epidermal-growth-factor and Sepsis

This study examined the effects of enterally administered epidermal growth factor (EGF) on nutrient absorption and tolerance of enteral feeds in pediatric patients with short bowel syndrome (SBS).. Patients identified with severe SBS (<25% bowel length predicted for age) were prospectively enrolled in treatment using human recombinant EGF (1-53); 100 microg/kg per day given mixed with enteral feeds and patients were treated for 6 weeks. End points followed were patient weight, tolerance of enteral feeds, nutrient absorption, and intestinal permeability as determined using carbohydrate probes and hematologic values for liver function parameters.. Five patients were treated with EGF; all showed a significant improvement in carbohydrate absorption (3-0 methylglucose): absorption 24.7% +/- 9.7% pretreatment vs 34.1% +/- 13.8% posttreatment and improved tolerance of enteral feeds (enteral energy as % of total energy, 25% +/- 28% pretreatment vs 36% +/- 24% posttreatment; mean +/- SD; P < .05 by Wilcoxon's signed rank test). Epidermal growth factor treatment was not associated with significant changes in intestinal permeability, the rate of weight gain, or liver function tests. During the treatment phase, no patients developed episodes of sepsis; however, within 2 weeks of discontinuation of EGF treatment, 3 patients developed septic episodes. No adverse effects of EGF administration were noted.. These results suggest that enteral treatment with EGF in pediatric SBS improves nutrient absorption, increases tolerance with enteral feeds, and may improve the infection rate. Further studies exploring treatment strategies including the timing and duration of EGF administration are indicated.

Topics: 3-O-Methylglucose; Child, Preschool; Dietary Carbohydrates; Enteral Nutrition; Enterocolitis, Necrotizing; Epidermal Growth Factor; Gastroschisis; Humans; Infant; Infant Food; Intestinal Absorption; Intestinal Volvulus; Lactulose; Liver Function Tests; Male; Mannitol; Pilot Projects; Postoperative Complications; Recombinant Proteins; Sepsis; Short Bowel Syndrome; Weight Gain

The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance.. This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations.. Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1β, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period.. EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal.. NCT03231748, registered on 27th July 2017.

Topics: Acute Kidney Injury; Aged; Chemokine CCL2; Cytokines; Epidermal Growth Factor; Female; Humans; Interferon-gamma; Interleukin-10; Interleukin-1alpha; Interleukin-1beta; Interleukin-2; Interleukin-4; Interleukin-6; Male; Metabolic Clearance Rate; Middle Aged; Peptide Fragments; Prospective Studies; Renal Replacement Therapy; Sepsis; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors

Sepsis is a major cause of death for ICU patients. Sepsis development depends heavily on the presence of mature IL-1β cytokine. This study evaluates the potential therapeutic properties of a bioactive compound known as 6-gingerol on sepsis. This compound has previously been demonstrated to possess anti-inflammatory properties both in vivo and in vitro.. C57BL/6 mice was used to establish models of sepsis by means of cecal ligation and puncture (CLP). Upon treatment with 6-gingerol, we assessed the survival rate of mice and measured the levels of key pro-inflammatory cytokines in serum and colon tissues. Sepsis pathogenesis was further explored using the RAW264.7 cell line and bone marrow-derived macrophages (BMDMs) treated with ATP and lipopolysaccharide (LPS). The impact of 6-gingerol on pyroptosis was also examined. In addition, we assessed the role of MAPK signaling in 6-gingerol-induced effects in BMDMs and RAW264.7 cells.. In CLP mice, 6-gingerol significantly ameliorated sepsis development, which was associated with the reduction of serum IL-1β. In BMDMs and RAW264.7 cells, 6-gingerol strongly attenuated pyroptosis as well as the release of caspase-1p20, HMGB1, mature IL-1β, IL-18 in response to ATP and LPS treatment. 6-Gingerol conferred these effects by blocking MAPK activation. Exposure to an ERK agonist (EGF) reversed effects of 6-gingerol, causing pyroptosis, LDH and caspase-1p20 release.. By targeting MAPK signaling, 6-gingerol significantly suppressed secretion of pro-inflammatory cytokines and inhibited macrophage cells pyroptosis resulting in overall inhibition of sepsis development.

Topics: Adenosine Triphosphate; Animals; Caspase 1; Catechols; Cytokines; Disease Models, Animal; Epidermal Growth Factor; Fatty Alcohols; HMGB1 Protein; Interleukin-18; Interleukin-1beta; Lipopolysaccharides; Macrophages; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Prognosis; Pyroptosis; RAW 264.7 Cells; Sepsis

The focus of sepsis has shifted from inflammation to organ dysfunction on the basis of a recent definition based on the sequential organ failure score (SOFA). A diagnostic and prognostic marker is necessary under this definition but is currently unknown. We enrolled 80 sepsis patients consecutively admitted to an intensive care unit through the emergency department and 80 healthy control patients who received routine health check-ups from August 2018 to January 2019. SEPSIS-3 criteria were used for the diagnosis of patients based on SOFA score ≥ 2 from the baseline along with evidence of infection. Concentrations of 28 cytokines, eight chemokines, and nine growth factors were measured on the day of diagnosis. Hierarchical cluster analysis was performed for molecules. The majority of infections were pneumonia (45% of patients) and urinary tract infections (40% of patients). Most of the measured molecules were increased in patients with sepsis. Area under receiver operating characteristic curve (AUROC) values were found to be as follows: hepatic growth factor (HGF), 0.899; interleukin-1 receptor antagonist (IL-1RA), 0.893; C-C motif ligand 5 (CCL5) 5, 0.887; C-X-C motif chemokine 10 (CXCL10), 0.851; CCL2, 0.840; and IL-6, 0.830. IL-1RA, IL-6, IL-8, IL-15, and CCL11 concentrations correlated with SOFA score with statistical significance. Prognosis multivariate analysis revealed an odds ratio of 0.968 for epidermal growth factor (EGF). Three clusters were formed, of which Clusters 2 and 3 were associated with nonsurvivors. Diagnosis of sepsis was performed using cytokines, chemokines, and growth factors. HGF revealed the highest diagnostic capability, and EGF predicted favorable prognosis among the tested molecules.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Biomarkers; Case-Control Studies; Cytokines; Epidermal Growth Factor; Female; Hepatocyte Growth Factor; Humans; Intensive Care Units; Male; Middle Aged; Odds Ratio; Organ Dysfunction Scores; Pneumonia; Prognosis; Retrospective Studies; ROC Curve; Sepsis; Survival Analysis; Urinary Tract Infections

Epidermal growth factor (EGF) is a cytoprotective protein that improves survival in preclinical models of sepsis through its beneficial effects on intestinal integrity. Alcohol use disorder worsens intestinal integrity and is associated with increased morbidity and mortality in critical illness. We sought to determine whether chronic alcohol ingestion alters the host response to systemic administration of EGF in sepsis. Six-week-old FVB/N mice were randomized to receive 20% alcohol or water for 12 weeks. All mice then underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive either intraperitoneal injection of EGF (150 μg/kg/day) or normal saline. Water-fed mice given EGF had decreased 7-day mortality compared with water-fed mice (18% vs. 55%). Alcohol-fed mice given EGF also had decreased 7-day mortality compared with alcohol-fed mice (48% vs. 79%). Notably, while systemic EGF improved absolute survival to a similar degree in both water-fed and alcohol-fed mice, mortality was significantly higher in alcohol+EGF mice compared with water+EGF mice. Compared with water-fed septic mice, alcohol-fed septic mice had worsened intestinal integrity with intestinal hyperpermeability, increased intestinal epithelial apoptosis, decreased proliferation and shorter villus length. Systemic administration of EGF to septic alcohol-fed mice decreased intestinal permeability compared with septic alcohol-fed mice given vehicle, with increased levels of the tight junction mediators claudin-5 and JAM-A. Systemic administration of EGF to septic alcohol-fed mice also decreased intestinal apoptosis with an improvement in the Bax/Bcl-2 ratio. EGF also improved both crypt proliferation and villus length in septic alcohol-fed mice. EGF administration resulted in lower levels of both pro- and anti-inflammatory cytokines monocyte chemoattractant protein-1, tumor necrosis factor, and interleukin 10 in alcohol-fed mice. EGF is therefore effective at improving both intestinal integrity and mortality following sepsis in mice with chronic alcohol ingestion. However, the efficacy of EGF in sepsis is blunted in the setting of chronic alcohol ingestion, as intestinal integrity and mortality in alcohol-fed mice given EGF improves animals to levels seen in water-fed mice given vehicle but does not approach levels seen in water-fed mice given EGF.

Topics: Alcohol Drinking; Animals; Apoptosis; bcl-2-Associated X Protein; Cell Adhesion Molecules; Cell Proliferation; Chemokine CCL2; Claudin-5; Epidermal Growth Factor; Interleukin-10; Intestinal Mucosa; Intestines; Male; Mice; Receptors, Cell Surface; Sepsis

Sepsis is a systemic host response to infection, and patients with sepsis are frequently handled in the intensive care unit. However, mortality related to sepsis remains high throughout the world. In addition, there have been no efficient prognostic biomarkers for sepsis to be employed in clinical practice. We therefore aimed to identify prognostic biomarkers for sepsis using the chemokine/cytokine array. This study included 143 patients with sepsis, who were divided into survivor and nonsurvivor groups according to their 28-day mortality status. The cytokine array analysis was performed with plasma samples from two randomly selected patients in each sepsiofgroup. We thus identified seven cytokines with significantly and consistently different expression levels between nonsurvivors and survivors. The validity of the selected cytokines was then assessed by enzyme-linked immunosorbent assay (ELISA). We finally found monocyte chemoattractant protein 1 (MCP-1) as the most useful biomarker to distinguish the two sepsis groups; namely, non-surviving patients (n = 56) exhibited significantly higher plasma concentrations of MCP-1 compared to survivors (n = 87). MCP-1 is a CC chemokine, a potent chemoattractant that contributes to systemic inflammatory response syndrome. Areas under the receiver operating characteristic curves for prediction of 28-day mortality were 0.763 for MCP-1, 0.680 for the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) score, 0.64 for the Sequential Organ Failure Assessment (SOFA) score, 0.621 for procalcitonin, and 0.785 for MCP-1 plus APACHE II score. In conclusion, we propose that plasma MCP-1 is a useful biomarker in predicting outcome of sepsis.

Topics: Biomarkers; C-Reactive Protein; Calcitonin; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Interleukin-6; Logistic Models; Male; Middle Aged; Prognosis; Prospective Studies; ROC Curve; Sepsis

Acute kidney injury (AKI) increases the morbidity of critically ill children. Thus, it is necessary to identify better renal biomarkers to follow the outcome of these patients. This prospective case-control study explored the clinical value of a urinary biomarker profile comprised of neutrophil gelatinase lipocalin (uNGAL), fibroblast growth factor-2 (uFGF-2), and epidermal growth factor (uEGF) to follow these patients.. Urine samples were collected from 21 healthy children, and 39 critically ill children (mean age 7.5 years ± 6.97 SD) admitted to a pediatric intensive care unit with sepsis or requiring extra corporeal membrane oxygenation (ECMO). uNGAL, uFGF-2, and uEGF levels were measured using ELISA kits during the first 24 h of admission to PICU, at peak of illness, and upon resolution of the critical illness.. On admission, the uNGAL and uFGF-2 levels were increased, and the uEGF levels were decreased, in critically ill children with AKI (n = 19) compared to those without AKI (n = 20), and healthy controls. A biomarker score using the combined cut-off values of uNGAL, uFGF-2, and uEGF (AUC = 0.90) showed the highest specificity to identify children with AKI, relative to each biomarker alone. uNGAL and uFGF-2 on admission showed high sensitivity and specificity to predict mortality (AUC = 0.82).. The biomarker profile comprised of uNGAL, uFGF-2, and uEGF increased the specificity to detect AKI in critically ill children, when compared to each biomarker used alone. uNGAL and uFGF-2 may also predict the risk of death. Further validation of these findings in a large sample size is warranted.

Topics: Acute Kidney Injury; Biomarkers; Case-Control Studies; Child; Child, Preschool; Creatinine; Critical Care; Critical Illness; Epidermal Growth Factor; Extracorporeal Membrane Oxygenation; Female; Fibroblast Growth Factor 2; Gelatinases; Humans; Infant; Length of Stay; Lipocalins; Male; Neutrophils; Pilot Projects; Predictive Value of Tests; Prognosis; Prospective Studies; ROC Curve; Sepsis; Survival Analysis

Epidermal growth factor (EGF) is a cytoprotective peptide that has healing effects on the intestinal mucosa. We sought to determine whether systemic administration of EGF after the onset of sepsis improved intestinal integrity and decreased mortality. FVB/N mice were subjected to either sham laparotomy or 2 x 23 cecal ligation and puncture (CLP). Septic mice were further randomized to receive injection of either 150 microg kg(-1) d(-1) (i.p.) EGF or 0.9% saline (i.p.). Circulating EGF levels were decreased after CLP compared with sham animals but were unaffected by giving exogenous EGF treatment. In contrast, intestinal EGF levels increased after CLP and were further augmented by exogenous EGF treatment. Intestinal EGF receptor was increased after CLP, whether assayed by immunohistochemistry, real-time polymerase chain reaction, or Western blot, and exogenous EGF treatment decreased intestinal EGF receptor. Villus length decreased 2-fold between sham and septic animals, and EGF treatment resulted in near total restitution of villus length. Sepsis decreased intestinal proliferation and increased intestinal apoptosis. This was accompanied by increased expression of the proapoptotic proteins Bid and Fas-associated death domain, as well as the cyclin-dependent kinase inhibitor p21 cip1/waf Epidermal growth factor treatment after the onset of sepsis restored both proliferation and apoptosis to levels seen in sham animals and normalized expression of Bid, Fas-associated death domain, and p21 cip1/waf . To determine whether improvements in gut homeostasis were associated with a decrease in sepsis-induced mortality, septic mice with or without EGF treatment after CLP were followed 7 days for survival. Mortality decreased from 60% to 30% in mice treated with EGF after the onset of sepsis (P < 0.05). Thus, EGF may be a potential therapeutic agent for the treatment of sepsis in part due to its ability to protect intestinal integrity.

Topics: Animals; Apoptosis; Cecum; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Epidermal Growth Factor; Intestines; Ligation; Mice; Punctures; Sepsis

To study an early comprehensive prevention and treatment of sepsis in severely burned patients with delayed fluid resuscitation.. From January 1990 to December 2001, 72 cases of patients with delayed fluid resuscitation were admitted to our burn department. Two different periods were divided and analyzed retrospectively. The first period was from January 1990 to December 2001 and the span of the second period was from January 1995 to December 2001.. (1)The mortality rate and incidence of sepsis in the second period (6.5 percent and 17.4 percent) were significantly lower than those of the first period (23.0 percent and 57.7 percent, P<0.05 and P<0.01). (2)The time of wound healing in the second period was (1.9+/-0.9) hours, it was lower than that of the first period (6.6+/-2.5) hours. (3)The serum contents of tumor necrosis factor (TNF) and blood lactic acid (BLA) were increased at all times in two periods and were markedly increased in the first period (all P<0.01).. Our data demonstrated that measures adopted in the second period for patients with delayed fluid resuscitation, including early excision, early rapid adequate resuscitation, early enteral feeding, increased immunity function, early applying antibactials, xenotransfusion of ultraviolet-irradiated blood, application of recombinant human-growth factor (rh-GH), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), are beneficial to the prevention and treatment of sepsis in severely burned patients with delayed fluid resuscitation.

Topics: Adult; Anti-Bacterial Agents; Burns; Epidermal Growth Factor; Female; Fibroblast Growth Factor 2; Fibroblast Growth Factors; Fluid Therapy; Human Growth Hormone; Humans; Lactic Acid; Male; Middle Aged; Nutrition Therapy; Prognosis; Sepsis; Time Factors; Trauma Severity Indices; Treatment Outcome; Tumor Necrosis Factor-alpha