Sepsis Inflammatory Response Research Articles

Effects of artemisinin and hydroxychloroquine on cytokines in experimental sepsis.

Pro-and anti-inflammatory cytokines mediate the inflammatory response in sepsis. Therefore, regulation of cytokines with medications in risky situations may protect the patients from sepsis. Hydroxychloroquine and artemisinin are antimalarial drugs with immunomodulatory properties. In this study, we intended to investigate the effects of artemisinin and hydroxychloroquine on the cytokines released during sepsis in the rat model. Twenty-four rats were randomized into four groups. The control group received oral saline, the sepsis group received oral saline and intraperitoneal lipopolysaccharide toxin (LPS), the artemisinin-treated sepsis group received oral 33.33 mg/kg of artemisinin, and the hydroxychloroquinetreated sepsis group received oral 33.33 mg/kg of hydroxychloroquine before LPS injection. Three hours later, serum cytokines were measured. An increase was detected in TNF-a, IL-1, and IL-6 levels in the sepsis group compared to the control (p<0.01). Oral pretreatment with artemisinin resulted in significant downregulation only of IL-1 levels (p<0.01). Cytokines IL-1 and IL-6 were significantly downregulated in the serum of LPS-induced rats pretreated with oral hydroxychloroquine than rats with sepsis (p<0.01). Decreases observed in TNF-a and IL-10 levels were insignificant. These results demonstrated that both artemisinin and hydroxychloroquine attenuate the release of pro-inflammatory cytokines three hours after LPS-induced sepsis in rats. A significant decrease was observed in serum IL-1 and IL-6 levels with hydroxychloroquine and IL-1 levels with artemisinin. Based on our findings, we suggest that the therapeutic potential of artemisinin and hydroxychloroquine may be beneficial in preventing cytokine storm during sepsis, and further research is needed to determine the optimal timing of administration.

Decreased VEGFA alleviates the symptoms of LPS-induced sepsis in a mouse model by inhibiting glycolysis and thereby regulating the polarization of macrophages

The immune imbalance caused by excessive inflammatory reactions is the primary cause of sepsis. Macrophages with M1 and M2 polarization states are important immune cells that regulate the balance of the inflammatory response in sepsis. Encouraging the conversion of macrophages from the M1 to the M2 type is an important strategy for relieving sepsis. Here, we demonstrated the upregulation of vascular endothelial growth factor A (VEGFA) in a mouse model of sepsis. Then, siRNA technology was applied to inhibit the expression of VEGFA in macrophages. Flow cytometry and RT‒qPCR results showed that low expression of VEGFA inhibited LPS-induced M1 polarization of macrophages. Decreased VEGFA was also proven to lower TNF-α, IL-1β, and IL-6 secretion by LPS-induced macrophages. In addition, the effects of knocking down VEGFA on the energy metabolism pattern of macrophages were investigated by glycolysis pressure tests and mitochondrial pressure tests, and VEGFA knockdown reversed the induction of glycolysis in macrophages by LPS. The mitochondrial content and ATP content results also confirmed this finding. After the tail vein of septic mice was injected with macrophages transfected with si-VEGFA, the liver and kidney damage and the pathological conditions of the lung were alleviated. The secretion of TNF-α and IL-6 was decreased, while IL-10 was increased in their serum. Immunohistochemical staining revealed decreased expression of CD86 and increased expression of CD206 in the si-VEGFA group. This study demonstrates that decreased VEGFA inhibits glycolysis and thus inhibits LPS-induced M1 polarization of macrophages, ultimately relieving sepsis.

A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis

Sepsis is a life-threatening condition driven by the dysregulation of the host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed to obtain a deeper mechanistic insight into sepsis pathogenesis and to evaluate promising novel therapeutic targets, with a focus on Toll-like receptor 4 (TLR4)-mediated pathways. A Boolean network of regulatory relationships was developed for key immune components associated with sepsis pathogenesis after TLR4 activation. Perturbation analyses were conducted to identify therapeutic targets associated with organ dysfunction or antibacterial activity. The developed model consisted of 42 nodes and 183 interactions. Perturbation analyses suggest that over-expression of tumour necrosis factor alpha (TNF-α) or inhibition of soluble receptor sTNF-R, tissue factor, and inflammatory cytokines (IFN-γ, IL-12) may lead to a reduced activation of organ dysfunction related endpoints. Over-expression of complement factor C3b and C5b led to an increase in the bacterial clearance related endpoint. We identified that combinatory blockade of IFN-γ and IL-10 may reduce the risk of organ dysfunction. Finally, we found that combining antibiotic treatment with IL-1β targeted therapy may have the potential to decrease thrombosis. In summary, we demonstrate how existing biological knowledge can be effectively integrated using Boolean network analysis for hypothesis generation of potential treatment strategies and characterization of biomarker responses associated with the early inflammatory response in sepsis.

KETONE ESTER THERAPY REDUCES CARDIAC INFLAMMATION AND CARDIAC DYSFUNCTION IN SEPSIS

Sepsis is the body's reaction to an infection that often causes lasting cardiac damage and multi-organ injury due to a dysregulated inflammatory response. Currently, there are no effective treatments to reduce inflammation during sepsis and assist in preventing the lasting cardiovascular damage. Not only are sepsis outcomes worse for cardiovascular disease patients, but the permanent organ damage to sepsis survivors also makes them more susceptible to diseases such as heart failure. Thus, therapeutic strategies to reduce the inflammatory response in sepsis are needed to mitigate the development of cardiovascular disease and improve the outcomes and quality of life for cardiovascular patients who survive sepsis.

Application of oXiris-continuous hemofiltration adsorption in patients with sepsis and septic shock: A single-centre experience in China.

oXiris is a new, high-adsorption membrane filter in continuous hemofiltration adsorption to reduce the inflammatory response in sepsis. The investigators retrospectively reviewed patients with sepsis/septic shock who underwent at least one oXiris-treatment from November 2020 to March 2022. The demographic data, baseline levels before treatment, clinical datas, prognosis, and the occurrence of adverse events during treatment were recorded. 90 patients were enrolled in this study. The hemodynamic indices, sequential organ failure assessment score, lactate, inflammatory biomarkers levels were significantly improved at 12 h and 24 h after treatment. Procalcitonin and interleukin-6 reduction post-treatment of oXiris were most pronounced in infection from skin and soft tissue, urinary and abdominal cavity. Logistic regression analysis showed that pre-treatment sequential organ failure assessment score (p = 0.034), percentage decrease in sequential organ failure assessment score (p = 0.004), and age (p = 0.011) were independent risk factors for intensive care unit mortality. In conclusion, oXiris-continuous hemofiltration adsorption may improve hemodynamic indicators, reduce the use of vasoactive drugs, reduce lactate level and infection indicators. Of note, oXiris improve organ function in sepsis, which may result to higher survival rate.

MiR-135a is highly expressed and aggravates inflammatory response in sepsis by targeting MYOM1.

Our research attempted to explore the effect of miR-135a on lipopolysaccharide (LPS)-induced THP-1cells damage and its potential mechanism. LPS (1 μg/mL) was selected to mimic the injury of sepsis in vitro. qRT-PCR was used to detect miR-135a expression. The association between miR-135a and Myomesin 1 (MYOM1) was speculated bythe predication website and confirmed by the dual-luciferase assay. MYOM1 expression was observed by qRT-PCR and western blotting assays. The biological properties of THP-1cells were analyzed by cell counting kit-8 and flow cytometry assays. The concentration of TNF-α, IL-6 and IL-8 in cell supernatant was calculated by enzyme-linkedimmunosorbentassay. A marked augmentation of miR-135a was observed in LPS-induced THP-1 cells. Moreover, depletion of miR-135a alleviated the LPS-induced THP-1 cells injury from the perspective of improving cell viability and reducing cell apoptosis. Importantly, MYOM1, which was under expressed in LPS-induced THP-1 cells, was identified as a target of miR-135a and negatively regulated by miR-135a. Additionally, the mitigative impact of miR-135a inhibitor on THP-1cells damage triggered by LPS was suppressed by MYOM1 depletion. Our study suggested that the protective effect of miR-135a inhibitor on LPS-induced THP-1 cells injury was realized by regulation of MYOM1, which might afford a pair of novel molecules for sepsis clinical diagnosis.

Magnoliae flos Downregulated Lipopolysaccharide-Induced Inflammatory Responses via NF-κB/ERK-JNK MAPK/STAT3 Pathways.

Background Magnoliae flos is the dried flower bud of Magnolia biondii and related plants. It has been used as a medicinal herb for the treatment of rhinitis, sinusitis, and sinus headaches. Nevertheless, the effects of Magnoliae flos in microbial infection or sepsis remain unclear. In this study, we investigated the anti-inflammatory effects of Magnoliae flos water extract (MF) in lipopolysaccharide- (LPS-) induced septic mice and LPS-stimulated RAW264.7 macrophages. Results We found that MF reduced the mortality of LPS-challenged mice. Enzyme immunoassays and reverse transcription polymerase chain reaction analysis revealed that MF administration attenuated mRNA expression and protein production of proinflammatory mediators, including cyclooxygenase 2, inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-6. In parallel to these results in mice, pretreatment with MF suppressed the LPS-induced production of proinflammatory mediators in RAW264.7 macrophages. In addition, we found that MF exerted its suppressive effects by inhibiting the activation of the mitogen-activated protein kinase, nuclear factor-κB, and signal transducer and activator of transcription pathways at the protein level. Conclusion MF could be a potential therapeutic agent for regulating excessive inflammatory responses in sepsis.

Ablation of long noncoding RNA MALAT1 activates antioxidant pathway and alleviates sepsis in mice

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly reduced ROS level in macrophages and other cell types and increased glutathione/oxidized glutathione (GSH/GSSG) ratio in macrophages, suggesting an increased antioxidant capacity. We showed a mechanism for MALAT1 ablation leading to enhanced antioxidant capacity is through activation of methionine cycle by epitranscriptomical regulation of methionine adenosyltransferase 2A (MAT2A). MAT2A 3′UTR can be methylated by METTL16 which was known to directly bind to MALAT1. MALAT1 ablation was found to reduce methylation in MAT2A hairpin1 and increase MAT2A protein levels. Our results suggest a MALAT1-METTL16-MAT2A interactive axis which may be targeted for treatments of sepsis.

TREM-1 Modulation Strategies for Sepsis.

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor, which can be upregulated in inflammatory diseases as an amplifier of immune responses. Once activated, TREM-1 induces the production and release of pro-inflammatory cytokines and chemokines, in addition to increasing its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). This amplification of the inflammatory response by TREM-1 has now been considered as a critical contributor to the dysregulated immune responses in sepsis. Studies have shown that in septic patients there is an elevated expression of TREM-1 on immune cells and increased circulating levels of sTREM-1, associated with increased mortality. As a result, a considerable effort has been made towards identifying endogenous ligands of TREM-1 and developing TREM-1 inhibitory peptides to attenuate the exacerbated inflammatory response in sepsis. TREM-1 modulation has proven a promising strategy for the development of therapeutic agents to treat sepsis. Therefore, this review encompasses the ligands investigated as activators of TREM-1 thus far and highlights the development and efficacy of novel inhibitors for the treatment of sepsis and septic shock.

Methyltransferase like 7B is upregulated in sepsis and modulates lipopolysaccharide-induced inflammatory response and macrophage polarization

ABSTRACT Macrophages play a critical role in the regulation of the inflammatory responses in sepsis. Methyltransferase like 7B (METTL7B) has been implicated in several pathophysiological conditions. Nevertheless, the potential engagement of METTL7B in sepsis remains to be elucidated. In this study, we retrieved transcriptomic profile data of septic patients and healthy donors and compared the expression level of METTL7B between septic patients and healthy controls. We also collected septic patient samples to analyze METTL7B expression via RT-qPCR. Murine bone marrow-derived macrophages (BMDMs) were isolated and treated with incremental doses of LPS as an in vitro cell model. METTL7B was overexpressed or knocked down in BMDMs, and lipopolysaccharide (LPS)-mediated inflammatory cytokines production and macrophage polarization were evaluated. We found that METTL7B was upregulated in the blood and peripheral blood mononuclear cells (PBMC) of septic patients, which also showed a significant diagnostic potential for sepsis. In BMDMs, METTL7B was induced in a time and dose-dependent manner by LPS. Modulating the expression level of METTL7B could regulate LPS-mediated inflammatory cytokines production and macrophage polarization. The functional role of METTL7B was also validated in a septic mouse model. Our findings indicate that METTL7B is implicated in the immunopathogenesis of sepsis through modulating macrophage-mediated inflammatory responses. METTL7B may serve as a potential diagnostic and therapeutic target for sepsis.

Ketone Therapy Reduces Systemic and Organ Inflammation in Sepsis

IntroductionSepsis is the body's reaction to an infection that often causes lasting multi‐organ injury due to a dysregulated inflammatory response. Currently, there are no effective treatments to reduce inflammation during sepsis and assist in preventing the lasting inflammation‐mediated damage and thus, sepsis accounts for approximately 20% of all global causes of death. In addition, many patients who recover from sepsis have permanent damage to many organ systems which makes them more susceptible to future injury that likely affects them more severely. Thus, therapeutic strategies to reduce the inflammatory response in sepsis are needed to save lives and improve the outcomes and quality of life of those who survive sepsis. Herein, we tested the efficacy of a ketone therapy that increases circulating ketones via ketone ester supplementation. Ketones are small molecules that are normally produced by the liver and are elevated during carbohydrate‐deprived states, such as fasting or exercise. While ketones are classically known to be a metabolic source of energy, they also have non‐metabolic effects, such as inhibiting inflammation, which can be of therapeutic importance. We hypothesized that ketones have potent anti‐inflammatory effects in a mouse model of lipopolysaccharide (LPS)‐induced sepsis and that ketones can be used to mitigate the inflammation‐mediated organ damage.ObjectiveTo determine if ketone supplementation can effectively reduce inflammation and organ dysfunction/damage in a model of LPS‐induced sepsis.Methods8‐week‐old mice orally received either vehicle or a clinically tested ketone ester (KE) for 3 days. On day 3, mice were injected with saline or LPS to induce systemic inflammation and organ damage. 24 hours post‐injection, cardiac function was assessed and then mice were euthanized to assess systemic and organ inflammation from the 3 groups (control, LPS, LPS+KE).ResultsLPS‐treated mice had higher blood ketones compared to controls, suggesting that ketones may be important as an innate defense mechanism, and this response was further augmented in KE‐treated septic mice. While LPS‐treated mice had an induction of systemic pro‐inflammatory cytokines (e.g., IL‐1β, IL‐6, interferon‐γ) these cytokines were significantly lower in KE‐treated septic mice. Similarly, LPS induced numerous inflammatory markers in the heart, kidney, and liver, a large majority of which were reduced in the KE‐treated septic mice. LPS‐induced cardiac dysfunction and renal fibrosis was also significantly lower in KE‐treated septic mice. Finally, there was either no change or a reduction of ketolytic enzymes in various organs, suggesting that these protective and anti‐inflammatory effects do not depend on ketone metabolism for energy production.ConclusionTogether, these data are the first to show that ketone therapy may be a novel approach to reducing systemic and organ inflammation and dysfunction, and subsequent organ damage in a model of LPS‐induced sepsis.

Central Adenosine A1 Receptors Arbitrate the Nicotine Counteraction of Cardiovascular and Autonomic Dysfunctions in Septic Rats

The cholinergic anti‐inflammatory pathway plays a crucial role in improving end‐organ damage provoked by inflammatory disorders. Given the interplay between cholinergic and adenosinergic neuronal circuits in the central nervous system, we tested the hypothesis that central adenosine A1 receptors (A1Rs) modulate the offsetting action of nicotine on cardiovascular and inflammatory insults induced by sepsis. Pharmacologic agonistic and antagonistic studies were conducted in conscious rats, pre‐instrumented with femoral vessel and intracisternal (i.c.) catheters. Sepsis was induced by cecal ligation and puncture (CLP) 24 hr before cardiovascular measurements. Nicotine (25 or 100 µg/kg i.v.) dose‐dependently reversed septic manifestations of hypotension and concomitant reductions in time and spectral measures of heart rate variability (HRV) and cardiac sympathovagal balance (low‐frequency/high‐frequency ratio). Like nicotine, the i.c. administration of N(6)‐cyclopentyladenosine (CPA, AR1 agonist) to CLP rats caused significant increases in indices of HRV and sympathovagal balance and greater surges in these parameters were noted upon simultaneous administration of CPA plus nicotine. We also show that the favorable influences of nicotine on blood pressure and HRV in septic rats were significantly inhibited after central blockade of A1Rs by i.c. 8‐Cyclopentyl‐1,3‐dipropylxanthine (DPCPX). Immunohistochemically, the alleviation by nicotine of the upregulated myocardial expression of NFκB in septic rats disappeared upon prior exposure to DPCPX. The data suggest that central adenosine A1Rs act tonically to facilitate the ameliorative effect of nicotine against the inflammatory response of sepsis and interrelated cardiomyopathic and neuropathic hitches.

Endothelial Damage in Sepsis: The Importance of Systems Biology.

The early diagnosis and appropriate stratification of sepsis continues to be one of the most important challenges in modern medicine. Single isolated biomarkers have not been enough to improve diagnostic and prognostic strategies and to progress toward therapeutic goals. The information generated by the human genome project has allowed a more holistic approach to the problem. The integration of genomics, transcriptomics, proteomics and metabolomics in sepsis has allowed us to progress in the knowledge of new pathways which are pathophysiologically involved in this disease. Thus, we have understood the importance of and complex interaction between the inflammatory response and the endothelium. Understanding the role of important parts of the microcirculation, such as the endothelial glycocalyx and its interaction with the inflammatory response, has provided early recognition elements for clinical practice that allow the rational use of traditional medical interventions in sepsis. This comprehensive approach, which differs from the classical mechanistic approach, uses systems biology to increase the diagnostic and prognostic spectrum of endothelial damage biomarkers in sepsis, and to provide information on new pathways involved in the pathophysiology of the disease. This, in turn, provides tools for perfecting traditional medical interventions, using them at the appropriate times according to the disease's pathophysiological context, while at the same time discovering new and improved therapeutic alternatives. We have the challenge of transferring this ideal scenario to our daily clinical practice to improve our patients' care. The purpose of this article is to provide a general description of the importance of systems biology in integrating the complex interaction between the endothelium and the inflammatory response in sepsis.

Macrophage Migration Inhibitory Factor Provides a Predictive Performance of Septic Acute Kidney Injury.

Septic acute kidney injury (AKI) is a common condition in ICU with poor outcomes. Septic AKI patients have a progressively decreased urine output and increased serum creatinine. However, urine volume and serum creatinine showed poor sensitivity to early diagnosis of septic AKI. Searching for potential biomarkers to early detect AKI is crucial in day-to-day clinical practice. Macrophage migration inhibitory factor (MIF), primarily released by renal tubular epithelial cells, vascular endothelial cells, and immune cells, was found to be closely associated with the inflammatory response in sepsis. MIF may be used as a biomarker of septic AKI indicating aggravation of systemic inflammatory response. Our study included sepsis patients admitted to the ICU. The KDIGO guideline was used to confirm the diagnosis and staging of septic AKI. Blood samples were collected and tested, as well as clinical data were recorded. Independent risk factors were selected via logistic regression analysis. By drawing the receiver operating characteristic (ROC) curves, the area under the ROC curves (AUC) was computed. The relationship between serum MIF level and mortality of septic AKI was analyzed using Cox regression analysis. With high serum MIF level at ICU admission, the patients were more likely to develop AKI. The AUC of serum MIF (MIFAUC = 0.797) was found to be a good predictor of septic AKI. In addition, higher serum MIF levels corresponded to more severe AKI as well as a higher mortality rate. Serum MIF might be a biomarker for predicting the occurrence, development, and outcomes of septic AKI. This conclusion will need to be confirmed by more robust investigations in the future.

Inflammatory mediators of cytokines and chemokines in sepsis: From bench to bedside.

Background: Sepsis is a serious clinical condition characterized by damage to the immune system as a result of an uncontrolled response to infection. Septic patients show complications such as fever, cardiovascular shock, and/or systemic organ failure. Acute organ failure formed in sepsis mostly affects the respiratory and cardiovascular systems. In sepsis, responses including pro-inflammatory and anti-inflammatory processes in addition to the Toll-Like Receptor 4 (TLR4) signals leading to the release of inflammatory mediators have been suggested to be fundamental pathways in the pathophysiology of sepsis. Purpose: In this context, unregulated levels of sepsis-associated inflammatory mediators may increase the risk of mortality. In sepsis, infection-induced pathogens lead to a systemic inflammatory response. These systemic responses may contribute to septic shock and organ dysfunction. In the unfavorable clinical course of sepsis, an uncontrolled inflammatory response is observed. Accordingly, the mechanism of inflammatory mediators such as cytokines and chemokines in sepsis might increase. Neurotransmitters and gene regulators affect inflammatory mediators and control the inflammatory response. In this review, we aimed to show the new therapeutic targets in sepsis treatment with current studies. New clinical implications targeting inflammatory mediators in high mortality affected by the uncontrolled inflammatory response in sepsis can contribute to the understanding of the symptoms.

Effect of lidocaine on oxidative activity of peripheral blood phagocytes

BACKGROUND: Excessive production of reactive oxygen species (ROS) by leukocytes can cause damage to intrinsic tissues. The pathogenesis of sepsis is based on an excessive inflammatory response of the body. Several studies have reported the inhibitory effect of lidocaine on neutrophilic granulocytes.&#x0D; AIM: This study aimed to analyze the effect of lidocaine on the oxidative activity of phagocytes.&#x0D; MATERIALS AND METHODS: Blood from 16 healthy donors was used in this study. Leukocyte mass was extracted using spontaneous sedimentation. Half of the leukocyte samples were incubated in buffered physiological saline with lidocaine. The other half of the leukocyte samples were incubated in physiological saline without lidocaine. The generation of ROS was studied using two methods. Method 1 included a nitro blue tetrazolium (NBT) test), which is based on the ability of ROS to reduce NBT to insoluble diformazan. Method 2 was based on the chemiluminescence reaction. A culture of S. Aureus was used to induce the production of ROS.&#x0D; RESULTS: NBT test revealed a decrease in the oxidative activity of leukocytes in the presence of lidocaine by 18% (p 0.05). The study of luminol-dependent chemiluminescence of leukocyte suspension in the presence of lidocaine revealed a significant 2-fold decrease in both spontaneous and stimulated respiratory activity of cells.&#x0D; CONCLUSIONS: After incubation with lidocaine, phagocytes generated ROS to a significantly lower extent. However, their complete blockade was not recorded. This property of lidocaine may be used in clinical practice to treat an excessive inflammatory response in sepsis.

Long non‑coding RNA FGD5‑AS1/microRNA‑133a‑3p upregulates aquaporin 1 to decrease the inflammatory response in LPS‑induced sepsis.

Sepsis is a systemic inflammatory response syndrome caused by infections. The present study aimed to investigate the potential mechanism of FGD5‑AS1 in sepsis and lipopolysaccharide (LPS)‑induced inflammatory response. An animal model of sepsis was constructed. LPS was used to induce mice HL‑1 cardiomyocytes to construct a cell model. The association between FGD5‑AS1 and miR‑133a‑3p was investigated through animal and cell models. FGD5‑AS1 overexpression was used to analyze the effect of FGD5‑AS1 on inflammatory reaction. Tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β and IL‑6 levels were detected by enzyme‑linked immunosorbent assay and reverse transcription‑quantitative polymerase chain reaction. The interaction of FGD5‑AS1, miR‑133a‑3p and aquaporin1 (AQP1) was detected by dual‑luciferase reporter assay and microRNA (miRNA/miR) pull‑down assay. Compared with the control group, the expression of FGD5‑AS1 was decreased and the expression of miR‑133a‑3p was increased in the sepsis group. FGD5‑AS1 overexpression increased LPS‑induced expression of FGD5‑AS1 and AQP1, decreased the expression of miR‑133a‑3p, and inhibited the expression of the inflammatory cytokines, TNF‑α, IL‑6 and IL‑1β. Dual‑luciferase reporter and miRNA pull‑down assays confirmed the interaction of FGD5‑AS1, miR‑133a‑3p and AQP1. These results indicated that FGD5‑AS1 is the competitive endogenous RNA of miR‑133a‑3p on AQP1, and thus FGD5‑AS1 overexpression may be able to inhibit the inflammatory response in sepsis.

17β-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression.

Excessive release of cytokines such as IL-1β and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17β-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3′-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.

The role and prognostic value of human peripheral blood interleukin-27, C-reactive protein, and serum amyloid a in inflammatory response of sepsis.

article: The role and prognostic value of human peripheral blood interleukin-27, C-reactive protein and serum amyloid A in inflammatory response of sepsis - Minerva Medica 2021 Jun 11 - Minerva Medica - Journals

A Precision Medicine Approach to Biomarker Utilization in Pediatric Sepsis-Associated Acute Kidney Injury.

Sepsis is a leading cause of morbidity and mortality in critically ill children, and acute kidney injury (AKI) is a frequent complication that confers an increased risk for poor outcomes. Despite the documented consequences of sepsis-associated AKI (SA-AKI), no effective disease-modifying therapies have been identified to date. As such, the only treatment options for these patients remain prevention and supportive care, both of which rely on the ability to promptly and accurately identify at risk and affected individuals. To achieve these goals, a variety of biomarkers have been investigated to help augment our currently limited predictive and diagnostic strategies for SA-AKI, however, these have had variable success in pediatric sepsis. In this mini-review, we will briefly outline the current use of biomarkers for SA-AKI, and propose a new framework for biomarker discovery and utilization that considers the individual patient's sepsis inflammatory response. Now recognized to be a key driver in the complex pathophysiology of SA-AKI, understanding the dysregulated host immune response to sepsis is a growing area of research that can and should be leveraged to improve the prediction and diagnosis of SA-AKI, while also potentially identifying novel therapeutic targets. Reframing SA-AKI in this manner – as a direct consequence of the individual patient's sepsis inflammatory response – will facilitate a precision medicine approach to its management, something that is required to move the care of this consequential disorder forward.