Intense Systemic Inflammatory Response Research Articles

Functional Evaluation of Microcirculation in Response to Fluid Resuscitation in Hypovolemic Adult Post-cardiac Surgical Patients

Objectives: Microcirculation is bound to be altered during cardiac surgery due to multiple factors, mainly the intense systemic inflammatory response syndrome which peaks in the first 24-h postoperatively. Decreased microvascular flow associated with increased postoperative morbidity has been reported. The literature suggests a potential independence of macrocirculation and microcirculation during fluid loading. The present study was conducted to assess thenar muscle tissue oxygen saturation (StO2) changes during vascular occlusion test (VOT) in response to hypovolemia and to assess the dynamic responses of the StO2 variables post-volume expansion (VE). Material and Methods: Thirty-five adult post-cardiac surgical patients, with stroke volume (SV) variation >12% were included in the study. Fifty-two fluid challenges were studied. Functional evaluation of microcirculation using VOT and near infrared spectroscopy (NIRS) variables along with monitoring of macrocirculatory indices was performed before and after VE. Statistical analysis was done using Student t-test. Results: Post-VE, 34 were responders with increase in SV ≥15% and 18 were non-responders (SV <15%). Rate of resaturation was significantly faster in responders compared to non-responders after VE (P = 0.0293 vs. P = 0.1480). However, macrocirculatory indices including cardiac output, SV, and delivery of oxygen showed significant improvement in both responders and non-responders. Conclusion: Preload dependence is associated with significant change in the StO2 recovery slope measured at the thenar eminence in volume responders. Functional evaluation of microcirculation using VOT and StO2 can be a useful complimentary tool along with the macrocirculatory indices for optimal fluid rescuscitaion in adult post-cardiac surgical patients.

Mitigating neutrophil trafficking and cardiotoxicity with DS-IkL in a microphysiological system of a cytokine storm.

A feature of severe COVID-19 is the onset of an acute and intense systemic inflammatory response referred to as the "cytokine storm". The cytokine storm is characterized by high serum levels of inflammatory cytokines and the subsequent transport of inflammatory cells to damaging levels in vital organs (e.g., myocarditis). Immune trafficking and its effect on underlying tissues (e.g., myocardium) are challenging to observe at a high spatial and temporal resolution in mouse models. In this study, we created a vascularized organ-on-a-chip system to mimic cytokine storm-like conditions and tested the effectiveness of a novel multivalent selectin-targeting carbohydrate conjugate (composed of DS - dermatan sulfate and IkL - a selectin-binding peptide, termed DS-IkL) in blocking infiltration of polymorphonuclear leukocytes (PMN). Our data shows that cytokine storm-like conditions induce endothelial cells to produce additional inflammatory cytokines and facilitate infiltration of PMNs into tissue. Treatment of tissues with DS-IkL (60 μM) reduced PMN accumulation in the tissue by >50%. We then created cytokine storm-like conditions in a vascularized cardiac tissue-chip and found that PMN infiltration increases the spontaneous beating rate of the cardiac tissue, and this effect is eliminated by treatment with DS-IkL (60 μM). In summary, we demonstrate the utility of an organ-on-a-chip platform to mimic COVID-19 related cytokine storm and that blocking leukocyte infiltration with DS-IkL could be a viable strategy to mitigate associated cardiac complications.

46 Bardoxolone-methyl Microparticles Ameliorate Immune Dysfunction Following Burn and Inhalation Injury Through the NRF2/KEAP1 Axis

IntroductionSevere burn injury leads to many systemic stresses that can seriously impact multiple systems throughout the body. These stresses are further exacerbated if there is a combined burn and inhalation injury, which leads to increased morbidity and mortality for many patients. Combined burn and inhalation injury causes an intense systemic inflammatory response and activation of the innate immune system which can lead to inflammatory complications, such as systemic inflammatory response syndrome and multiple organ failure. Nuclear Factor-Erythroid-2-Related Factor (NRF2) is a transcription factor that acts to downregulate overt damaging pro-inflammatory and oxidative responses and maintain immune homeostasis. This transcription factor remains bound to Kelch-like ECH-associated protein 1 (KEAP1) in the cytoplasm. Under oxidative stress, NRF2 dissociates from KEAP1 and translocates to the nucleus where it facilitates the transcription of anti-inflammatory and antioxidant genes. We hypothesized that NRF2 is a key regulator after burn and inhalation injury, and activation of NRF2 can limit the severity of burn and inhalation injury.MethodsTo test this, we have developed a mouse model of combined cutaneous burn and woodsmoke inhalation injury. After burn and inhalation injury, we found that NRF2-/- knockout mice have higher mortality compared to wild-type (WT) mice and suffer from increased vascular permeability and lung edema, suggesting that this transcription factor is important for controlling morbidity and mortality. In WT mice, NRF2 is activated following burn and inhalation injury, however, based on immunohistochemical staining, it is not sufficiently induced following this insult since it remains in the cytoplasm and is unable to transcribe anti-inflammatory genes. Therefore, we treated WT mice with an intraperitoneal injection of bardoxolone-methyl microparticles, a NRF2 activator that separates KEAP1 from NRF2 in the cytoplasm, immediately after burn and inhalation injury in WT miceResultsWe observed significant decreases in mortality as well as reduced concentrations of certain pro-inflammatory cytokines in the blood and bronchoalveolar-lavage fluid of these mice. In the lungs of these mice, there was an upregulation in numerous pathways involved in the management of inflammation and immune response compared to mice that did not receive bardoxolone-methyl microparticles.ConclusionsIn conclusion, treatment with bardoxolone-methyl microparticles immediately after burn and inhalation injury might be effective for reducing the severity of the inflammatory response and limiting inflammatory complications.

Surgical procedures suppress autophagic flux in the kidney

Many surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy. Genes associated with lysosomal biogenesis and function were decreased in sham surgery and UNX kidneys. In both sham surgery and UNX, there was suppressed autophagic flux in the kidney as indicated by the lack of an increase in LC3-II or autophagosomes seen on immunoblot, IF and EM after bafilomycin A1 administration and a concomitant increase in p62, a marker of autophagic cargo. There was a massive increase in pro-inflammatory cytokines, which are known to activate ERK1/2, in the serum after sham surgery and UNX. There was a large increase in ERK1/2 in sham surgery and UNX kidneys, which was blocked by the MEK1/2 inhibitor, trametinib. Trametinib also resulted in a significant decrease in p62. In summary, there was an intense systemic inflammatory response, an ERK-mediated increase in p62 and suppressed autophagic flux in the kidney after sham surgery and UNX. It is important that researchers are aware that changes in systemic pro-inflammatory cytokines, ERK1/2 and autophagy can be caused by sham surgery as well as the kidney injury/disease itself.

Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF

Systemic inflammation and organ failure(s) are the hallmarks of acute-on-chronic liver failure (ACLF), yet their pathogenesis remains uncertain. Herein, we aimed to assess the role of amino acids in these processes in patients with ACLF. The blood metabolomic database of the CANONIC study (comprising 137 metabolites, with 43% related to amino acids) - obtained in 181 patients with ACLF and 650 with acute decompensation without ACLF (AD) - was reanalyzed with a focus on amino acids, in particular 9 modules of co-regulated metabolites. We also compared blood metabolite levels between ACLF and AD. The main findings in ACLF were: i) Metabolite modules were increased in parallel with increased levels of markers of systemic inflammation and oxidative stress. ii) Seventy percent of proteinogenic amino acids were present and most were increased. iii) A metabolic network, comprising the amino acids aspartate, glutamate, the serine-glycine one-carbon metabolism (folate cycle), and methionine cycle, was activated, suggesting increased purine and pyrimidine nucleotide synthesis. iv) Cystathionine, L-cystine, glutamate and pyroglutamate, which are involved in the transsulfuration pathway (a methionine cycle branch) were increased, consistent with increased synthesis of the antioxidant glutathione. v) Intermediates of the catabolism of 5 out of the 6 ketogenic amino acids were increased. vi) The levels of spermidine (a polyamine inducer of autophagy with anti-inflammatory effects) were decreased. In ACLF, blood amino acids fueled protein and nucleotide synthesis required for the intense systemic inflammatory response. Ketogenic amino acids were extensively catabolized to produce energy substrates in peripheral organs, an effect that was insufficient because organs failed. Finally, the decrease in spermidine levels may cause a defect in autophagy contributing to the proinflammatory phenotype in ACLF. Systemic inflammation and organ failures are hallmarks of acute-on-chronic liver failure (ACLF). Herein, we aimed to characterize the role of amino acids in these processes. The blood metabolome of patients with acutely decompensated cirrhosis, and particularly those with ACLF, reveals evidence of intense skeletal muscle catabolism. Importantly, amino acids (along with glucose), are used for intense anabolic, energy-consuming metabolism in patients with ACLF, presumably to support de novo nucleotide and protein synthesis in the activated innate immune system.

Vasopressor Therapy in the Intensive Care Unit

After fluid administration for vasodilatory shock, vasopressors are commonly infused. Causes of vasodilatory shock include septic shock, post-cardiovascular surgery, post-acute myocardial infarction, postsurgery, other causes of an intense systemic inflammatory response, and drug -associated anaphylaxis. Therapeutic vasopressors are hormones that activate receptors-adrenergic: α1, α2, β1, β2; angiotensin II: AG1, AG2; vasopressin: AVPR1a, AVPR1B, AVPR2; dopamine: DA1, DA2. Vasopressor choice and dose vary widely because of patient and physician practice heterogeneity. Vasopressor adverse effects are excessive vasoconstriction causing organ ischemia/infarction, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. To date, no randomized controlled trial (RCT) of vasopressors has shown a decreased 28-day mortality rate. There is a need for evidence regarding alternative vasopressors as first-line vasopressors. We emphasize that vasopressors should be administered simultaneously with fluid replacement to prevent and decrease duration of hypotension in shock with vasodilation. Norepinephrine is the first-choice vasopressor in septic and vasodilatory shock. Interventions that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality significantly. In patients not responsive to norepinephrine, vasopressin or epinephrine may be added. Angiotensin II may be useful for rapid resuscitation of profoundly hypotensive patients. Inotropic agent(s) (e.g., dobutamine) may be needed if vasopressors decrease ventricular contractility. Dopamine has fallen to almost no-use recommendation because of adverse effects; angiotensin II is available clinically; there are potent vasopressors with scant literature (e.g., methylene blue); and the novel V1a agonist selepressin missed on its pivotal RCT primary outcome. In pediatric septic shock, vasopressors, epinephrine, and norepinephrine are recommended equally because there is no clear evidence that supports the use of one vasoactive agent. Dopamine is recommended when epinephrine or norepinephrine is not available. New strategies include perhaps patients will be started on several vasopressors with complementary mechanisms of action, patients may be selected for particular vasopressors according to predictive biomarkers, and novel vasopressors may emerge with fewer adverse effects.

Influence of postoperative complications on long-term outcome after oncologic lung resection surgery. Substudy of a randomized control trial.

Lung resection surgery (LRS) causes an intense local and systemic inflammatory response. There is a relationship between inflammation and postoperative complications (POCs). Also, it has been proposed that the inflammation and complications related with the surgery may promote the recurrence of cancer and therefore deteriorationof survival. We investigated the association between inflammatory biomarkers, severity of POCs and long-term outcome in patients who were discharged after LRS. This is a prospective substudy of a randomized control trial. We established three groups based in the presence of POCs evaluated by Clavien-Dindo (C-D) classification: Patients with no postoperative complications (No-POCs group) (C-D = 0), patients who developed light POCs (L-POCs group) (C-D = I-II), and major POCs (M-POCs group) (C-D = III, IV, or V). Kaplan-Meier curves and Cox regression model were created to compare survival and oncologic recurrence in those groups. Patients who developed POCs (light or major) had an increase in some inflammatory biomarkers (TNF-α, IL-6, IL-7, IL-8) compared with No-POCs group. This pro-inflammatory status plays a fundamental role in the appearance of POCs and therefore in a shorter life expectancy. Individuals in the M-POCs group had a higher risk of death (HR = 3.59, 95% CI 1.69 to 7.63) compared to individuals in the No-POCs group (p = 0.001). Patients of L-POCs group showed better survival than M-POCs group (HR = 2.16, 95% CI 1.00 to 4.65, p = 0.049). Besides, M-POCs patients had higher risk of recurrence in the first 2years, when compared with L-POCs (p = 0,008) or with No-POCs (p = 0.002). In patients who are discharged after undergoing oncologic LRS, there is an association between POCs occurrence and long term outcome. Oncologist should pay special attention in patients who develop POCs after LRS.

Polymyalgia Rheumatica: a Common Disease in Seniors.

Polymyalgia rheumatica (PMR) is one of the most common inflammatory rheumatologic condition occurring in older adults. It is characterized by proximal pain and stiffness in the shoulders, neck, and/or pelvic girdle in individuals over 50years of age along with evidence of an intense systemic inflammatory response. Although the above clinical symptoms are very characteristic for the condition, it can be mimicked by other autoimmune, infectious, malignant, and endocrine disorders chief among which are giant cell arteritis (GCA) and elderly-onset rheumatoid arthritis (EORA). Recently, PMR was reported in relation to treatment with immune checkpoint inhibitors. Current treatment of PMR consists of low-to-medium doses of glucocorticosteroids (GC) with variable response rates and disease recurrence estimated to occur in 50% of patients while tapering down GC doses. In addition, GC-based regimens cause much of the morbidity associated with PMR in older adults, requiring close monitoring for GC-induced toxicity during therapy and highlighting the need for novel therapeutic strategies. Here, we review the latest findings in the field regarding specific etiologic factors, genetic associations, diagnostic methods, and advancements in treatment strategies and disease monitoring indices. Recent discoveries involving novel therapeutic targets in GCA have accelerated the study of PMR pathophysiology and have advanced treatment strategies in PMR management leading to current trials in IL-6 blocking agents. PMR remains an enigmatic inflammatory condition affecting older adults, with current treatment approach causing much morbidity in this patient population. Advancements in our understanding of novel immunopathologic targets can serve as a solid foundation for future treatment strategies in the field.

Systemic inflammation status at admission affects the outcome of intracerebral hemorrhage by increasing perihematomal edema but not the hematoma growth

Acute stress and inflammation responses are associated with worse outcomes in intracerebral hemorrhage (ICH) but the precise mechanisms involved are unclear. We evaluated the effect of neutrophil-to-lymphocyte ratio (NLR) in ICH outcome, with focus on hematoma expansion and early cerebral edema. In a retrospective study, we included all patients with primary ICH admitted to our center within 24-h from symptom onset from January 2014 to February 2015. We retrieved demographic and medical history data, Glasgow Coma Scale scores, blood cell counts, glucose, and C-reactive protein, and calculated NLR. We obtained hematoma volumes by computerized planimetry. Outcomes included independence at 90days (modified Rankin scale 0-2), mortality at 30days, significant hematoma expansion (> 33% or > 6mL) and early cerebral edema causing significant midline shift (> 2.5mm) at 24h. We included 135 patients. NLR independently associated with independence at 90days (adjusted odds ratio (aOR) 0.79, 95% CI 0.67-0.93, p = 0.006) significant cerebral edema (aOR 1.08, 95%CI 1.01-1.15, p = 0.016) but not hematoma expansion (aOR 0.99, 95%CI 0.94-1.04, p = 0.736). The severity of midline shift was positively correlated with NLR (adjusted beta = 0.08, 95% CI 0.05-0.11, p < 0.001). In ICH, an immediate and intense systemic inflammatory response reduces the likelihood of a better functional outcome at 90days, which is more likely to be explained by perihematomal edema growth than due to a significant hematoma expansion. These findings could have implications in new treatment strategies and trial designs, which endpoints tend to target exclusively hematoma enlargement.

COVID-19 and heart: relationship of cardiac tropism of the new coronavirus in affected patients/COVID-19 e coração: relação do tropismo cardíaco do novo coronavírus em doentes afectados

At the end of a year 2019, an epidemic began in China, causing a severe respiratory syndrome, and in the months of March considered a pandemic. A family of this virus, however, has been known in the scientific community since 2002, since SARS. Among the severe forms of the disease, there is an intense systemic inflammatory response caused by COVID-19 that can cause cardiac injuries. In view of this, the global impact caused by the epidemic of the new coronavirus associated with the cardiac manifestations triggered by it has become necessary to carry out studies, aiming to better establish this relationship. Therefore, a bibliographic review was carried out in different databases such as Scielo and PubMed, using the descriptors "COVID-19", "new coronavirus". How results were found several researches were carried out after the evidence of influencing SARS-COV-19 on the cardiovascular system, including some published materials, which show cases of heart failure initiated in infarction, myocardial infarction, myocardium and cardiac arrest present in patients infected with COVID - 19. In view of the current world scenario that presents a pandemic, patients with previous comorbidities, especially cardiovascular and metabolic diseases, are at a higher risk of developing a serious disease and this requires more frequent monitoring and follow-up under heart failure.

Nasopharyngeal Carriage of Invasive Pneumococcal Serotypes During Childhood Community-Acquired Alveolar Pneumonia Is Associated With Specific Clinical Presentation.

Streptococcus pneumoniae (Pnc) serotypes differ in invasive potential. We examined whether community-acquired alveolar pneumonia (CAAP) in children carrying commonly recognized pneumonia invasive pneumococcal serotypes ([PnIST] 1, 5, 7F, 14, and 19A) differs from CAAP in children carrying less invasive serotypes (non-PnIST) or no Pnc (Pnc-neg). Children <5 years, visiting the only regional Pediatric Emergency Room, with radiologically proven CAAP were enrolled. Nasopharyngeal cultures were processed for pneumococcal isolation and serotyping. Clinical and demographic characteristics were recorded. The study was conducted before pneumococcal conjugate vaccine implementation in Israel. A total of 1423 CAAP episodes were recorded: PnIST, 300 (21.1%); non-PnIST, 591 (41.5%); and Pnc-neg, 532 (37.4%). After adjustment for age, ethnicity, seasonality, and previous antibiotics, the following variables were positively associated with PnIST carriage compared with both groups: temperature ≥39°C, peripheral white blood cell count ≥20 000/mm3, C-reactive protein ≥70.0 mg/L, and serum sodium <135 mEq/L. Lower oxygen saturation, viral detection, and comorbidities were negatively associated with Pn-IST carriage (odds ratios, <1.0). Differences between non-PnIST carriers and Pnc-neg groups were smaller or nonsignificant. Young children with CAAP carrying common PnIST had a lower proportion of comorbidities, hypoxemia, and viral detection and had more intense systemic inflammatory response than those carrying non-PnIST or not carrying Pnc.

Inflammatory response and recurrence after minimally invasive esophagectomy.

Esophagectomy for esophageal cancer is a very invasive surgery that induces an intense systemic inflammatory response. Postoperative infectious complications worsen survival after esophagectomy through inflammatory responses, and this study aimed to investigate the impact of the response on disease recurrence. We assessed 230 patients who underwent curative minimally invasive esophagectomy for esophageal squamous cell carcinoma. The area under the curve of serum C-reactive protein levels from preoperative day through postoperative day 7 was defined as the cumulative magnitude of postoperative inflammatory response. Relapse-free survival was compared among quartiles of the area, and fourth quartile showed the worst relapse-free survival. Patients in the fourth quartile were the high group, and others were low group. Compared with low group (n = 173), high group (n = 57) showed significantly worse relapse-free survival and overall survival (P = 0.014 and 0.028, respectively). Multivariate analyses found that high group (P = 0.048) was an independent risk factor for recurrence but not overall survival. Higher body mass index (P < 0.001) and postoperative infections (P < 0.001) were independent risk factors to become high group. However, the influence of high group on recurrence was not affected by postoperative infections in interaction analysis (P = 0.889). Postoperative intense systemic inflammatory response independently increased the risk of recurrence after curative minimally invasive esophagectomy for esophageal squamous cell carcinoma. Factors associating with intensified inflammatory response are higher body mass index and postoperative infections. Therefore, surgeons should make every effort to prevent postoperative infections to improve the long-term outcomes of patients.

Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis.

Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in leukocyte dysregulation and host tissue damage. The lung is particularly susceptible to systemic inflammation, leading to acute lung injury. Key to inflammation-induced lung damage is the excessive migration of neutrophils across the vascular endothelium. The mechanisms which regulate neutrophil activation and migration in sepsis are not well defined but there is growing evidence that platelets are actively involved and play a key role in microvascular permeability and neutrophil-mediated organ damage. We previously identified PKC-delta (PKCδ) as a critical regulator of the inflammatory response in sepsis and demonstrated PKCδ inhibition was lung protective. However, the role of PKCδ in sepsis-induced platelet activation and platelet-leukocyte interactions is not known. In this study, rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Following surgeries, a PKCδ inhibitor (200μg/kg) or vehicle (PBS) was administered intra-tracheally. At 24 hours post-surgeries, lung tissue, BAL fluid, and blood samples were collected. While sepsis caused thrombocytopenia, the remaining circulating platelets were activated as demonstrated by increased p-selectin expression, elevated plasma PF4, and enhanced platelet-leukocyte aggregate formation compared to Sham animals. Platelet activation was associated with increased platelet PKCδ activity. Inhibition of PKCδ attenuated sepsis-induced platelet activation, secretion and aggregate formation. Sepsis-induced thrombocytopenia was also significantly reduced and circulating platelet numbers were similar to sham animals. In the lung, sepsis induced significant influx of platelets and neutrophils and the development of lung injury. Administration of the PKCδ inhibitor decreased platelet and neutrophil influx, and was lung protective. Thus, PKCδ inhibition modulated platelet activity both locally and systemically, decreased neutrophil influx into the lung, and was lung protective. We demonstrate for the first time that PKCδ plays an important role in platelet activation and platelet-neutrophil interaction during sepsis.

The Acute-on-Chronic Liver Failure Syndrome, or When the Innate Immune System Goes Astray.

The acute-on-chronic liver failure (ACLF) syndrome is characterized by acute decompensation of cirrhosis, organ failure, and high 28-d mortality. ACLF displays key features of systemic inflammation and its poor outcome is closely associated with exacerbated systemic inflammatory responses. In this review, we describe the prevailing characteristics of systemic inflammation in patients with decompensated cirrhosis and ACLF, with special emphasis on the principal features of the cytokine storm the mechanisms underlying this intense systemic inflammatory response (i.e., presence of circulating pathogen- and damage-associated molecular patterns), and their implication in tissue and organ damage in this condition.

Activation of the cholinergic anti-inflammatory pathway by nicotine ameliorates lipopolysaccharide-induced preeclampsia-like symptoms in pregnant rats

IntroductionPreeclampsia (PE) exerts a more intense systemic inflammatory response than normal pregnancy. Recently, the role of the cholinergic anti-inflammatory pathway (CAP) in regulating inflammation has been extensively studied. The aim of this study was to investigate the effect of nicotine, a selective cholinergic agonist, on lipopolysaccharide (LPS)-induced preeclampsia-like symptoms in pregnant rats and to determine the molecular mechanism underlying it. MethodsRats were administered LPS (1.0 μg/kg) via tail vein injection on gestational day 14 to induce preeclampsia-like symptoms. Nicotine (1.0 mg/kg/d) and α-bungarotoxin (1.0 μg/kg/d) were injected subcutaneously into the rats from gestational day 14–19. Clinical symptoms were recorded. Serum and placentas were collected to determine cytokine levels using Luminex. The mRNA and protein expression levels of α7 nicotinic acetylcholine receptor (α7nAChR) were determined using Real time-PCR and Western blot analysis. Immunohistochemistry was performed to determine the level of activation of nuclear factor-κB (NF-κB) in placentas. ResultsNicotine significantly ameliorated LPS-induced preeclampsia-like symptoms in pregnant rats (P < 0.05). Nicotine treatment decreased the levels of LPS-induced pro-inflammatory cytokines in the serum (P < 0.05) and placenta (P < 0.05). Nicotine significantly increased the expression of α7nAChR (P < 0.01) and attenuated the activation of NF-κB p65 in the placenta in LPS-induced preeclampsia (P < 0.01). Meanwhile, these protective effects of nicotine were abolished by the administration of the cholinergic antagonist α-bungarotoxin in preeclampsia rats. DiscussionOur findings suggest that the activation of α7nAChR by nicotine attenuates preeclampsia-like symptoms, and this protective effect is likely the result of the inhibition of inflammation via the NF-κB p65 pathway.

Preoperative High Dose of Methylprednisolone Improves Early Postoperative Pulmonary Function, in Super-Obese Patients Undergoing Open Surgery; a Prospective, Comparative Study

BackgroundSurgery stimulates an intense systemic inflammatory response which might increase postoperative morbidity. Corticosteroids may reduce this inflammatory reaction. The purpose of this study was to investigate any possible effect on postoperative morbidity and recovery after administrating methylprednisolone in super-obese patients undergoing open surgery. MethodsSixty super-obese patients with BMI ≥50 kg/m2 (mean 57.48 ± 7.33), mean age of 39 ± 9 years, who underwent an open bariatric procedure, were enrolled. Thirty patients (group A) were allocated to a preoperative single dose of 30 mg/kg (ideal body weight) methylprednisolone versus placebo (group B, 30 patients). Endpoints included assessment of IL-6 and CRP; evaluation of postoperative pulmonary function, pain management, nausea, and vomiting; and documentation of postoperative complications. ResultsSignificant improvement in spirometry parameters and arterial blood gas analysis, in the first and third postoperative days, was observed in the methylprednisolone group. IL-6 and CRP levels were significantly lower in that group. Administration of methylprednisolone was associated with less postoperative pain, nausea, and vomiting, with no statistical difference in septic complications. ConclusionsPreoperative administration of a single high dose of methylprednisolone in super-obese patients undergoing open surgery inhibits the inflammatory signaling cascade, lessens the systemic inflammatory response, and results in fewer pulmonary complications and better patient recovery.

Elevated plasma heparin-binding protein is associated with early death after resuscitation from cardiac arrest.

BackgroundAn intense systemic inflammatory response is observed following reperfusion after cardiac arrest. Heparin-binding protein (HBP) is a granule protein released by neutrophils that intervenes in endothelial permeability regulation. In the present study, we investigated plasma levels of HBP in a large population of patients resuscitated from out-of-hospital cardiac arrest. We hypothesized that high circulating levels of HBP are associated with severity of post-cardiac arrest syndrome and poor outcome.MethodsPlasma was obtained from 278 patients enrolled in a prospective multicenter observational study in 21 intensive care units (ICU) in Finland. HBP was assayed at ICU admission and 48 h later. Multiple organ dysfunction syndrome (MODS) was defined as the 24 h Sequential Organ Failure Assessment (SOFA) score ≥ 12. ICU death and 12-month Cerebral Performance Category (CPC) were evaluated. Multiple linear and logistic regression tests and receiver operating characteristic curves with area under the curve (AUC) were performed.ResultsEighty-two percent of patients (229 of 278) survived to ICU discharge and 48 % (133 of 276) to 1 year with a favorable neurological outcome (CPC 1 or 2). At ICU admission, median plasma levels of HBP were markedly elevated, 15.4 [9.6–31.3] ng/mL, and persisted high 48 h later, 14.8 [9.8–31.1] ng/mL. Admission levels of HBP were higher in patients who had higher 24 h SOFA and cardiovascular SOFA score (p < 0.0001) and in those who developed MODS compared to those who did not (29.3 [13.7–60.1] ng/mL vs. 13.6 [9.1–26.2] ng/mL, p < 0.0001; AUC = 0.70 ± 0.04, p = 0.0001). Admission levels of HBP were also higher in patients who died in ICU (31.0 [17.7–78.2] ng/mL) compared to those who survived (13.5 [9.1–25.5] ng/mL, p < 0.0001) and in those with an unfavorable 12-month neurological outcome compared to those with a favorable one (18.9 [11.3–44.3] ng/mL vs. 12.8 [8.6–30.4] ng/mL, p < 0.0001). Admission levels of HBP predicted early ICU death with an AUC of 0.74 ± 0.04 (p < 0.0001) and were independently associated with ICU death (OR [95 %CI] 1.607 [1.076–2.399], p = 0.020), but not with unfavorable 12-month neurological outcome (OR [95 %CI] 1.154 [0.834–1.596], p = 0.387).ConclusionsElevated plasma levels of HBP at ICU admission were independently associated with early death in ICU.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1412-4) contains supplementary material, which is available to authorized users.

40 Gestational choline supplementation prevents inflammatory responses of lipopolysaccharide-induced preeclampsia in pregnant rats

Introduction Pre-eclampsia (PE) exerts more intense systemic inflammatory response than normal pregnancy. We have demonstrated that the cholinergic anti-inflammatory pathway may contribute to the relief of Pre-eclampsia through α 7 nicotinic acetylcholine receptor ( α 7 nAChR). Furthermore, choline, an essential nutrient that is meanwhile a selective α 7 nAChR agonist, has been proved to prevent LPS-induced preeclampsia symptoms in rats. Objectives The objective of the study was to examine the effects of choline, an essential nutrient that is meanwhile a selective α 7 nAChR agonist, on the prevention of symptoms and inflammatory responses of preeclampsia in rats. Methods Preeclampsia model was induced by lipopolysaccharide (1.0 μ g/kg) via tail vein injection on gestational day (GD) 14. Pregnant SD rats were placed on a supplemented (5.0 g/kg diet) or normal (1.1 g/kg diet) choline diet throughout gestation. All the rats were divided into 4 groups (P = normal pregnant +1.1 g/kg choline diet; P-CHOLINE = normal pregnant +5.0 g/kg choline diet; PE = LPS +1.1 g/kg choline diet; PE-CHOLINE = LPS +5.0 g/kg choline diet). Maternal blood and placentas were collected on GD20 and assayed for pro-inflammatory cytokines (TNF- α , IL-1 β , IL-6, IL-2, IL-17, IFN- γ , GM-CSF) and anti-inflammatory cytokines (IL-4, IL-10). Results LPS treatment significantly elevates maternal blood levels of TNF- α , IL-1 β , IL-6, IL-17, IFN- γ , GM-CSF and reduced the levels of IL-4. The blood levels of IL-2 and IL-10 show no significant differences between the P and PE group. Of interest, choline supplementation during pregnancy significantly inhibited LPS-induced release of TNF-a, IL-1 β , IL-6, IL-17, IFN- γ , except for GM-CSF , and increased the level of IL-4. Correspondingly, in placenta, the levels of TNF- α , IL-1 β , IL-6, IL-17, GM-CSF and IL-2 were significantly increased after LPS administration, while the level of IL-4 was significantly decreased. The placenta levels of IFN- γ and IL-10 show no significant differences between the P and PE group. Similarly, choline supplementation during pregnancy significantly attenuated LPS-induced TNF- α , IL-1 β , IL-6 and IL-17 concentrations, except for IL-2, meanwhile, increased the level of IL-4. Conclusions Choline supplementation during pregnancy prevents the LPS-induced symptoms and inflammatory responses of preeclampsia in rats. These observations have important implications for prevention of inflammatory responses in preeclampsia.

6 Association between proinflammatory cytokines and deficient vitamin D levels in early-onset preeclampsia

Introduction Preeclampsia (PE) is a pregnancy specific syndrome characterized by intense systemic inflammatory response and abnormally activated phenotype of immune cells. The imbalance between pro- and anti-inflammatory cytokines seems to be dependent on the deficiency of regulatory factors capable of modulating this inflammatory response. Vitamin D plays an important role in the modulation of immune/inflammation system by regulating the production of inflammatory cytokines and generating an immune tolerogenic status. Objectives Since vitamin D deficiency has been reported in pregnant women with PE the present study assessed whether there is an association between plasma levels of vitamin D and pro-inflammatory and anti-inflammatory cytokines in this gestational pathology. Methods Plasma concentrations of 25-hydroxyvitamin D [25(OH)D] was evaluated by chemiluminescence, and the levels of Interleukin-1beta (IL-1b), IL-10 and tumor necrosis factor (TNF- α \) were determined by enzyme-linked immunosorbent assay (ELISA) in the plasma of 40 normotensive pregnant women, 45 women with early-onset PE and 75 women with late-onset PE. Differences between groups were analyzed by non-parametric tests with significance level set at 5%. Results The plasma concentration of 25(OH)D was significantly lower in early-onset PE group compared with the late-onset PE and normotensive groups, while the levels of TNF- α and IL-1 β were significantly higher in the early-onset PE group. Moreover, IL-10 levels were significantly lower in the both groups of preeclamptic women than in the normotensive group. A negative correlation between the values of 25(OH)D and TNF- α ( r =−0.6454, p β ( r =−0.4330, p =0.0059) was detected in early-onset PE women. Positive correlation between IL-10 and 25(OH)D plasma levels was observed in the three groups studied: early PE ( r =0.3403, p =0.0340), late-onset PE ( r =0.3512, p =0.0023) and normotensive pregnant women ( r =0.5629, p =0.0127). Conclusion The inverse association between circulating levels of 25(OH)D and the inflammatory cytokines TNF- α and IL-1 β detected in early-onset PE women suggest a deficient immunomodulatory role of vitamin D in the systemic inflammatory response of this form of PE.

Acute-on-chronic liver failure: a new syndrome in cirrhosis.

Patients with cirrhosis who are hospitalized for an acute decompensation (AD) and also have organ failure(s) are at high risk of short-term death. These patients have a syndrome called Acute-on-Chronic Liver Failure (ACLF). ACLF is now considered as a new syndrome that it is distinct from “mere” AD not only because of the presence of organ failure(s) and high short-term mortality but also because of younger age, higher prevalence of alcoholic etiology of cirrhosis, higher prevalence of some precipitants (such as bacterial infections, active alcoholism), and more intense systemic inflammatory response. ACLF is a new syndrome also because severe sepsis or severe alcoholic hepatitis do not account for 100% of the observed cases; in fact, almost 50% of the cases are of “unknown” origin. In other words, severe sepsis, severe alcoholic hepatitis and ACLF of “unknown origin” are subcategories of the syndrome.