Inhibition of mast cell tryptase attenuates neuroinflammation via PAR-2/p38/NFκB pathway following asphyxial cardiac arrest in rats

Background Different factors may lead to hepatitis. Among which are liver inflammation and poisoning. We chose two hepatitis models, typical for these two underlying causes. Thus, we aimed to characterize the role of protease-activated receptor 2 (Par2) in liver regeneration and inflammation to reconcile Par2 conflicting role in many damage models, which sometimes aggravates the induced damage and sometimes alleviates it. Methods WT and knockout (Par2KO) mice were injected with concanavalin A (ConA) to induce immune-mediated hepatitis or with carbon tetrachloride (CCl4) to elicit direct hepatic damage. To distinguish the immune component from the liver regenerative response, we conducted bone marrow (BM) replacements of WT and Par2KO mice and repeated the damage models. Results ConA injection caused limited damage in Par2KO mice livers, while in the WT mice severe damage followed by leukocyte infiltration was evident. Reciprocal BM replacement of WT and Par2KO showed that WT BM-reconstituted Par2KO mice displayed marked liver damage, while in Par2KO BM-reconstituted WT mice, the tissue was generally protected. In the CCl4 direct damage model, hepatocytes regenerated in WT mice, whereas Par2KO mice failed to recover. Reciprocal BM replacement did not show significant differences in hepatic regeneration. In Par2KO mice, hepatitis was more apparent, while WT recovered regardless of the BM origin. Conclusions We conclude that Par2 activation in the immune system aggravates hepatitis and that Par2 activation in the damaged tissue promotes liver regeneration. When we incorporate this finding and revisit the literature reports, we reconciled the conflicts surrounding Par2’s role in injury, recovery, and inflammation.

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“…]. In cerebral mast cells, Par2 was suggested to activate neuroinflammation through NFkB pathways [ 34. , 35.…”

Section: Introductionmentioning

confidence: 99%

Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries

et al. 2022

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“…Hypoxic injury to the CNS leads to local release of leukocyte chemoattractant molecules, 17 making it susceptible to infiltration of neutrophils and secondary inflammatory damage 18,19 . A recent preclinical study in rats demonstrated that the expression of multiple inflammatory mediators is increased in the CNS after cardiac arrest and that pharmacological increasing of these mediators increased seizure activity and worsened neurological outcome, whereas pharmacological reduction of the mediators had an opposite effect 20 …”

Section: Discussionmentioning

confidence: 99%

“…18,19 A recent preclinical study in rats demonstrated that the expression of multiple inflammatory mediators is increased in the CNS after cardiac arrest and that pharmacological increasing of these mediators increased seizure activity and worsened neurological outcome, whereas pharmacological reduction of the mediators had an opposite effect. 20 Multiple studies have shown that elevated levels of inflammatory biomarkers in circulation are associated with poor outcome after cardiac arrest. 3,21,22 This association may depend on case-mix, being stronger in a patient population including more moribund patients 23 compared to a more selected population.…”

Section: Discussionmentioning

confidence: 99%

Markers of neutrophil mediated inflammation associate with disturbed continuous electroencephalogram after out of hospital cardiac arrest

Pekkarinen

Carbone

Minetti

et al. 2022

Acta Anaesthesiol Scand

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Background Achieving an acceptable neurological outcome in cardiac arrest survivors remains challenging. Ischemia‐reperfusion injury induces inflammation, which may cause secondary neurological damage. We studied the association of ICU admission levels of inflammatory biomarkers with disturbed 48‐hour continuous electroencephalogram (cEEG), and the association of the daily levels of these markers up to 72 h with poor 6‐month neurological outcome. Methods This is an observational, post hoc sub‐study of the COMACARE trial. We measured serum concentrations of procalcitonin (PCT), high‐sensitivity C‐reactive protein (hsCRP), osteopontin (OPN), myeloperoxidase (MPO), resistin, and proprotein convertase subtilisin/kexin type 9 (PCSK9) in 112 unconscious, mechanically ventilated ICU‐treated adult OHCA survivors with initial shockable rhythm. We used grading of 48‐hour cEEG monitoring as a measure for the severity of the early neurological disturbance. We defined 6‐month cerebral performance category (CPC) 1–2 as good and CPC 3–5 as poor long‐term neurological outcome. We compared the prognostic value of biomarkers for 6‐month neurological outcome to neurofilament light (NFL) measured at 48 h. Results Higher OPN (p = .03), MPO (p < .01), and resistin (p = .01) concentrations at ICU admission were associated with poor grade 48‐hour cEEG. Higher levels of ICU admission OPN (OR 3.18; 95% CI 1.25–8.11 per ln[ng/ml]) and MPO (OR 2.34; 95% CI 1.30–4.21) were independently associated with poor 48‐hour cEEG in a multivariable logistic regression model. Poor 6‐month neurological outcome was more common in the poor cEEG group (63% vs. 19% p < .001, respectively). We found a significant fixed effect of poor 6‐month neurological outcome on concentrations of PCT (F = 7.7, p < .01), hsCRP (F = 4.0, p < .05), and OPN (F = 5.6, p < .05) measured daily from ICU admission to 72 h. However, the biomarkers did not have independent predictive value for poor 6‐month outcome in a multivariable logistic regression model with 48‐hour NFL. Conclusion Elevated ICU admission levels of OPN and MPO predicted disturbances in cEEG during the subsequent 48 h after cardiac arrest. Thus, they may provide early information about the risk of secondary neurological damage. However, the studied inflammatory markers had little value for long‐term prognostication compared to 48‐hour NFL.

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“…For the pharmacological studies, we used stabilizer of MCs and showed the link between MCs degranulation and neuroinflammation. Tryptase is the major proteins in MCs and has been used as a marker for MCs activation and degranulation ( Oliveira et al, 2013 ; Ocak et al, 2020 ). Our results showed that DSCG treatment decreased the expression of tryptase after early GA exposure.…”

Section: Discussionmentioning

confidence: 99%

Mast cell stabilizer disodium cromoglycate improves long-term cognitive impairment after general anesthesia exposure in neonatal mice

Zhang

Zheng

et al. 2022

Front. Neurosci.

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BackgroundProlonged exposure to general anesthesia (GA) results in long-lasting cognitive impairment, especially during critical stages of brain development. An exaggerated neuroinflammation induced by anesthesia is generally considered to be a key cause of cognitive impairment.Materials and methodsPostnatal day 7 (PND 7) mice were exposed to GA by isoflurane inhalation for 6 h or mock anesthesia. Disodium cromoglycate (DSCG) was intraperitoneally injected daily for 2 weeks, beginning from 30 min before anesthesia. The post-anesthesia evaluation included behavioral tests, toluidine blue staining, immunofluorescence and western blot.ResultsOur results demonstrated the long-term cognition were impaired after 6 h GA exposure in neonatal mice. DSCG treatment ameliorated early mast cells (MCs) degranulation and mast cell tryptase (MCT) expression, which helps to attenuate subsequent neuroinflammation, activation of microglia and astrocytes, and damage to oligodendrocytes and synapses to improve cognitive impairment.ConclusionDisodium cromoglycate could effectively improve long-term cognitive impairment after GA exposure in neonatal mice.

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Inhibition of mast cell tryptase attenuates neuroinflammation via PAR-2/p38/NFκB pathway following asphyxial cardiac arrest in rats

Cited by 14 publications

References 79 publications

Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries

Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries

Markers of neutrophil mediated inflammation associate with disturbed continuous electroencephalogram after out of hospital cardiac arrest

Mast cell stabilizer disodium cromoglycate improves long-term cognitive impairment after general anesthesia exposure in neonatal mice

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