Positive Effects of Neutrophil Elastase Inhibitor (Sivelestat) on Gut Microbiome and Metabolite Profiles of Septic Rats

Sun, Yali; Ding, Xianfei; Cui, Yuqing; Li, Hongyi; Wang, Dong; Liang, Huoyan; Liu, Shaohua; Zhang, Xiaojuan; Wang, Haixu; Sun, Tongwen

doi:10.3389/fcimb.2022.818391

Cited by 8 publications

(4 citation statements)

References 53 publications

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“…Because NE exhibited minimum bactericidal activity against periodontal pathogen, it has the potential to induce compositional changes that causes periodontitis severity. In addition, it was reported that administration of NE inhibitor in septic rats improved gut microbiota composition 34 . The composition of the oral microbiota closely related to the severity of periodontitis 35 , thus, further studies are required to determine the effects of NE and NE inhibitors on the oral microbiota.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

Hiyoshi

Domon

Maekawa

et al. 2022

Sci Rep

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Neutrophil elastase (NE) functions as a host defense factor; however, excessive NE activity can potentially destroy human tissues. Although NE activity is positively correlated to gingival crevicular fluid and clinical attachment loss in periodontitis, the underlying mechanisms by which NE aggravates periodontitis remain elusive. In this study, we investigated how NE induces periodontitis severity and whether NE inhibitors were efficacious in periodontitis treatment. In a ligature-induced murine model of periodontitis, neutrophil recruitment, NE activity, and periodontal bone loss were increased in the periodontal tissue. Local administration of an NE inhibitor significantly decreased NE activity in periodontal tissue and attenuated periodontal bone loss. Furthermore, the transcription of proinflammatory cytokines in the gingiva, which was significantly upregulated in the model of periodontitis, was significantly downregulated by NE inhibitor injection. An in vitro study demonstrated that NE cleaved cell adhesion molecules, such as desmoglein 1, occludin, and E-cadherin, and induced exfoliation of the epithelial keratinous layer in three-dimensional human oral epithelial tissue models. The permeability of fluorescein-5-isothiocyanate-dextran or periodontal pathogen was significantly increased by NE treatment in the human gingival epithelial monolayer. These findings suggest that NE induces the disruption of the gingival epithelial barrier and bacterial invasion in periodontal tissues, aggravating periodontitis.

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Section: Discussionmentioning

confidence: 99%

Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

Hiyoshi

Domon

Maekawa

et al. 2022

Sci Rep

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“…Reports in animal models of sepsis indicate that microbiota metabolites modulate outcomes (231)(232)(233) and implicate the gut microbiome in injury in multiple organs (234,235). Further, targeting the microbiome for therapeutic gain-by probiotics, prebiotics, synbiotics, microbial spores, fecal microbial transplantation, or selective decontamination of the digestive system-has been helpful in disorders such as dementia and cognitive disorders, inflammatory bowel disease, and lupus (236)(237)(238)(239)(240) and may have therapeutic benefit in sepsis (232,233,241). However, the contribution of the microbiome to sepsis pathobiology is underexplored (242), and the therapeutic potential of microbiota manipulation is untapped.…”

Section: Bts4: How Does the Microbiome Affect Sepsis Pathobiology? Ho...mentioning

confidence: 99%

Surviving Sepsis Campaign Research Priorities 2023

De Backer,

Deutschman,

Hellman

et al. 2024

Critical Care Medicine

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OBJECTIVES: To identify research priorities in the management, epidemiology, outcome, and pathophysiology of sepsis and septic shock. DESIGN: Shortly after publication of the most recent Surviving Sepsis Campaign Guidelines, the Surviving Sepsis Research Committee, a multiprofessional group of 16 international experts representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine, convened virtually and iteratively developed the article and recommendations, which represents an update from the 2018 Surviving Sepsis Campaign Research Priorities. METHODS: Each task force member submitted five research questions on any sepsis-related subject. Committee members then independently ranked their top three priorities from the list generated. The highest rated clinical and basic science questions were developed into the current article. RESULTS: A total of 81 questions were submitted. After merging similar questions, there were 34 clinical and ten basic science research questions submitted for voting. The five top clinical priorities were as follows: 1) what is the best strategy for screening and identification of patients with sepsis, and can predictive modeling assist in real-time recognition of sepsis? 2) what causes organ injury and dysfunction in sepsis, how should it be defined, and how can it be detected? 3) how should fluid resuscitation be individualized initially and beyond? 4) what is the best vasopressor approach for treating the different phases of septic shock? and 5) can a personalized/precision medicine approach identify optimal therapies to improve patient outcomes? The five top basic science priorities were as follows: 1) How can we improve animal models so that they more closely resemble sepsis in humans? 2) What outcome variables maximize correlations between human sepsis and animal models and are therefore most appropriate to use in both? 3) How does sepsis affect the brain, and how do sepsis-induced brain alterations contribute to organ dysfunction? How does sepsis affect interactions between neural, endocrine, and immune systems? 4) How does the microbiome affect sepsis pathobiology? 5) How do genetics and epigenetics influence the development of sepsis, the course of sepsis and the response to treatments for sepsis? CONCLUSIONS: Knowledge advances in multiple clinical domains have been incorporated in progressive iterations of the Surviving Sepsis Campaign guidelines, allowing for evidence-based recommendations for short- and long-term management of sepsis. However, the strength of existing evidence is modest with significant knowledge gaps and mortality from sepsis remains high. The priorities identified represent a roadmap for research in sepsis and septic shock.

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“…The main examples of synthetic inhibitors are Sivelestat and β-lactam inhibitors, which are highly specific inhibitors with high potency and excellent permeability, that have demonstrated effects in reducing markers of lung lesions [83].…”

Section: Synthetic Hne Inhibitorsmentioning

confidence: 99%

Human neutrophil elastase inhibitors: Classification, biological‐synthetic sources and their relevance in related diseases

Ocampo‐Gallego,

Pedroza‐Escobar,

Caicedo‐Ortega

et al. 2023

Fundamemntal Clinical Pharma

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BackgroundHuman neutrophil elastase is a multifunctional protease enzyme whose function is to break the bonds of proteins and degrade them to polypeptides or amino acids. In addition, it plays an essential role in the immune mechanism against bacterial infections and represents a key mediator in tissue remodeling and inflammation. However, when the extracellular release of this enzyme is dysregulated in response to low levels of its physiological inhibitors, it ultimately leads to the degradation of proteins, in particular elastin, as well as other components of the extracellular matrix, producing injury to epithelial cells, which can promote sustained inflammation and affect the innate immune system, and, therefore, be the basis for the development of severe inflammatory diseases, especially those associated with the cardiopulmonary system.ObjectiveThis review aims to provide an update on the elastase inhibitory properties of several molecules, either synthetic or biological sources, as well as their classification and relevance in related pathologies since a clear understanding of the function of these molecules with the inhibitory capacity of this protease can provide valuable information for the development of pharmacological therapies that manage to modify the prognosis and survival of various inflammatory diseases.MethodsCollected data from scientific databases, including PubMed, Google Scholar, Science Direct, Nature, Wiley, Scopus, and Scielo. Articles published in any country and language were included.ResultsWe reviewed and included 132 articles conceptualizing neutrophil elastase activity and known inhibitors.ConclusionUnderstanding the mechanism of action of elastase inhibitors based on particular aspects such as their kinetic behavior, structure–function relationship, chemical properties, origin, pharmacodynamics, and experimental progress has allowed for a broad classification of HNE inhibitors.

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Positive Effects of Neutrophil Elastase Inhibitor (Sivelestat) on Gut Microbiome and Metabolite Profiles of Septic Rats

Cited by 8 publications

References 53 publications

Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

Surviving Sepsis Campaign Research Priorities 2023

Human neutrophil elastase inhibitors: Classification, biological‐synthetic sources and their relevance in related diseases

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