Hydrogen Sulfide and Neurogenic Inflammation in Polymicrobial Sepsis: Involvement of Substance P and ERK-NF-κB Signaling

Hydrogen sulfide (H2S) has been shown to induce transient receptor potential vanilloid 1 (TRPV1)-mediated neurogenic inflammation in polymicrobial sepsis. However, endogenous neural factors that modulate this event and the molecular mechanism by which this occurs remain unclear. Therefore, this study tested the hypothesis that whether substance P (SP) is one important neural element that implicates in H2S-induced neurogenic inflammation in sepsis in a TRPV1-dependent manner, and if so, whether H2S regulates this response through activation of the extracellular signal-regulated kinase-nuclear factor-κB (ERK-NF-κB) pathway. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with TRPV1 antagonist capsazepine 30 minutes before CLP. DL-propargylglycine (PAG), an inhibitor of H2S formation, was administrated 1 hour before or 1 hour after sepsis, whereas sodium hydrosulfide (NaHS), an H2S donor, was given at the same time as CLP. Capsazepine significantly attenuated H2S-induced SP production, inflammatory cytokines, chemokines, and adhesion molecules levels, and protected against lung and liver dysfunction in sepsis. In the absence of H2S, capsazepine caused no significant changes to the PAG-mediated attenuation of lung and plasma SP levels, sepsis-associated systemic inflammatory response and multiple organ dysfunction. In addition, capsazepine greatly inhibited phosphorylation of ERK1/2 and inhibitory κBα, concurrent with suppression of NF-κB activation even in the presence of NaHS. Furthermore, capsazepine had no effect on PAG-mediated abrogation of these levels in sepsis. Taken together, the present findings show that H2S regulates TRPV1-mediated neurogenic inflammation in polymicrobial sepsis through enhancement of SP production and activation of the ERK-NF-κB pathway

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Abstract Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene-deficient mice, which encode for SP, and PPT-A−/− mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-κB, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11-7082, which are specific NK1R, MEK-1, and NF-κB antagonists, respectively. Additionally, burn-injured PPT-A−/− mice showed suppressed lung COX-2 levels, whereas PPT-A−/− mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A−/− mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A−/− mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-κB, leading to remote ALI after burn.</jats:p

Effect of NaHS or PAG and capsazepine on IκBα phosphorylation and degradation levels in the lungs and liver of septic mice.

<p>Mice were randomly given NaHS (10 mg/kg, i.p.) at the same time of CLP or PAG (50 mg/kg, i.p.) 1 hour before (“prophylactic”) or 1 hour after (“therapeutic”) CLP; and capsazepine (<i>Capz</i>) (15 mg/kg, s.c.) or vehicle (DMSO) 30 minutes before CLP. Sham mice were used as controls. Eight hours after CLP or sham operation, effect of NaHS or PAG and capsazepine on (A and B) phospho-IκBα and (C and D) IκBα expression levels were measured. A representative western blot image is shown, with densitometry data expressed as average ratios of phospho-IκBα to HPRT and IκBα to HPRT levels. Results shown are the mean values ± SEM (n = 6 mice per group). *P<0.01 versus sham; **P<0.01 versus CLP+vehicle; ‡P<0.05 versus CLP+vehicle; †P<0.01 versus CLP+NaHS+vehicle.</p

Hydrogen Sulfide Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite in Sepsis-Evoked Acute Lung Injury via Transient Receptor Potential Vanilloid Type 1 Channel Activation

Abstract Hydrogen sulfide (H2S) has been shown to promote transient receptor potential vanilloid type 1 (TRPV1)-mediated neurogenic inflammation in sepsis and its associated multiple organ failure, including acute lung injury (ALI). Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)/PGE2 pathway plays an important role in augmenting inflammatory immune response in sepsis and respiratory diseases. However, the interactions among H2S, COX-2, and PGE2 in inciting sepsis-evoked ALI remain unknown. Therefore, the aim of this study was to investigate whether H2S would upregulate COX-2 and work in conjunction with it to instigate ALI in a murine model of polymicrobial sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in male Swiss mice. dl-propargylglycine, an inhibitor of H2S formation, was administrated 1 h before or 1 h after CLP, whereas sodium hydrosulfide, an H2S donor, was given during CLP. Mice were treated with TRPV1 antagonist capsazepine 30 min before CLP, followed by assessment of lung COX-2 and PGE2 metabolite (PGEM) levels. Additionally, septic mice were administrated with parecoxib, a selective COX-2 inhibitor, 20 min post-CLP and subjected to ALI and survival analysis. H2S augmented COX-2 and PGEM production in sepsis-evoked ALI by a TRPV1 channel-dependent mechanism. COX-2 inhibition with parecoxib attenuated H2S-augmented lung PGEM production, neutrophil infiltration, edema, proinflammatory cytokines, chemokines, and adhesion molecules levels, restored lung histoarchitecture, and protected against CLP-induced lethality. The strong anti-inflammatory and antiseptic actions of selective COX-2 inhibitor may provide a potential therapeutic approach for the management of sepsis and sepsis-associated ALI.</jats:p

Effect of NaHS and capsazepine on protein levels of adhesion molecules in the lungs and liver of septic mice.

<p>Mice were randomly given NaHS (10 mg/kg, i.p.) or vehicle (DMSO) at the same time of CLP; and capsazepine (<i>Capz</i>) (15 mg/kg, s.c.) or vehicle (DMSO) 30 minutes before CLP. Sham mice were used as controls. Eight hours after CLP or sham operation, protein levels of (A) P-selectin, (B) E-selectin, (C) ICAM-1, and (D) VCAM-1 were measured. Results shown are the mean values ± SEM (n = 8–12 mice per group). *P<0.01 versus sham; **P<0.01 versus CLP+vehicle; ‡P<0.05 versus CLP+vehicle; †P<0.01 versus CLP+NaHS+vehicle.</p

Effect of PAG and capsazepine on protein levels of adhesion molecules in the lungs and liver of septic mice.

<p>Mice were randomly given PAG (50 mg/kg, i.p.) 1 hour before (“prophylactic”; PAG+CLP+Vehicle or PAG+CLP+Capz) or 1 hour after (“therapeutic”; CLP+PAG+Vehicle or CLP+PAG+Capz) CLP; and capsazepine (<i>Capz</i>) (15 mg/kg, s.c.) or vehicle (DMSO) 30 minutes before CLP. Sham mice were used as controls. Eight hours after CLP or sham operation, protein levels of (A) P-selectin, (B) E-selectin, (C) ICAM-1, and (D) VCAM-1 were measured. Results shown are the mean values ± SEM (n = 8–12 mice per group). *P<0.01 versus sham; **P<0.01 versus CLP+vehicle.</p