Synergistic Therapeutic Potential of Dexamethasone and l-arginine in Lipopolysaccharide-Induced Septic Shock

AbstractSepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

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Therapeutic Potential of NOS Inhibitors in Septic Shock

Nitric Oxide - Handbook of Experimental Pharmacology ◽

10.1007/978-3-642-57077-3_17 ◽

2000 ◽

pp. 385-397

Author(s):

P. Vallance ◽

D. Rees ◽

S. Moncada

Keyword(s):

Septic Shock ◽

Therapeutic Potential ◽

Nos Inhibitors

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Immunoneutralization of the aminoprocalcitonin peptide of procalcitonin protects rats from lethal endotoxaemia: neuroendocrine and systemic studies

Clinical Science ◽

10.1042/cs20100007 ◽

2010 ◽

Vol 119 (12) ◽

pp. 519-534 ◽

Cited By ~ 23

Author(s):

Eva Tavares ◽

Francisco J. Miñano

Keyword(s):

Septic Shock ◽

Amino Acid ◽

Therapeutic Potential ◽

Shock Therapy ◽

Inflammatory Factor ◽

Central Administration ◽

Term Survival ◽

Mortality And Morbidity ◽

Il Interleukin ◽

Tnf Α

Severe sepsis and septic shock are an important cause of mortality and morbidity. These illnesses can be triggered by the bacterial endotoxin LPS (lipopolysaccharide) and pro-inflammatory cytokines, particularly TNF-α (tumour necrosis factor-α) and IL (interleukin)-1β. Severity and mortality of sepsis have also been associated with high concentrations of N-PCT (aminoprocalcitonin), a 57-amino-acid neuroendocrine peptide derived from ProCT (procalcitonin). Previous studies in a lethal model of porcine polymicrobial sepsis have revealed that immunoneutralization with IgG that is reactive to porcine N-PCT significantly improves short-term survival. To explore further the pathophysiological role of N-PCT in sepsis, we developed an antibody raised against a highly conserved amino acid sequence of human N-PCT [N-PCT-(44–57)]. This sequence differs by only one amino acid from rat N-PCT. First, we demonstrated the specificity of this antibody in a well-proven model of anorexia induced in rats by central administration of human N-PCT-(1–57). Next we explored further the therapeutic potential of anti-N-PCT-(44–57) in a rat model of lethal endotoxaemia and determined how this immunoneutralization affected LPS-induced lethality and cytokine production. We show that this specific antibody inhibited the LPS-induced early release of TNF-α and IL-1β and increased survival, even if treatment began after the cytokine response had occurred. In addition, anti-N-PCT-(44–57) may increase long-term survival in LPS-treated rats by up-regulating the late production of counter-regulatory anti-inflammatory mediators such as ACTH (adrenocorticotropic hormone) and IL-10. In conclusion, these results support N-PCT as a pro-inflammatory factor in both the early and the late stages of lethal endotoxaemia, and suggest anti-N-PCT as a candidate for septic shock therapy.

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NAD+ prevents septic shock by non-canonical inflammasome blockade and IL-10

10.1101/2020.03.29.013649 ◽

2020 ◽

Author(s):

Jasper Iske ◽

Rachid El Fatimy ◽

Yeqi Nian ◽

Siawosh K. Eskandari ◽

Hector Rodriguez Cetina Biefer ◽

...

Keyword(s):

Septic Shock ◽

Signaling Pathway ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Therapeutic Potential ◽

Endotoxic Shock ◽

Immune Homeostasis ◽

Inflammasome Activation ◽

Specific Inhibition ◽

Inflammatory Cytokine Production

AbstractNon-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and pro-inflammatory cytokine production via caspase-11 and Gasdermin-D (GSDMD). Here, we show that NAD+ treatment protected mice towards bacterial and LPS induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11-/- survival but rendered WT mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.SummaryNAD+ protects against septic shock by blocking the non-canonical inflammasome specifically and via a systemic production of IL-10 cytokine

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Chronic Critically Ill Septic Patients Exhibit Persistent Expression of Pro-Inflammatory Lipidomics

Current Developments in Nutrition ◽

10.1093/cdn/nzaa055_004 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1119-1119

Author(s):

J Christian Brown ◽

Stacey Kirkpatrick ◽

Dijoia Darden ◽

Tyler Loftus ◽

Amir Kamel ◽

...

Keyword(s):

Septic Shock ◽

Severe Sepsis ◽

Patient Population ◽

Therapeutic Potential ◽

Low Grade ◽

Omega 3 ◽

University Of Florida ◽

Funding Sources ◽

Persistent Inflammation ◽

Sepsis Survivors

Abstract Objectives In order to evaluate the therapeutic potential of resolvins to reduce inflammation in CCI-PICS, we recapitulated Glue Grant leukotriene and resolvin lipidomic scores above to quantify lipidomics in severe sepsis/septic shock survivors. Methods Ongoing University of Florida (UF) Sepsis Critical Illness Research Center (SCIRC) research studies indicate that Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) occurs as a result of a self-perpetuating cycle of low-grade inflammation. However, specialized pro-resolving mediators (SPMs) – metabolically active lipid byproducts of omega-3 fatty acids – can promote inflammatory deceleration and resolution.,1 Post hoc analysis of the Glue Grant Data developed a mathematical lipidomic expression to better understand genes responsible for production and degradation of resolvins and leukotrienes.,2 Leukotriene Score = (ALOX5 * ALX5AP * LTA4H * LTB4R)/(HPGD + PTGR1 + CYP4F3) Resolvin Score = [(ALOX5 * ALOX15) * (FPR2 + GPR32 + CMKLR1)]/(HPGD + PTGR1) When the targeted genes were scored using a weighted scheme accounting for enzyme and receptor activity, patients with uncomplicated recoveries had higher resolvin scores (P < 0.001) and lower leukotriene scores (P < 0.001). Utilizing our PICS patient data, we recapitulated the aforementioned lipidomic scores above to quantify expression in severe sepsis/septic shock survivors. Results Leukotriene and resolvin scores are depicted in Figure 1 at specific time points 0 (healthy controls), 3 hours, 1 and 14 days. The leukotriene score remains elevated consistent with ongoing inflammatory genotypic expression. Interestingly, the resolvin score also remains elevated in the CCI (Glue Grant complicated cohort) patient population when compared to our Rapid Recovery (RAP or uncomplicated) patients *Accompanied by two graphs depicting correlating numerical values for the aforementioned Leukotriene and Resolvin scores. Conclusions In our patient population of sepsis survivors, the leukotriene score is similarly elevated to the complicated Glue Grant patients of polytrauma. The resolvin score, however, remains elevated in the CCI-PICS population compared to RAP; this is contrary to expected scores if resolution of inflammation is predicted. Funding Sources University of Florida.

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Abstract 21: Endothelial Epsins Promote LPS-Induced Inflammation During Septic Shock

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.21 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Hong Chen

Keyword(s):

Septic Shock ◽

Proinflammatory Cytokine ◽

Cytokine Production ◽

Therapeutic Potential ◽

Lethal Dose ◽

Myeloid Cell ◽

Mutant Mice ◽

Proinflammatory Cytokine Production ◽

Knock Out ◽

Lps Challenge

Introduction: Sepsis is caused by a deleterious host response to infection, which is primarily responsible for further injury of host tissue and cause of organ dysfunction. Despite significant progress, the pathophysiology of sepsis and the underlying regulatory mechanisms are still not fully understood. We have established that endothelial epsins play a pivotal role in mediating internalization and degradation of Thrombomodulin after LPS challenge. Hypothesis: Given LPS triggers “cytokine storm” that causes hyper-permeability in the endothelium of lungs and excessive inflammation, we assessed the hypothesis that epsins play a role in promoting endothelial permeability and augmenting inflammation. Methods and Results: Using innovative tissue-specific inducible epsins double knock out animal models, we investigated the role for epsins during sepsis. We administered lethal dose of LPS into endothelial-specific inducible epsins mutant mice, myeloid cell-specific epsins mutant mice, and platelet-specific epsins mutant mice (n>10). We uncover a potent protective role for endothelial epsins deficiency against the development of LPS-induced sepsis, whereas deletion of epsins in myeloid cells offers 40% ~ 50% of protection, and loss of epsins in platelets exhibits no protection. We further show that endothelial epsin-deficiency upregulates Thrombomodulin surface protein expression by preventing its internalization and subsequent degradation induced by LPS exposure. Sustained surface Thrombomodulin activity subsequently impaired the heightened Tissue Factor expression and activation that usually occurs in response to LPS. Given LPS challenge mimics chronic inflammatory conditions, we show endothelial epsin-deficiency downregulates LPS-induced proinflammatory cytokine production and suppresses endothelial hyper-permeability in lungs assessed by ELSA and Evans Blue perfusion, respectively. Conclusions: Endothelial epsins depletion inhibits septic shock after LPS challenge by protecting Thrombomodulin against internalization and degradation, blocking proinflammatory cytokine production and inhibiting endothelial leakage in the lungs, highlighting the therapeutic potential for targeting epsins during sepsis.

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