Glucosamine attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling.
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, 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 by inhibiting both the ROS-sensitive NADPH oxidase/AMPK/MAPK signaling pathway and the downstream transcriptional factors NF-κB and STAT3.
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Yuh-Lin
YL
Wu
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
An-Hsuan
AH
Lin
Division of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan; Department of Cosmetic Applications and Management, Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
Chao-Hung
CH
Chen
Division of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan; Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Wen-Chien
WC
Huang
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Hsin-Yi
HY
Wang
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Meng-Han
MH
Liu
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: tslee@ym.edu.tw.
Tzong-Shyuan
TS
Lee
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: yrkou@ym.edu.tw.
Yu
Y
Ru Kou
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D005944:Glucosamine / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*
D000893:Anti-Inflammatory Agents; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D055372:AMP-Activated Protein Kinases; D005944:Glucosamine
AMP-activated protein kinase; Cigarette smoke; Free radicals; Glucosamine; Lung inflammation; Mitogen-activated protein kinases; NADPH oxidase; NF-κB; Reactive oxygen species; SAT3