Research progress on the development of human neutrophil elastase inhibitors / 药学学报

Human neutrophil elastase (hNE) is a serine proteolytic enzyme mainly distributed in neutrophils. When the balance between anti-hNE protein and hNE is broken, excessive release of hNE can cause the occurrence of various diseases. Therefore, inhibition of hNE is a promising therapeutic strategy. In this paper, the structure, action mechanism, physiological function of hNE and the development of hNE inhibitors were briefly summarized, in order to provide information for the related research.

Research progress of effect of neutrophil elastase and its inhibitors in sepsis / 中华危重病急救医学

Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by infection. When an infection occurs, as the first line of defense of the body's immune system, neutrophils are first recruited to the site of infection to capture and kill pathogens by releasing neutrophil elastase (NE). However, a large amount of NE release will injury the surrounding normal tissues and induce organ dysfunction or failure. NE inhibitors can inhibit NE activity and reduce inflammatory response, which may be a promising drug for the treatment of sepsis. Currently, a variety of NE inhibitors have been developed and reported, but there is no systematic overview of their characteristics, and the role and underlying mechanisms of NE and related inhibitors in sepsis have not been thoroughly discussed. This article will make a review in this regard, in order to elucidate the effect of NE and its inhibitors in sepsis.

Identification and characterization of a novel elastase inhibitor from Hirudinaria manillensis / 中国天然药物

A large number of protease inhibitors have been found from leeches, which are essential in various physiological and biological processes. In the curret study, a novel elastase inhibitor was purified and characterized from the leech of Hirudinaria manillensis, which was named HMEI-A. Primary structure analysis showed that HMEI-A belonged to a new family of proteins. HMEI-A exerted inhibitory effects on elastase and showed potent abilities to inhibit elastase with an inhibition constant (K

Cloning of Guamerin gene in Whitmania pigra and its spatio-temporal expression analysis after ingestion / 中国中药杂志

The present study cloned wpGuamerin gene from a non-bloodsucking leech (Whitmania pigra), and the bioinformatics analysis of the sequence was performed. Additionally, the effects of feeding duration on the expression profile of the wp Guamerin gene were explored. The results showed that its sequence consisted of 295 nucleotides encoding a peptide of 83 amino acids(Genbank: KX768545), and its relative molecular weight is 9 145.95 Da. wp Guamerin does not encode proteins with a signal peptide, belonging to the hydrophilic protein. Its secondary structure is mainly composed of α-helix, extending chain, folding and random curl. Its similarity with other blood-sucking leeches ranges from 29% to 65%. The results revealed that wpGuamerin mRNA was detected higher expression in muscle than in salivary glands of Wh. pigra, and did not expressed in ingluvies and intestine. Its expression in muscle and salivary glands showed a single peak curve after feeding and the peak was observed in the 1st and 3rd after feeding, respectively. In summary, wp Guamerin in Wh. pigra is a small molecule polypeptide protein and is different from the Guamerin in blood-sucking leeches. wpGuamerin does not express in the digestive tract of Wh. pigra, and mainly express in muscle. Feeding behavior would stimulate the expression of wpGuamerin gene in muscle and salivary glands, but not in digestive tract.

Research Progress of Human Neutrophil Elastase Inhibitors and Their Application in Diverse Diseases / 中国药学杂志

To comprehensively understand the research status of human neutrophil elastase inhibitors (HNEI) and their clinical application prospect, the papers about novel HNEI discovered since 2011 and diseases related to human neutrophil elastase (HNE) in addition to pulmonary diseases were summarized. The results showed that a lot of highly selective and potent HNE inhibitors have been discovered since 2011. HNE participates in the development of many diseases. In addition to the infectious and inflammatory pulmonary diseases reported in the past, it is also associated with ischemia-reperfusion injury, rheumatoid arthritis, autoimmune diabetes, nephritis, cancer and other diseases. The development of novel HNEI with high potency and low toxicity has been an important direction for HNE-related diseases.

Effect of the Neutrophil Elastase Inhibitor on Acute Lung Injury after Pulmonary Resection for Lung Cancer: A Preliminary Study / 대한구급학회지

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the leading causes of death after lungresection. Neutrophil elastase is thought to be an important mediator in the pathogenesis of ALI. Sivelestat is a new neutrophil elastase inhibitor which may improve the outcome in patients with ALI/ARDS after lung resection. The objective of this study was to determine whether or not sivelestat can reduce mortality in patients with ALI after pulmonary resection for lung cancer. METHODS: This study was a retrospective case-control study of twenty three patients who developed ALI/ARDS within seven days of lung resection for lung cancer. The control group (n = 12) received standard care, while the sivelestat group (n = 11) received a continuous infusion of sivelestat (0.2 mg/kg/hr) for seven days in addition to standard care. RESULTS: There was no significant difference in the baseline characteristics between the control and sivelestat groups, except for heart rate. Six of twelve patients (50%) in the control group survived, while seven of twelve patients (64%) survived in the sivelestat group (p = 0.34). There was also no significant difference between the two groups in the progression to ARDS. In the sivelelestat group, survivors had lower APACHE II and SOFA scores than the patients in the control group. CONCLUSIONS: There was no additional effect of a neutrophil elastase inhibitor in the treatment of ALI after pulmonary resection for lung cancer.

Anti-inflammatory Effects of Pentoxifylline and Neutrophil Elastase Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury In Vitro / 결핵

BACKGROUND: Acute lung injury (ALI) is a commonly encountered respiratory disease and its prognosis is poor when the treatment is not provided promptly and properly. However no specific pharmacologic treatment is currently available for ALI, although recently several supportive drugs have been under scrutiny. We studied anti-inflammatory effects of pentoxifylline (PF), a methylated xanthine, and ONO-5046, a synthetic neutrophil elastase inhibitor on lipopolysaccharide (LPS)-induced ALI in vitro. METHODS: To establish an in vitro model of LPS-induced ALI, primary rat alveolar macrophages and peripheral neutrophils in various ratios (1:0, 5:1,1:1,1:5,0:1) were co-cultured with transformed rat alveolar epithelial cells (L2 cell line) or vascular endothelial cells (IP2-E4 cell line) under LPS stimulation. Each experiment was divided into five groups-control, LPS, LPS+PF, LPS+ONO, and LPS+PF+ONO. We compared LPS-induced superoxide anion productions from primary rat alveolar macrophages and peripheral neutrophils in various ratios, and the resultant cytotoxxicity on L2 cells or IP2-E4 cells between groups. In addition we also compared the productions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemotactic protein(MCP)-1, IL-6, and IL-10 as will as mRNA expressions of TNF-α, inducible nitric oxide synthetase(iNOS), and MCP-1 from LPS-stimulated primary rat alveolar macrophages between groups. RESULTS: (1) PF and ONO-5046 in each or both showed a trend to suppress LPS-induced superoxide anion productions from primary rat alveolar macrophages and peripheral neutrophils regardless of their ratio, except for the LPS+PF+ONO group with the 1:5 ratio, although statistical significance was limited to a few selected experimental conditions. (2) PF and ONO-5046 in each or both showed a trend to prevent IP2-E4 cells from LPS-induced cytotoxicity by primary rat alveolar macrophages and peripheral neutrophils regardless their ratio, although statistical significance was limited to a few selected experimental conditions. The effects of PF and/or ONO-5046 on LPS-induced L2 cell cytotoxicity varied according to expaerimental conditions. (3) PF showed a trend to inhibit LPS-induced productions of TNF-α, MCP-1, and IL-10 from primary rat alveolar macrophages. ONO-5046 alone didnot affect the LPS-induced productions of proinflammatory cytokines from primary rat alveolar macrophages but the combination of PF and ONO-5046 showed a trend to suppress LPS-induced productions of TNF-αand IL-10 PF and ONO-5046 in each or both showed a trend to increase LPS-induced IL-β and IL-6 productions from primary rat alveolar macrophages. (4) PF and ONO-5046 in each or both showed atrend to attenuate LPS-induced mRNA expressions of TNF-α and MCP-1 from primary rat alveolar macrophages but at the same time showed a trend increase iNOS mRNA expression. CONCLUSION: These results suggest that PF and ONO-5046 may play a role in attenuating inflammation in LPS-induced ALI and that further study is needed to use these drugs as a new supportive therapeutic strategy for ALI.