Daily Sepsis Research Analysis
Analyzed 5 papers and selected 3 impactful papers.
Summary
Today’s top studies span mechanistic and clinical domains of severe inflammation. A preclinical study identifies RIPK1-driven necroptosis as a modifiable driver of hemodynamic collapse in septic shock, while another elucidates an EP300–HSF1–PRKN mitophagy axis that mitigates inflammatory injury in acute pancreatitis. A focused clinical series links combined cerebral and extracerebral complications with mortality in otogenic purulent meningitis, underscoring risk stratification needs.
Research Themes
- Targeting necroptosis (RIPK1/RIPK3/MLKL) to stabilize hemodynamics in septic shock
- EP300–HSF1–PRKN mitophagy axis as a protective pathway in inflammatory injury
- Complication patterns driving mortality in otogenic purulent meningitis
Selected Articles
1. EP300 confers protection against acute pancreatitis via acetylating HSF1 and promoting PRKN-mediated mitophagy in pancreatic acinar cells.
Across two mouse models and acinar cell systems, EP300-dependent acetylation stabilizes HSF1, which transcriptionally upregulates PRKN to drive mitophagy, reduce ROS, and suppress NLRP3 activation. Pharmacologic EP300 activation restored HSF1 and mitigated pancreatic and systemic inflammation, nominating the EP300–HSF1–PRKN axis as a therapeutic target in acute pancreatitis.
Impact: Defines a mechanistic, druggable pathway linking stress responses to mitophagy and inflammasome control with in vivo validation. Provides a translational rationale for EP300 activators in inflammatory injury.
Clinical Implications: Although preclinical, targeting EP300 to stabilize HSF1 and enhance PRKN-mediated mitophagy could reduce inflammatory damage in acute pancreatitis and potentially related systemic inflammation.
Key Findings
- HSF1 deficiency worsened acute pancreatitis with higher mortality, necrosis, and systemic inflammation in two mouse models.
- HSF1 directly bound the PRKN promoter to enhance transcription, promoting PRKN-mediated mitophagy, reducing ROS, and suppressing NLRP3 activation.
- EP300-dependent acetylation stabilized HSF1; reduced acetylation led to proteasomal degradation and impaired mitophagy.
- Pharmacologic activation of EP300 (e.g., CTB) restored HSF1, enhanced mitophagy, and attenuated inflammation in vivo and in vitro.
Methodological Strengths
- Two complementary in vivo AP models (L-arginine and cerulein) plus acinar cell validation
- Mechanistic dissection linking EP300 acetylation to HSF1 stability and PRKN transcription
- Use of genetic and pharmacologic perturbations to triangulate causality
Limitations
- Preclinical models may not fully recapitulate human acute pancreatitis pathophysiology.
- Limited validation in human tissues; clinical efficacy and safety of EP300 activation remain unknown.
Future Directions: Validate the EP300–HSF1–PRKN axis in human pancreatic tissues and organoids; assess efficacy/safety of EP300 modulators in large-animal models; explore impact on systemic inflammation and sepsis progression.
BACKGROUND: Acute pancreatitis (AP) is a severe inflammatory disorder characterized by pancreatic self-digestion, often progressing to systemic inflammation. Despite advances in understanding its pathogenesis, effective therapeutic strategies remain limited. Heat shock factor 1 (HSF1), a critical transcription factor that maintains cellular homeostasis and regulates the stress response, is downregulated in the pancreas of L-arginine-induced AP mice. However, its role and regulatory mechanisms in the pathogenesis of AP remain unclear. This study aims to elucidate the molecular function and mechanisms of HSF1 in AP, focusing on its regulation by E1A binding protein p300 (EP300) and the downstream effects on mitophagy and inflammation. METHODS: Two distinct mouse models of AP were established using L-arginine and cerulein. Pancreatic acinar cells (AR42J) were used to study the effects of HSF1 and parkin RBR E3 ubiquitin protein ligase (PRKN) on mitophagy and inflammation. The expression and regulation between HSF1, PRKN, and EP300 were assessed using genetic and pharmacological approaches. RESULTS: HSF1 deficiency exacerbates AP severity in two distinct mouse models, with increased mortality, pancreatic necrosis, and systemic inflammation. Mechanistically, HSF1 directly binds to the promoter of PRKN, enhancing its transcriptional activity. Thus, HSF1 alleviates the inflammatory response in pancreatic acinar cells during AP by promoting PRKN-mediated mitophagy, reducing ROS production, and inhibiting NLRP3 inflammasome activation. HSF1 expression is downregulated in pancreatic acinar cells due to decreased acetylation by EP300, leading to proteasomal degradation and impaired mitophagy. Pharmacological activation of EP300 (e.g., CTB) restores HSF1 expression, enhances mitophagy, and attenuates inflammation in both in vivo and in vitro settings. CONCLUSION: These findings highlight the critical role of EP300 in regulating HSF1 acetylation and stability, which in turn modulates mitophagy and pyroptosis in AP. Targeting EP300 and its downstream pathways, such as HSF1-PRKN axis, may offer novel therapeutic strategies for AP.
2. Inhibition of the RIPK1-driven necroptotic pathway protects against hypotensive and tachycardic responses to LPS in a rat model of septic shock.
Selective RIPK1 inhibition with Nec-1s ameliorated LPS-induced hypotension and tachycardia in conscious rats, reduced circulating injury markers, and dampened TLR4/TRIF-, MyD88/NF-κB-, and caspase-8–related signaling in arterial tissue. Nec-1s also improved renal histopathology, supporting necroptosis as a hemodynamic and organ-injury driver in septic shock.
Impact: Identifies RIPK1-driven necroptosis as a modifiable mechanism directly linked to septic shock hemodynamics, providing a tractable preclinical target with multi-tissue validation.
Clinical Implications: RIPK1 inhibitors could stabilize blood pressure and reduce organ injury during septic shock; findings support advancing RIPK1-targeted strategies to polymicrobial models and early-phase trials.
Key Findings
- Nec-1s prevented LPS-induced hypotension and tachycardia measured by tail-cuff in conscious rats.
- Serum iNOS, HMGB1, MPO, and LDH elevations were attenuated by Nec-1s after LPS challenge.
- Nec-1s reduced activation of TLR4/TRIF/RIPK1/RIPK3/MLKL/HMGB1 and MyD88/TAK1/IKKβ/NF-κB/iNOS/NO/VASP, and modulated caspase-8–related pathways in arterial tissue.
- Renal histopathological injury scores increased by LPS were reduced by Nec-1s; no increase in RIPK1/3/MLKL expression in heart, kidney, and lung with Nec-1s.
Methodological Strengths
- Conscious rat measurements of MAP/HR with multi-organ biochemical, histologic, and immunoblot/IHC readouts
- Pathway-resolved analysis spanning TLR4/TRIF, MyD88/NF-κB, RIPK1/RIPK3/MLKL, and caspase-8 axes
- Consistent effects across hemodynamics, serum biomarkers, and tissue pathology
Limitations
- Single LPS model may not capture the complexity of human sepsis; survival and organ function outcomes beyond histology were not reported.
- Potential off-target effects of Nec-1s and optimal dosing/timing were not explored in depth.
Future Directions: Test RIPK1 inhibition in polymicrobial sepsis (e.g., CLP), assess survival and organ function, and evaluate translational RIPK1 inhibitors in larger animals.
Necroptosis, a lytic type of cell death that is dependent on RIPK1-activated RIPK3 and MLKL, has been implicated in the progression of septic shock-related events. However, the role of RIPK1/RIPK3/MLKL necrosome in hemodynamic alterations associated with necroptotic and inflammatory tissue injury due to bacterial infections has not been explored. Therefore, we aimed to investigate whether inhibition of the RIPK1-driven necroptosis by a selective inhibitor of RIPK1, Nec-1s, protects against hypotension and tachycardia associated with necroptotic-, inflammatory-, and injury-related changes induced by bacterial LPS in rats. We also investigated the effects of RIPK1 inhibition on TLR4/TRIF- and caspase-8-related pathways that may contribute to these changes induced by LPS. The MAP and HR values were recorded from the conscious animals using a tail-cuff method. Serum iNOS, HMGB1, MPO, and LDH levels were determined using ELISA kits. The immunoblotting method was used to determine the changes in the expression of proteins related to the TLR4/TRIF- and caspase-8-mediated necroptotic and inflammatory pathways in the TA, RA, PA, and MCA. In the heart, kidney, lung, and brain, histopathological changes were evaluated by the H&E staining method. Expression of RIPK1, RIPK3, MLKL, and HMGB1 proteins in these organs was determined using immunohistochemical staining. Nec-1s prevented LPS-induced hypotension and tachycardia, increased serum iNOS, HMGB1, MPO, and LDH levels as well as expression of unphosphorylated and/or phosphorylated proteins of TLR4/TRIF/RIPK1/RIPK3/MLKL/HMGB1-, TLR4/MyD88/TAK1/IKKβ/NF-kB/iNOS/NO/VASP-, and caspase-8-related pathways in the arterial vasculature, but did not increase RIPK1, RIPK3, and MLKL protein expression induced by LPS in the heart, kidney, and lung tissues. The LPS-induced increase in scores related to histopathological changes in the kidney was attenuated by Nec-1s. These findings suggest that inhibition of the RIPK1-driven necroptosis protects against hypotension and tachycardia, along with arterial and/or renal necroptotic-, inflammatory-, and injury-related changes during septic shock. It also seems that suppression of the TLR4/TRIF- and caspase-8-related pathways may contribute to the beneficial effects of Nec-1s during septic shock.
3. [Cerebral and extrancerebral complications combined with otogenic meningitis with various outcomes].
In a 51-patient series of otogenic purulent meningitis, 66.7% had combined cerebral complications—most commonly encephalitis, epidural empyema, venous sinus thrombophlebitis, and intracerebral abscess. Fatal cases were associated with markedly higher rates of cerebral complications alongside acute purulent otitis media, indicating that combined cerebral and extracerebral complications elevate mortality risk.
Impact: Provides clinically actionable insights into complication patterns that portend mortality in otogenic meningitis, highlighting the need for aggressive surveillance and management.
Clinical Implications: Early imaging and multidisciplinary management should target detection and control of cerebral and extracerebral complications in otogenic meningitis, especially when acute purulent otitis media coexists.
Key Findings
- Among 51 patients with otogenic purulent meningitis, 66.7% had combined cerebral complications, most commonly encephalitis, epidural empyema, venous sinus thrombophlebitis, and intracerebral abscess.
- Fatal outcomes were associated with a marked increase in cerebral complications compared with favorable outcomes, particularly in the presence of acute purulent otitis media.
- Combined cerebral and extracerebral complications substantially increased the risk of lethal complications.
Methodological Strengths
- Focused clinical characterization of otogenic purulent meningitis with identification of immediate causes of death
- Systematic categorization of cerebral and extracerebral complications
Limitations
- Small, single-center retrospective series with limited statistical analysis; potential selection bias and unmeasured confounding.
- Incomplete reporting of effect sizes and absence of multivariable modeling limit causal inference.
Future Directions: Prospective multicenter cohorts with standardized imaging and multivariable risk modeling to validate complication-driven mortality risks and guide intervention timing.
OBJECTIVE: To increase the effectiveness of treatment of patients with otogenic meningitis based on the analysis of the frequency and structure of cerebral complications (CC) and extracerebral complications (ECC) with different outcomes. MATERIAL AND METHODS: The analysis of variants of the clinical course of otogenic purulent meningitis OPM in 51 patients with the isolation of combined CC and ECC, the immediate causes of death, was carried out. RESULTS: OPM in 66.7±6.6% of cases was accompanied by combined central nervous system diseases, which in descending order included encephalitis, epidural empyema, thrombophlebitis of the cerebral sinuses and intracerebral abscess. In case of fatal outcomes of OPM, compared with favorable ones, the frequency of CC increased significantly in association with acute purulent otitis media (APOM) - from 50.0±10.7% to 92.9±8.5 ( CONCLUSION: An analysis of the clinical course and thanatogenesis of OPM allows us to state that combined CC and ECC significantly increase the risk of fatal complications. ЦЕЛЬ ИССЛЕДОВАНИЯ: Повысить эффективность лечения пациентов с отогенными менингитами на основе анализа частоты и структуры церебральных осложнений (ЦО) и экстрацеребральных осложнений (ЭЦО) с различными исходами. МАТЕРИАЛ И МЕТОДЫ: Проведен анализ вариантов клинического течения отогенного гнойного менингита (ОГМ) у 51 пациента с выделением комбинированных ЦО и ЭЦО, непосредственных причин смерти. РЕЗУЛЬТАТЫ: В 66,7±6,6% случаев ОГМ сопровождался комбинированными ЦО, которые в порядке убывания включали энцефалит, эпидуральную эмпиему, тромбофлебит мозговых синусов и внутримозговой абсцесс. При летальных исходах ОГМ по сравнению с благоприятными исходами частота комбинированных ЦО значительно возрастала в ассоциации с острым гнойным средним отитом (ОГСО) — с 50,0±10,7% до 92,9±8,5% ( ЗАКЛЮЧЕНИЕ: Анализ клинического течения и танатогенеза отогенного гнойного менингита позволяет констатировать, что комбинированные церебральные и экстрацеребральные осложнения существенно увеличивают риск развития смертельных осложнений.