Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy

Sun, Guozhe; Ota, Chiharu; Kitaoka, Setsuko; Chiba, Yutaka; Takayanagi, Motowo; Kitamura, Taro; Yamamoto, Katsuya; Fujie, Hiromi; Mikami, Hitoshi; Uematsu, Mitsugu; Hino‐Fukuyo, Naomi; Munakata, Mitsutoshi; Kure, Shigeo; Haginoya, Kazuhiro

doi:10.1016/j.jns.2015.01.017

Cited by 31 publications

(25 citation statements)

References 33 publications

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“…[89]). High concentrations of IL-1b and IL-18 in the lung and sera are associated with severe and fatal IAV infections in humans [90][91][92]. A number of single-nucleotide polymorphisms in the human Il1b gene have been shown to be associated with increased susceptibility to 2009 H1N1 pandemic IAV infection [93][94][95], suggesting that IL-1b may play a protective role during IAV infections in humans.…”

Section: Downstream Of Nlrp3: Il-1b and Il-18 Responsesmentioning

confidence: 99%

Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection

Ong

Mansell

Tate

2016

Journal of Leukocyte Biology

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The severity of influenza A virus (IAV) infection can range from asymptotic to mild to severe. Infections, such as those seen following outbreaks of avian IAV, are associated with hyperinflammatory responses and the development of fatal disease. There is a continual threat that a novel or pandemic IAV will circulate in humans with high rates of mortality. The neuronal apoptosis inhibitor protein, class 2 transcription activator of the MHC, heterokaryon incompatibility, telomerase-associated protein 1, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is an innate immune sensor that has been shown to be critical for the secretion of the potent proinflammatory cytokines, IL-1β and IL-18, as well as chemokine production and cellular inflammation in vivo following IAV infection. Initial studies illustrated a protective role of NLRP3 during severe IAV infection in mice. However, the NLRP3 inflammasome may be a hero that turns villain in the later stages of severe IAV infection via the promotion of a hyperinflammatory state. Current treatments for patients who present to hospitals with a severe IAV infection are limited. The understanding of the mechanisms involved in the induction of NLRP3-dependent inflammation during severe IAV infections may provide new therapeutic targets that reduce human mortality.

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Section: Downstream Of Nlrp3: Il-1b and Il-18 Responsesmentioning

confidence: 99%

Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection

Ong

Mansell

Tate

2016

Journal of Leukocyte Biology

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“…C,D) indicated that elastase‐digested thrombin produced T3 peptide. Here, it has been shown that elastase acts at 0.14 p m , which is much lower than 221 p m , the physiological concentration of elastase . However, it is still speculative if optimal concentration of T3‐like peptide is generated by elastase in vivo .…”

Section: Discussionmentioning

confidence: 90%

Destabilization of β‐amyloid aggregates by thrombin derived peptide: plausible role of thrombin in neuroprotection

Bhattacharjee

Das

et al. 2020

The FEBS Journal

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b-amyloid (Ab) aggregates involved in Alzheimer's disease (AD) are resistant to proteases but could be destabilized by small peptides designed to target specific hydrophobic regions of Ab that take part in aggregate assembly. Since thrombin and AD are intricately connected, and elastase modulates thrombin activity, elastase-digested thrombin peptides were verified for intervention in the Ab-aggregation pathway. Intact or elastase-digested thrombin destabilized Ab fibril, as demonstrated by thioflavin T assay. Peptides were synthesized employing thrombin as a template, of which, a hexapeptide (T3) showed maximum destabilization at 1 µM. ExPASy peptide cutter software coupled with mass spectrometric analysis confirmed the generation of T3 peptide from elastase-digested thrombin. TEM micrographs revealed that 30-day incubation of preformed Ab fibrils or monomers with T3 resulted in destabilization or inhibition, respectively, leading mostly to particles of 1.74 AE 0.17 nm, which roughly corresponded to Ab monomer. Surface plasmon resonance employing CM5 chip coupled with Ab40 mouse monoclonal antibody showed a drop in response when T3 was incubated with Ab fibrils between 2 and 8 h. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and confocal microscopy demonstrated the ability of T3 to rescue neuroblastoma cells from Ab oligomerinduced cytotoxic damage. Although no [Ab-T3] adduct could be detected by mass spectrometry, an initial interaction appeared to facilitate the process of destabilization/inhibition of aggregation. T3 was comparable to standard b-sheet breaker peptides, LPFFD and KLVFF in terms of Ab aggregate destabilization. High hydrophobicity values coupled with recognition and breaking elements make T3 a potential candidate for future therapeutic applications.

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“…Neopterin levels were elevated in the majority of tested children (8/10) with encephalopathy, suggesting a potential use as a diagnostic biomarker11]. Sun et al showed that serum neutrophil elastase was significantly elevated in IAE compared with uncomplicated influenza [32].…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Outcome of Influenza-Associated Encephalopathy/Encephalitis Among Children in a Tertiary Pediatric Hospital in Italy, 2017-2019

Mastrolia

Rubino

Resti

et al. 2019

Preprint

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BACKGROUND: Influenza is the most frequent cause of acute upper respiratory tract infections during winter season. Although rare, neurological manifestations are known to occur during influenza infection and approximatively three-quarters of cases are in children. In this study, we aimed to characterize the burden and clinical spectrum of influenza-associated encephalopathy and encephalitis in children admitted at a tertiary pediatric hospital in Italy over two influenza seasons (2017-2019). METHODS: We retrospectively analyzed clinical, laboratory, instrumental data and outcome of patients discharged with ICD9-CM 487.0 code RESULTS: Fifteen children (13.1% of those discharged with a diagnosis of influenza infection in the study period), had influenza-associated central nervous system (CNS) manifestations. Eight patients (53.3%) were diagnosed as influenza encephalitis, 7 (46.7%) as influenza encephalopathy. Median age was 27 months. In children under 2 years of age (40% of all cases) altered consciousness was the most frequent neurological manifestation while respiratory symptoms were present at admission in all cases. Younger children also required intensive care support more frequently. Five subjects (33.3%) presented comorbidity. None of the patients had received seasonal influenza vaccination. The median time from onset of respiratory signs to onset of neurological manifestations was 24 hours. Cerebrospinal fluid (CSF) analysis was normal in most patients and polymerase chain reaction for influenza virus RNA on CSF, when performed, was negative in all samples. Neuroradiological investigations, performed in 5 children, reported cortical and subcortical white matter signal alterations. Oseltamivir was administered only in 2 cases. Fourteen patients recovered without sequelae, and only a 2-year-old girl had minimal impairment in fine motor skills at discharge. CONCLUSIONS: All children presenting acute neurological features during influenza season should be evaluated for influenza-associated CNS complications even if the respiratory involvement is mild. Absence of underlying diseases or other risk factors are not protective factors against CNS influenza-associated complications. The lack of CSF pleocytosis does not exclude CNS involvement. Children under 2 years of age are at higher risk of requiring intensive care support.

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Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy

Cited by 31 publications

References 33 publications

Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection

Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection

Destabilization of β‐amyloid aggregates by thrombin derived peptide: plausible role of thrombin in neuroprotection

Characteristics and Outcome of Influenza-Associated Encephalopathy/Encephalitis Among Children in a Tertiary Pediatric Hospital in Italy, 2017-2019

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