Sirtinol inhibits neutrophil elastase activity and attenuates lipopolysaccharide-mediated acute lung injury in mice

• Published in: Scientific reports Vol. 5; no. 1; p. 8347
• Main Authors: Tsai, Yung-Fong, Yu, Huang-Ping, Chang, Wen-Yi, Liu, Fu-Chao, Huang, Zhen-Cheng, Hwang, Tsong-Long
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.02.2015
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Acute Lung Injury - enzymology; Acute Lung Injury - pathology; AKT protein; Animals; Benzamides - pharmacology; c-Jun protein; Calcium (extracellular); Disease Models, Animal; Edema; Elastase; Humans; JNK protein; Kinases; Leukocyte Elastase - antagonists & inhibitors; Leukocyte Elastase - metabolism; Leukocytes (neutrophilic); Lipopolysaccharides; Lipopolysaccharides - toxicity; Lung diseases; Male; MAP kinase; Mice; Naphthols - pharmacology; Neutrophils; Neutrophils - enzymology; Neutrophils - pathology; Peroxidase; Peroxidase - metabolism; Protein kinase A; Protein Kinases - metabolism; Respiratory distress syndrome; Rodents; Src protein; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep08347

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.