Glucosamine attenuates cigarette smoke‐induced lung inflammation via its antioxidant function and by inhibiting ROS‐sensitive inflammatory signaling (869.12)

Abstract

Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox‐sensitive pathways. We have reported that cigarette smoke (CS) activates a NADPH oxidase‐dependent reactive oxygen species (ROS)‐sensitive AMP‐activated protein kinase (AMPK) signaling pathway leading to induction of lung inflammation. Glucosamine, a dietary supplement used to treat osteoarthritis, has antioxidant and anti‐inflammatory properties. However, whether glucosamine has similar beneficial effects against CS‐induced lung inflammation remains unclear. Using a murine model we show that chronic CS exposure for 4 weeks increased lung levels of 4‐hydroxynonenal (an oxidative stress biomarker), phospho‐AMPK, and macrophage inflammatory protein 2, and induced lung inflammation; all of these CS‐induced events were suppressed by chronic treatment with glucosamine. Using human bronchial epithelial cells (HBECs), we demonstrate that cigarette smoke extract (CSE) sequentially activated NADPH oxidase; increased intracellular levels of ROS; activated AMPK, mitogen‐activated protein kinases (MAPKs), nuclear factor‐κB (NF‐κB), and signal transducer and activator of transcription proteins 3 (STAT3); and induced interleukin‐8 (IL‐8). Additionally, using a ROS scavenger, a siRNA that targets AMPK, and various pharmacological inhibitors, we identified the signaling cascade that leads to induction of IL‐8 by CSE. All these CSE‐induced events were inhibited by glucosamine pretreatment. Our findings suggest a novel role for glucosamine in alleviating the oxidative stress and lung inflammation induced by chronic CS exposure in vivo and in suppressing the CSE‐induced IL‐8 in vitro via its antioxidant function and by inhibiting both ROS‐sensitive NADPH oxidase/AMPK/MAPK signaling pathway and the downstream transcriptional factors NF‐κB and STAT3.