40‐matured lung DCs. In parallel to the observation that oxidative stress is important in smoking‐induced chemokine generation by DCs, we observed an increase in endogenous DC heme‐oxygenase‐1 [HO‐1] levels in human DCs activated by CSE and also in DCs harvested from mice exposed to cigarette smoke. Generation of IL‐8 by maturing DCs activated by CSE was abrogated when induction of cellular HO‐1 was inhibited by zinc protoporhyrin, suggesting that HO‐1‐dependent pathways are necessary for cigarette smoke‐induced IL‐8 production by DCs. These studies indicate a role for DCs in the pathogenesis of neutrophilic airway inflammation observed in smokers with emphysema. Funded by a Parker B Francis Fellowship grant and a Flight Attendant Medical Research Institute award to RV.