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

Yung-Fong Tsai,Fu-Chao Liu,Huang-Ping Yu,Tsong-Long Hwang,Wen-Yi Chang,Zhen-Cheng Huang

doi:10.1038/srep08347

Yung-Fong Tsai, Fu-Chao Liu + Show 4 more

Open Access

https://doi.org/10.1038/srep08347

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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.

Highlights

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
Superoxide generation and HNE release are considered to represent the major neutrophil functions of respiratory burst and degranulation that occur in activated human neutrophils
When fMLF-stimulated neutrophils were incubated with sirtinol, it had no effect on superoxide generation (Fig. 1A)

Summary

Introduction

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. 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. Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), have high morbidity and mortality rates, with an overall mortality estimated at 46%1 These life-threatening diseases can result from bacterial infection, trauma/hemorrhagic shock, chemical inhalation, blood transfusion, and ventilator-associated or aspiration pneumonia. In rats, sirtinol treatment greatly reduced neutrophil infiltration and cytokine production in lung and liver after trauma/hemorrhage injury[13,14] It remains unknown whether sirtinol directly affects neutrophil functions, especially the activity of released NE, and whether administration of sirtinol can protect mice from HNE- and lipopolysaccharide (LPS)-induced tissue damage. We hypothesized that sirtinol inhibits HNE activity to attenuate LPS-induced lung injury and HNE-induced paw edema

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