title: Sirtinol inhibits neutrophil elastase activity and attenuates lipopolysaccharide-mediated acute lung injury in mice.
abstract: Enhanced activity of neutrophil elastase leads to a protease-antiprotease imbalance, and plays an essential pathogenic role in acute lung injury (ALI) and acute respiratory distress syndrome. We assayed the pharmacological effects and mechanisms of the action of sirtinol in human neutrophils, and in neutrophil elastase (HNE)-induced paw edema and lipopolysaccharide (LPS)-mediated ALI in mice. Sirtinol significantly inhibited the activity of HNE from human neutrophils in response to various stimulators. The inhibitory effects on HNE activity were not mediated through protein kinase A, calcium, extracellular-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, Akt, or Src family kinases. Analysis of enzymatic activities showed that sirtinol inhibited HNE activity in a concentration-dependent manner. These results demonstrate that sirtinol does not affect neutrophil function and is an HNE inhibitor. In addition, administration of sirtinol significantly inhibited HNE-induced paw edema, and attenuated the myeloperoxidase activity and reduced pulmonary wet/dry weight ratio in the LPS-induced ALI mouse model. Our study indicates that sirtinol has anti-inflammatory effects through direct inhibition of HNE activity and attenuates HNE-induced and LPS-mediated tissue or organ injury in vivo. Sirtinol is a novel HNE inhibitor and may have the potential for clinical application in the treatment of inflammatory lung diseases.
authors: 1] Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kweishan 333, Taoyuan, Taiwan [2] Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan 333, Taoyuan, Taiwan [3] Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Yung-Fong
authors: YF
authors: Tsai
authors: 1] Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan 333, Taoyuan, Taiwan [2] Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Huang-Ping
authors: HP
authors: Yu
authors: 1] Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kweishan 333, Taoyuan, Taiwan [2] Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan 333, Taoyuan, Taiwan.
authors: Wen-Yi
authors: WY
authors: Chang
authors: 1] Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan 333, Taoyuan, Taiwan [2] Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Fu-Chao
authors: FC
authors: Liu
authors: Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Zhen-Cheng
authors: ZC
authors: Huang
authors: 1] Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kweishan 333, Taoyuan, Taiwan [2] Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan 333, Taoyuan, Taiwan.
authors: Tsong-Long
authors: TL
authors: Hwang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D009284:Naphthols / Q000494:pharmacology*; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D001549:Benzamides; D008070:Lipopolysaccharides; D009284:Naphthols; C439060:sirtinol; D009195:Peroxidase; D011494:Protein Kinases; D019272:Leukocyte Elastase