Search Results (53)

This study aimed to characterize the time-dependent effects of methane (CH₄) inhalation, initiated at defined intervals following sepsis onset, on organ function, systemic oxygen utilization, and mitochondrial respiration in a rodent model. Adult rats were subjected to abdominal sepsis or sham operation. Septic animals were assigned to groups receiving 2.2% CH₄ in normoxic air at specific post-insult phases (early: 3–6 h; intermediate: 16–19 h; late: 19–22 h), while a control group remained untreated. At 24 h, organ function was evaluated using a Rat-Specific Organ Failure Assessment (ROFA) score, along with measurements of plasma myeloperoxidase (MPO) activity, Complex I–II-linked oxidative phosphorylation in renal and cerebellar tissues, systemic oxygen extraction, and global tissue perfusion (pCO₂-gap). Sepsis induced significant organ dysfunction, impaired hemodynamics, reduced oxygen utilization, and decreased mitochondrial respiration. CH₄ inhalation improved survival when administered early, restored cerebellar mitochondrial respiration during the intermediate phase, and in the late phase reduced ROFA scores and MPO levels, while attenuating mitochondrial dysfunction in renal and cerebellar tissues. All CH₄-treated groups demonstrated improved renal function and enhanced tissue oxygenation. Targeted CH₄ inhalation during sepsis confers protective effects by preserving mitochondrial function, reducing inflammation, and improving oxygen dynamics, suggesting promising therapeutic potential. Full article

The hemodynamic stabilization of patients after complex cardiac surgery is a daily challenge. The use of high doses of catecholamines is common but has potential adverse effects. Glibenclamide, a K_ATP blocker, seems to attenuate vasoplegia in different animal models of septic shock. Therefore, the aim of this study was to investigate the impact of Glibenclamide on the vasoplegic syndrome after cardiopulmonary bypass in a porcine model. In this experimental study, 20 landrace pigs were randomized into two groups and examined: In the control group, standard medical therapy, including norepinephrine, was used, and in the study group standard medical therapy plus additional Glibenclamide was administered. Following general anesthesia, prolonged cardiopulmonary bypass and aortic cross-clamping was performed. In the study group, Glibenclamide was administered 45 min after weaning from cardiopulmonary bypass. The dosage used was 10 mg/kg as a bolus, followed by a continuous infusion of 10 mg/kg/h. Hemodynamic and laboratory measurements were performed. Glibenclamide had a relevant effect on circulatory parameters. With increasing vascular resistance and blood pressure, norepinephrine was able to be reduced. While the heart rate dropped to physiological levels, the cardiac index decreased as well. The results lead to the conclusion that Glibenclamide was able to break through vasoplegic syndrome and could therefore serve as a potent drug to stabilize patients after cardiac surgery. Full article

Background and Objective: Probiotics have been shown to be effective in controlling various adverse health conditions such as antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and neurological diseases. However, to our knowledge, there is no research on the preventive effect of probiotics on heart damage caused by infections. This study examined the preventive benefits of probiotics against sepsis-related heart injury using a rat model caused by lipopolysaccharide (LPS). Materials and Methods: Four groups of twenty-four male Wistar albino rats, each with six rats, were set up. For 14 days, Group 1 (Sham Group) was given oral normal saline, intraperitoneal Escherichia coli O111-B4 lipopolysaccharide (LPS Group) was given to Group 2, and oral probiotics were given to Group 3 (Probiotic Group). Escherichia coli O111-B4 lipopolysaccharide was injected intraperitoneally after Group 4 (Probiotic + LPS) received oral probiotics containing Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 (10⁹ CFU/day). Blood samples were taken twenty-four hours following the administration of LPS. The animals were then euthanized by cervical dislocation, and samples of cardiac tissue were taken in order to assess any damage to the heart. The following serum values were measured: C-reactive protein (CRP), creatine kinase-myocardial band (CK-MB), cardiac troponin subunit I (cTn-I), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). The TNF-α, IL-1β, IL-6, glutathione (GSH), malondialdehyde (MDA), Total Oxidant Status (TOS), Total Antioxidant Status (TAS), Oxidative Stress Index (OSI), CRP, CK-MB, and cTn-I levels were assessed in tissue samples. Additionally, staining techniques were used to analyze histopathological alterations in tissues. Results: With the exception of serum IL-6 (p = 0.111), tissue and serum cytokine levels were considerably greater in the sepsis group (Group 2) than in the other groups (p < 0.05 to <0.001). The TAS, GSH, and SOD levels were significantly lower (p < 0.05 to <0.001) in septic rats, although the tissue levels of TOS, OSI, and MDA were significantly higher. With the exception of serum CRP in Group 3 (p = 0.328), the CK-MB, CRP, and cTn-I levels were considerably higher in Group 2 than in the other groups (p < 0.01 to <0.001). When compared to the other groups, histopathological examination showed significant alterations in the LPS group. Conclusions: Probiotics showed positive effects on oxidative stress markers and dramatically decreased sepsis-induced cardiac damage in the LPS-induced sepsis model. These results imply that probiotics could be used as a therapeutic approach to lessen the cardiac damage brought on by sepsis. Full article

The gut microbiota influences and contributes to kidney health and disease. Butyrate, a short-chain fatty acid molecule generated via the fermentation of gut bacterial catabolism of nondigestible dietary fiber, has been shown to exert numerous beneficial effects on kidney disorders. The objective of this review was to discuss the latest findings on the protective effects of butyrate on a variety of animal models of kidney injury. We conducted a PubMed search using the title word “butyrate” and keyword “kidney” to generate our literature review sources. The animal models covered in this review include ischemia–reperfusion renal injury, cisplatin- and folic acid-induced kidney injury, septic kidney injury, diabetic kidney disease (DKD), high-fat diet (HFD)-induced glomerulopathy, adenine-induced chronic kidney disease (CKD), high-salt-induced renal injury, and T-2 toxin-induced kidney injury in birds. The protective mechanisms of butyrate that are most shared among these animal model studies include antioxidative stress, anti-fibrosis, anti-inflammation, and anti-cell death. This review ends with suggestions for future studies on potential approaches that may modulate gut microbiota butyrate production for the well-being of kidneys with the kidney disorders covered in this review. Full article

Sepsis remains a huge unmet medical need for which no approved drugs, besides antibiotics, are on the market. Despite the clinical impact of sepsis, its molecular mechanism remains inadequately understood. Recent insights have shown that profound hepatic transcriptional reprogramming, leading to fatal metabolic abnormalities, might open a new avenue to treat sepsis. Translation of experimental results from rodents to larger animal models of higher relevance for human physiology, such as pigs, is critical and needs exploration. We performed a comparative analysis of the transcriptome profiles in murine and porcine livers using the following sepsis models: cecal ligation and puncture (CLP) in mice and fecal instillation (FI) in pigs, both of which induce polymicrobial septic peritonitis, and lipopolysaccharide (LPS)-induced endotoxemia in pigs, inducing sterile inflammation. Using bulk RNA sequencing, Metascape pathway analysis, and HOMER transcription factor motif analysis, we were able to identify key genes and pathways affected in septic livers. Conserved upregulated pathways in murine CLP and porcine LPS and FI generally comprise typical inflammatory pathways, except for ER stress, which was only found in the murine CLP model. Conserved pathways downregulated in sepsis comprise almost exclusively metabolic pathways such as monocarboxylic acid, steroid, biological oxidation, and small-molecule catabolism. Even though the upregulated inflammatory pathways were equally induced in the two porcine models, the porcine FI model more closely resembles the metabolic dysfunction observed in the CLP liver compared to the porcine LPS model. This comprehensive comparison focusing on the hepatic responses in mouse CLP versus LPS or FI in pigs shows that the two porcine sepsis models generally resemble quite well the mouse CLP model, with a typical inflammatory signature amongst the upregulated genes and metabolic dysfunction amongst the downregulated genes. The hepatic ER stress observed in the murine model could not be replicated in the porcine models. When studying metabolic dysfunction in the liver upon sepsis, the porcine FI model more closely resembles the mouse CLP model compared to the porcine LPS model. Full article

Background/Objectives: Stimulated capsaicin-sensitive peptidergic sensory nerves release somatostatin (SST), which has systemic anti-inflammatory and analgesic effects, correlating with the severity of tissue injury. Previous studies suggest that SST release into the systemic circulation is likely to serve as a protective mechanism during thoracic and orthopedic surgeries, scoliosis operations, and septic conditions, all involving significant tissue damage, pain, and inflammation. In a severe systemic inflammation rat model, SST released from sensory nerves into the bloodstream enhanced innate defense, reducing mortality. Inflammation is the key pathophysiological process responsible for the formation, progression, instability, and healing of atherosclerotic plaques. Methods: We measured SST-like immunoreactivity (SST-LI) in the plasma of healthy volunteers in different age groups and also that of stable angina patients with coronary heart disease (CHD) using ELISA and tracked changes during invasive coronary interventions (coronarography) with and without stent implantation. Samples were collected at (1) pre-intervention, (2) after coronarography, (3) 2 h after coronarography initiation and coronary stent placement, and (4) the next morning. Results: There was a strong negative correlation between SST-LI concentrations and age; the plasma SST-LI of older healthy volunteers (47–73 years) was significantly lower than in young ones (24–27 years). Baseline SST-LI in CHD patients who needed stents was significantly reduced compared to those not requiring stents. Plasma SST-LI significantly increased two hours post stent insertion and the next morning compared to pre-intervention levels. Conclusions: Age-related SST decrease might be a consequence of lower gene expression within specific hypo-thalamic nuclei as has been previously demonstrated in rodent animals. Reperfusion of ischemic myocardium post-stent implantation may trigger SST release, potentially offering protective benefits in coronary heart disease. Investigating this SST-mediated mechanism could offer valuable insights for future therapies. Full article

Sepsis is a potentially fatal clinical condition that results from an immune imbalance in the host during an infection. It presents systemic alterations due to excessive activation of pro-inflammatory mediators that contribute to inflammation, formation of reactive species, and tissue damage. Anti-inflammatory mediators are then extensively activated to regulate this process, leading to immune exhaustion and, consequently, immunosuppression of the host. Considering the biological activities of the nutraceutical Agaricus brasiliensis (A. brasiliensis), such as immunomodulatory, antioxidant, and antitumor activities, the present study investigated the therapeutic potential of the lipid fraction of A. brasiliensis (LF) in a model of lethal sepsis in mice (Mus musculus), induced by cecal ligation and perforation (CLP). The results showed that treatment of septic animals with LF or LF associated with ertapenem (LF-Erta) reduced systemic inflammation, promoting improvement in clinical parameters and increased survival. The data show a reduction in pro-inflammatory and oxidative stress markers, regulation of the anti-inflammatory response and oxidizing agents, and increased bacterial clearance in the peritoneal cavity and liver. Thus, it can be concluded that LF as a treatment, and in conjunction with antibiotic therapy, has shown promising effects as a hepatoprotective, antioxidant, antimicrobial, and immunomodulatory agent. Full article

The use of stable isotopes, specifically δ¹⁸O_PO4 ratios, in differentiating potential sources of inorganic phosphorus (e.g., wastewater, septic, wild animals, domesticated animals, livestock, substrates, or commercial fertilizers) to watersheds is a growing field. This method produces data that, used in conjunction with statistical mixing models, enables a better understanding of contributing sources of runoff. However, given the recent development of this research area there are obvious limitations that have arisen, due in large part to the limited available reference data to compare water samples. Here, we attempt to expand the availability of reference samples by applying stable isotope methods to three types of common agricultural manures: poultry, dairy, and swine. We also aim to concatenate the organic waste literature on this topic, creating a more robust comparison database for future study and application in phosphorus source partitioning research. Among our samples, δ¹⁸O_PO4 ratios for poultry were considerably elevated compared to dairy and swine manures (values of 18.5‰, 16.5‰, and 17.9‰, respectively). Extending this to other published ratios of δ¹⁸O_PO4 from various types of waste products (e.g., septic, wastewater, livestock, other animals), a total range from 8.7‰ to 23.1‰ emerged (with existing poultry manure samples also ranking among the highest overall). Variation among samples in the larger dataset demonstrates the need for a further compilation of δ¹⁸O_PO4 ratios for various types of waste, especially specific to geographic regions and watershed scales. With an increased sample size, the statistical strength associated with these methods would greatly improve. Full article

Treatment of critically ill patients with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance in the last few decades. However, the use of V-V ECMO in septic shock remains controversial. The effect of ECMO-induced inflammation on the microcirculation of the intestine, liver, and critically damaged lungs is unknown. Therefore, the aim of this study was to measure the hepatic and intestinal microcirculation and pulmonary inflammatory response in a model of V-V ECMO and septic shock in the rat. Twenty male Lewis rats were randomly assigned to receive V-V ECMO therapy or a sham procedure. Hemodynamic data were measured by a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by the intravenous infusion of lipopolysaccharide (1 mg/kg). During V-V ECMO therapy, rats received lung-protective ventilation. The hepatic and intestinal microcirculation was assessed by micro-lightguide spectrophotometry after median laparotomy for 2 h. Systemic and pulmonary inflammation was measured by enzyme-linked immunosorbent assays of plasma and bronchoalveolar lavage (BAL), respectively, which included tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-10, C-X-C motif ligand 2 (CXCL2), and CXCL5. Reduced oxygen saturation and relative hemoglobin concentration were measured in the hepatic and intestinal microcirculation during treatment with V-V ECMO. These animals also showed increased systolic, mean, and diastolic blood pressures. While no differences in left ventricular ejection fraction were observed, animals in the V-V ECMO group presented an increased heart rate, stroke volume, and cardiac output. Blood gas analysis showed dilutional anemia during V-V ECMO, whereas plasma analysis revealed a decreased concentration of IL-10 during V-V ECMO therapy, and BAL measurements showed increased concentrations of TNF-α, CXCL2, and CXCL5. Rats treated with V-V ECMO showed impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Despite lung-protective ventilation, increased pulmonary inflammation was recognized during V-V ECMO therapy in septic shock. Full article

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO₂)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO₂ levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver. Full article

Emphysema is prevalent in various respiratory diseases like Chronic Obstructive Pulmonary Disease (COPD) and cystic fibrosis. Colistin and vasoconstrictive drugs are crucial for treating these patients when diagnosed with sepsis in the ICU. This study examines colistin impact in ether-induced emphysematous septic and non-septic animals, focusing on lung pathophysiology and inflammatory responses, including IL-1β, TNF-α, AMPK, caspase-3, cyclin-D1, and colistin levels in lung tissue. All animals exhibited significant emphysematous changes, accentuated by LPS-induced septic conditions, validating the emphysema model and highlighting the exacerbating effect of sepsis on lung pathology. Colistin, alone or with vasoconstrictive drugs, stimulated immune responses through increased inflammatory cell infiltration and the presence of lymphocytes, indicating potential immunomodulatory effects. Vasoconstriction did not alter the effects of colistin or sepsis but correlated with increased colistin levels in the lungs of septic animals. These observations suggest a potential interplay between vasoconstrictive drugs and colistin distribution/metabolism, leading to enhanced local concentrations of colistin in the lung microenvironment. The findings suggest the need for further investigations to optimize colistin and vasoconstrictive drug delivery in critically ill patients with lung pathologies. Understanding these complexities may guide more effective management of inflammatory responses and lung pathologies in these critical conditions. Full article

Septic shock is characterized by endothelial dysfunction, leading to tissue edema and organ failure. Heparan sulfate (HS) is essential for vascular barrier integrity, possibly via albumin as a carrier. We hypothesized that supplementing fluid resuscitation with HS would improve endothelial barrier function, thereby reducing organ edema and injury in a rat pneumosepsis model. Following intratracheal inoculation with Streptococcus pneumoniae, Sprague Dawley rats were randomized to resuscitation with a fixed volume of either Ringer’s Lactate (RL, standard of care), RL supplemented with 7 mg/kg HS, 5% human albumin, or 5% human albumin supplemented with 7 mg/kg HS (n = 11 per group). Controls were sham inoculated animals. Five hours after the start of resuscitation, animals were sacrificed. To assess endothelial permeability, 70 kD FITC-labelled dextran was administered before sacrifice. Blood samples were taken to assess markers of endothelial and organ injury. Organs were harvested to quantify pulmonary FITC-dextran leakage, organ edema, and for histology. Inoculation resulted in sepsis, with increased lactate levels, pulmonary FITC-dextran leakage, pulmonary edema, and pulmonary histologic injury scores compared to healthy controls. RL supplemented with HS did not reduce median pulmonary FITC-dextran leakage compared to RL alone (95.1 CI [62.0–105.3] vs. 87.1 CI [68.9–139.3] µg/mL, p = 0.76). Similarly, albumin supplemented with HS did not reduce pulmonary FITC-dextran leakage compared to albumin (120.0 [93.8–141.2] vs. 116.2 [61.7 vs. 160.8] µg/mL, p = 0.86). No differences were found in organ injury between groups. Heparan sulfate, as an add-on therapy to RL or albumin resuscitation, did not reduce organ or endothelial injury in a rat pneumosepsis model. Higher doses of heparan sulfate may decrease organ and endothelial injury induced by shock. Full article

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The brain is one of the organs involved in sepsis, and sepsis-induced brain injury manifests as sepsis-associated encephalopathy (SAE). SAE may be present in up to 70% of septic patients. SAE has a very wide spectrum of clinical symptoms, ranging from mild behavioral changes through cognitive disorders to disorders of consciousness and coma. The presence of SAE increases mortality in the population of septic patients and may lead to chronic cognitive dysfunction in sepsis survivors. Therefore, therapeutic interventions with neuroprotective effects in sepsis are needed. Melatonin, a neurohormone responsible for the control of circadian rhythms, exerts many beneficial physiological effects. Its anti-inflammatory and antioxidant properties are well described. It is considered a potential therapeutic factor in sepsis, with positive results from studies on animal models and with encouraging results from the first human clinical trials. With its antioxidant and anti-inflammatory potential, it may also exert a neuroprotective effect in sepsis-associated encephalopathy. The review presents data on melatonin as a potential drug in SAE in the wider context of the pathophysiology of SAE and the specific actions of the pineal neurohormone. Full article

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, with septic cardiomyopathy being a common and severe complication. Despite its significant clinical impact, the molecular mechanisms underlying sepsis-induced cardiomyopathy (SICM) remain incompletely understood. In this study, we performed a comparative analysis of whole transcriptome profiles using RNA sequencing in mouse hearts in two widely used mouse models of septic cardiomyopathy. CLP-induced sepsis was achieved by surgical cecal ligation and puncture, while LPS-induced sepsis was induced using a 5 mg/kg intraperitoneal (IP) injection of lipopolysaccharide (LPS). For consistency, we utilized sham-operated mice as the control for septic models. Our aim was to identify key genes and pathways involved in the development of septic cardiomyopathy and to evaluate the similarities and differences between the two models. Our findings demonstrated that both the CLP and lipopolysaccharide LPS methods could induce septic heart dysfunction within 24 h. We identified common transcriptional regulatory regions in the septic hearts of both models, such as Nfkb1, Sp1, and Jun. Moreover, differentially expressed genes (DEGs) in comparison to control were involved in shared pathways, including regulation of inflammatory response, regulation of reactive oxygen species metabolic process, and the JAK-STAT signaling pathway. However, each model presented distinctive whole transcriptome expression profiles and potentially diverse pathways contributing to sepsis-induced heart failure. This extensive comparison enhances our understanding of the molecular basis of septic cardiomyopathy, providing invaluable insights. Accordingly, our study also contributes to the pursuit of effective and personalized treatment strategies for SICM, highlighting the importance of considering the specific causative factors. Full article

Sex and gender dimorphisms are found in a large variety of diseases, including sepsis and septic shock which are more prevalent in men than in women. Animal models show that the host response to pathogens differs in females and males. This difference is partially explained by sex polarization of the intracellular pathways responding to pathogen–cell receptor interactions. Sex hormones seem to be responsible for this polarization, although other factors, such as chromosomal effects, have yet to be investigated. In brief, females are less susceptible to sepsis and seem to recover more effectively than males. Clinical observations produce more nuanced findings, but men consistently have a higher incidence of sepsis, and some reports also claim higher mortality rates. However, variables other than hormonal differences complicate the interaction between sex and sepsis, including comorbidities as well as social and cultural differences between men and women. Conflicting data have also been reported regarding sepsis-attributable mortality rates among pregnant women, compared with non-pregnant females. We believe that unraveling sex differences in the host response to sepsis and its treatment could be the first step in personalized, phenotype-based management of patients with sepsis and septic shock. Full article