Course Of Systemic Inflammation Research Articles

MO680: Association of Systemic Inflammation with Changing Peritoneal Membrane Characteristics

Abstract BACKGROUND AND AIMS Increasing transport status with ultrafiltration (UF) and solute-removal inadequacy is among the most challenging issues in peritoneal dialysis (PD) continuity. Decreased transport status is less frequent but also results in solute clearance. Although the current incidence of peritonitis has reduced considerably, defined membrane disruptions are still frequently observed. Our study examines the relationship between different types of membrane disruptions and the course of systemic inflammation in incident PD patients. METHOD This is a retrospective, single-site, cohort study of incident adult PD patients (n = 202) sampled between January 2000 and January 2020. An increase or decrease in transport status is defined as two or more categories of a rise or decline in peritoneal equilibration test (PET) from their baseline during follow-up. The 4-h dialysate/plasma creatinine ratio was used to classify PET categories. C-reactive protein (CRP) values were obtained from the annual tests in the routine controls of the patients. RESULTS Baseline demographics, diabetes frequency, residual renal function, baseline laboratory, frequency of renin–angiotensin–aldosterone system blockers, high glucose–containing dialysate and icodextrin use were similar among the groups. Total episodes of peritonitis and peritonitis rates within the first 5 years of follow-up was higher in patients with stable transport status with a median rate of 0 (min:0 to max:5) than patients with increased transport status [median rate of 0 (min:0 to max:3)] and decreased transport status [median rate of 0 (min:0 to max:1)] (P = 0.009). The main time-dependent effect of CRP was statistically significant [Wilks’ λ = 0.76, F (5, 127) = 7.75, P < 0.001]. The joint effect of the mean CRP value depending on time and group was also significant [Wilks’ λ = 0.91, F (10, 254) = 1.10, P = 0.36]. The effect of CRP and time was significantly different between the groups [F (2, 131) = 3.49, P = 0.03; partial η2 = 0.05]. While there was a significant difference between stable and increased transporters in the post-hoc analysis, no similar significance was found between stable and decreased transporters (P = 0.03 and P = 0.99, respectively). CONCLUSION Our study shows that the peritoneal membrane kinetics may change into different characteristics in many patients over time, despite the very low frequency of peritonitis episodes and similar baseline characteristics, and may be significantly affected by systemic inflammation. Systemic inflammation, in particular, appears to be related to increased transport status, which is most often responsible for the deterioration of UF and solute clearance over time.

[Pro-inflammatory cytokines in chronic cardiac failure: state of problem].

Systemic inflammation is characterized by the induction of pro-inflammatory cytokines, the increased level of which in the blood of patients with chronic heart failure (CHF) correlates with unfavorable clinical outcomes. However, it is unclear whether pro-inflammatory cytokines are the cause or the consequence of the disease progression. CHF with preserved ejection fraction and CHF with reduced ejection fraction demonstrate different inflammatory features, which suggests different degrees of pro-inflammatory pathway activation. The review deals with participation of pro-inflammatory cytokines in pathophysiological processes of CHF development, emphasizing the role of interleukin-6 activation and the effects of accompanying diseases on the course of systemic inflammation. The search for new approaches to prevention and therapy of CHF remains actual. The review presents the results of clinical trials of targeted anti-cytokine therapy which have revealed difficulties in controlling inflammation under the conditions of CHF. Identification of specific pro-inflammatory pathways in CHF pathogenesis will allow one to control inflammatory cascades, thus providing a prospective therapeutic strategy.

Role of proteins MRP8 (S100A8) and MRP14 (S100A9) in the development of critical condition in patients with pneumonia with A/H1N1 influenza

Background . Today, the critical care medicine is actively developing, and rapid progress is closely related to the achievements of molecular biology, immunology, and pathological physiology. The study of the role of individual molecular structures in the realization of the reactions of innate and adaptive immunity, which underlie the pathogenesis of critical conditions, is an urgent scientific direction and is of interest. Aims. To assess the contribution of the protein complex MRP-8/14 to the development of systemic inflammation by determining its plasma concentration in patients with pneumonia with influenza A/H1N1. Materials and methods . 85 patients with pneumonia associated with influenza A/H1N1 were examined. Of these, 30 patients with severe pneumonia, 55 with non-severe pneumonia. The plasma concentration of the S100A8/A9 protein complex (MRP-8/14) was determined by flow cytometry on an analyzer (Beckman Coulter, USA). Results. It was found that in patients with severe pneumonia with influenza A/H1N1, the concentration of MRP-8/14 increased in 1.9 times compared with healthy. At the same time, in patients with severe pneumonia with influenza A/H1N1 with a fatal outcome, the concentration of MRP-8/14 increased in 2.1 times. Conclusion. An increase in the level of MRP-8/14 in patients with severe pneumonia associated with influenza A/H1N1, on the one hand, reflects the severity of the course of systemic inflammation, on the other hand, the molecules MRP-8 and MRP-14, acting as damage-associated molecular patterns (DAMPs) stimulate a pro-inflammatory response and contribute to the development of critical state. Thereby, the protein complex MRP-8/14 can be considered as a potential point of application of pharmacological action in the intensive care of critical conditions.

ASSOCIATION BETWEEN PERIODONTITIS AND LIVER DISEASE.

SUMMARYRecent clinical and scientific evidence confirms the negative impact of long-term periodontitis on the clinical course and progression of various liver diseases. Periodontitis is a chronic, slow-progressing infectious disease of the tooth supporting tissues caused mainly by the gram-negative bacteria Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola and Tannerella forsythia. These specific pathogens can be easily translocated from oral cavity to the intestine. Disruption of the intestine microbiota composition by orally derived periodontal pathogenic bacteria has recently been suggested to be a causal mechanism between periodontitis and liver disease. Furthermore, both diseases have the ability to induce an inflammatory response and lead to the creation of inflammatory mediators through which they may influence each other. Recent epidemiologic studies have demonstrated that individuals with liver cirrhosis have considerably poorer periodontal clinical parameters than those without cirrhosis. Periodontal therapy in cirrhosis patients favorably modulates oral and gut microbiome, the course of systemic inflammation, cirrhosis prognostic factors, and cognitive function. Therefore, future clinical researches should be focused on detailed examination of the biological mechanisms, strength and direction of the association between advanced liver disease and periodontitis.

An observational study of innate immune responses in patients with acute appendicitis

Acute appendicitis is a common surgical emergency worldwide. Exaggerated immune responses could be associated with appendicitis. This study aimed at characterizing immune responses towards a large variety of gut commensals and pathogens, and pattern recognition receptor (PRR) ligands, and investigating the course of systemic inflammation in a prospective cohort of acute appendicitis patients. PBMC responses of 23 patients of the cohort and 23 healthy controls were characterized more than 8 months post-surgery. Serum cytokine levels were measured in 23 patients at the time of appendicitis and after one month. CRP, WBC and percentage of neutrophils were analyzed in the total cohort of 325 patients. No differences in PBMC responses were found between patients and controls. Stronger IL-10 responses were found following complicated appendicitis. A trend towards lower IL-8 responses was shown following gangrenous appendicitis. Serum IL-10 and IL-6 were significantly elevated at presentation, and IL-6, IL-8 and TNF-α levels were higher in complicated appendicitis. Routine biomarkers could predict severity of appendicitis with high specificities, but low sensitivities. Cytokine responses in patients following acute appendicitis did not differ from healthy controls. Higher serum cytokine levels were found in acute complicated and gangrenous cases. Further research into discriminative biomarkers is warranted.

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n= 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n= 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n= 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. NCT03056612. Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.

Special aspects of systemic inflammation course in animals.

Aim:In this study, we identified characteristics of systemic inflammation associated with surgical sepsis in animals. We evaluated the role of purine metabolism, functionally associated lipoperoxidation processes of membrane structures, and the antioxidant system in the development of surgical sepsis in dogs.Materials and Methods:Dogs with a provisional exclusion of sepsis were included in the study. The control group (Group 1) included clinically healthy dogs (n=5), and medium-breed dogs with systemic inflammation response syndrome (n=30) were categorized in the experimental group (Group 2). Along with hemogram and biochemical analysis, we determined the amount of malondialdehyde, glutathione, superoxide dismutase, catalase, glutathione reductase, and glucose-6-phosphate dehydrogenase on the 1st and 14th day of the study. Treatment included a thorough reorganization of the septic focus, followed by antibacterial therapy. Sick animals were injected with a drug (dexamethasone) that suppresses the synthesis and inhibits the action of inflammatory mediators. Decompensation of the functions of organs and systems was carried out using symptomatic therapy.Results:We found that enhanced lipid peroxidation of unsaturated fatty acids of membrane structures stimulates the generalization of inflammatory process, as evidenced by the significant deviation from the physiologically normal values of lipid peroxidation, C-reactive protein, blood cell count, etc. The course of systemic inflammation associated with surgical sepsis in animals can be attributed to several consistently developing processes that function as a result of increased purine mononucleotide catabolism, peroxide compound formation, and their excessive breakdown in reactions associated with the consumption of glutathione due to the insufficient recovery of glutathione disulfide.Conclusion:The amount of uric acid, glycosaminoglycans, hyaluronic acid in blood plasma, and the content of malondialdehyde, glutathione, and glutathione reductase in erythrocytes should be considered when assessing the severity of the systemic inflammatory process. The increased glutathione requirement in dogs with surgical sepsis requires intervention with pharmacological agents, and further research is needed in this aspect.

Dynamics of Ventilatory Pattern Variability (VPV), Cardio‐Respiratory Coupling (CRC) and Cytokines in an E. coli Sepsis Model

Cardio‐respiratory control is disrupted in sepsis. We hypothesized that increases in inflammatory cytokines that are expressed in the brainstem in a rat model of Escherichia coli (E. coli) peritonitis would correlate with decreases in VPV and the uncoupling of CRC. We implanted fibrin clots containing either 25×106 or 0 E. coli in the peritoneal cavity of chronically instrumented, adult Sprague‐Dawley Rats (n=19). We recorded cardiorespiratory patterns of awake, freely moving rats at 3, 6, 12, 24, and 48 hours after implantation. At each time point, blood, bronchoalveolar lavage fluid (BALF), peripheral and central nervous system (CNS) tissues were collected to measure cytokine concentrations. We quantified VPV and CRC using a set of complementary measures sensitive to both linear and nonlinear dynamics. We measured interleukin 1β (IL‐1b), interleukin 6 (IL‐6) and tumor necrosis factor α (TNF‐a) concentrations in serum, BALF and tissue supernatants by Luminex assay. Compared to the sham group, infected rats developed a systemic inflammatory response by 3h [increased serum IL‐6 (p<0.05), IL‐1b (p=0.05)], which peaked at 6h and then decreased progressively. Also, brainstem inflammation was evident at 3h post inoculation, with increases in IL‐1β in the medulla (p<0.01) and pons (p<0.05). Brainstem inflammation was associated with increased predictability in VPV, indicated by increases in mutual information (p<0.05) and nonlinear complexity index (NLCI). In our initial analysis of CVC (n=8 rats at 24h), the X2 values of the distribution of R‐wave timings relative to the onset of inspiration were highly significant but were not different between sham and septic groups. We conclude that decreases in VPV (i.e., increased pattern predictability) were present early in the course of systemic inflammation following E. coli infection in rats and these changes were associated with elevated serum and brainstem cytokines. In contrast, the persistence of CVC in the inoculated rats was unexpected; however, at 24h the NLCI was decreasing indicating that these rats may be recovering from the peritonitis.Support or Funding InformationVA Research Service (I01BX004197); NIH (U01 EB021960)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

TLR-independent activation of NK cells during systemic inflammation

During the course of systemic inflammation, most of the immune cell types get activated to a certain degree as part of, or contributing to, the cascade of physiopathological events. Whether for some cells, classically phagocytes of the innate immune system, it is clear that direct sensing of pathogen-associated molecular patterns leads to activation initiating systemic inflammation, the picture is not so clear for natural killer (NK) cells. While NK cells have been shown to express toll-like receptors (TLR), the role of these receptors on NKs during systemic inflammation has not been directly addressed.

Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation

Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.

Continuous Administration of Enteral Lipid- and Protein-Rich Nutrition Limits Inflammation in a Human Endotoxemia Model

An overzealous inflammatory response is an important cause of morbidity and mortality in surgical, trauma, and critically ill patients. Enteral administration of lipid-rich nutrition was previously shown to attenuate inflammation and reduce organ damage via a cholecystokinin-1 receptor-mediated vagovagal reflex in animal studies. The current preclinical study investigates the immunomodulatory potential of a custom-made enteral nutrition during systemic inflammation in man. Double-blind, randomized controlled trial. Intensive care research unit. Male volunteers. After an overnight fast, 18 healthy male subjects received an IV bolus of Escherichia coli lipopolysaccharide (2 ng/kg). Subjects in the fasted group (n = 6) were deprived of food throughout the study, while subjects in the intervention groups were fed either custom-made lipid- and protein-rich nutrition (n = 6) or isocaloric control nutrition (n = 6) via nasojejunal tube, starting 1 hour prior to lipopolysaccharide administration until 6 hours afterward. Bolus lipopolysaccharide administration resulted in a marked inflammatory response. Continuous postpyloric administration of nutrition significantly increased plasma cholecystokinin levels throughout the lipopolysaccharide-induced inflammatory response. Lipid- and protein-rich nutrition attenuated circulating levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and the interleukin-1 receptor antagonist compared with control nutrition (all p < 0.05) and fasted subjects (all p < 0.05). In additional, lipid- and protein-rich nutrition augmented the anti-inflammatory response, reflected by increased plasma levels of interleukin-10 compared with fasted subjects (p < 0.0001). The current preclinical study expands the immunomodulating effects of enteral nutrition as previously observed in rodents to man. Continuous administration of enteral nutrition resulted in a rapid anti-inflammatory effect. Furthermore, enrichment of the nutritional composition with lipid and protein was shown to enhance the anti-inflammatory potential. Therefore, continuous enteral administration of lipid- and protein-rich nutrition is a promising intervention to modulate the immune response in the early course of systemic inflammation in man.

STAT3 Regulates Monocyte TNF-Alpha Production in Systemic Inflammation Caused by Cardiac Surgery with Cardiopulmonary Bypass

BackgroundCardiopulmonary bypass (CPB) surgery initiates a controlled systemic inflammatory response characterized by a cytokine storm, monocytosis and transient monocyte activation. However, the responsiveness of monocytes to Toll-like receptor (TLR)-mediated activation decreases throughout the postoperative course. The purpose of this study was to identify the major signaling pathway involved in plasma-mediated inhibition of LPS-induced tumor necrosis factor (TNF)-α production by monocytes.Methodology/Principal FindingsPediatric patients that underwent CPB-assisted surgical correction of simple congenital heart defects were enrolled (n = 38). Peripheral blood mononuclear cells (PBMC) and plasma samples were isolated at consecutive time points. Patient plasma samples were added back to monocytes obtained pre-operatively for ex vivo LPS stimulations and TNF-α and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation by patient plasma was assessed by Western blotting. A cell-permeable peptide inhibitor was used to block STAT3 signaling. We found that plasma samples obtained 4 h after surgery, regardless of pre-operative dexamethasone treatment, potently inhibited LPS-induced TNF-α but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or IκB-α degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-α production in the presence of suppressive patient plasma.Conclusions/SignificanceOur findings suggest that STAT3 signaling plays a crucial role in the downregulation of TNF-α synthesis by human monocytes in the course of systemic inflammation in vivo. Thus, STAT3 might be a potential molecular target for pharmacological intervention in clinical syndromes characterized by systemic inflammation.

Activated Protein C Does Not Alleviate the Course of Systemic Inflammation in the APCAP Trial

The study aimed to determine the effect of the activated protein C on the course of systemic inflammation in the APCAP (activated protein C in acute pancreatitis) trial where we randomized 32 patients with severe acute pancreatitis to receive either recombinant activated protein C (drotrecogin alfa activated) (n = 16) or placebo (n = 16) for 96 hours. In the present study, we present the time course of the patients' plasma or serum levels of soluble markers (IL-8, IL-6, IL-10, IL-1ra, sE-selectin, PCT) and monocyte and neutrophil cell surface (CD11b, CD14, CD62L, HLA-DR) markers of systemic inflammatory response during the first 14 days after the randomization. The results of the intervention and placebo groups were comparable showing that recombinant APC treatment did not alter the course of systemic inflammation in severe acute pancreatitis. Our finding is in accordance with the clinical findings in the APCAP trial indicating that the intervention did not affect evolution of multiple organ dysfunctions.

Local inflammation occurs before systemic inflammation in patients with COPD

COPD is associated not only with an abnormal inflammatory response in the lung but also with systemic inflammation, including systemic oxidative stress, activation of circulating inflammatory cells and increased circulating levels of inflammatory cytokines. Understanding the nature and course of systemic inflammation in COPD is important given the potential for anti-inflammatory therapy. This study explored whether local and systemic inflammation occur concurrently in patients with COPD. Forty-four patients with stable COPD, 10 smoking controls and 10 non-smoking controls were enrolled in this observational study. Induced sputum and peripheral blood samples were obtained simultaneously for measurement of inflammatory cell numbers and the concentrations of IL-6 and CRP. The total number of cells in the sputum total cell number, percentage of neutrophils and the concentration of IL-6 were significantly higher in smoking controls and patients with COPD than in non-smoking controls (P < 0.05 and P < 0.01, respectively). As the disease stage progressed, airway inflammatory cells and IL-6 levels increased. CRP levels in sputum were significantly higher in stage II, III and IV COPD patients than in smoking and non-smoking controls (P < 0.01). However, the peripheral WCC and percentage of neutrophils were similar in patients with COPD, smoking and non-smoking controls. Circulatory concentrations of IL-6 and CRP in stages III and IV COPD patients were significantly higher than in smoking and non-smoking controls (P < 0.05 and P < 0.01, respectively). Additionally, there were positive correlations between sputum and blood IL-6 and CRP levels (r = 0.566, P < 0.01 and r = 0.443, P < 0.01, respectively). The increase in the inflammatory cell population and IL-6 and CRP levels in the airway may occur earlier than in the peripheral blood, and reflect the degree of airflow limitation better than do peripheral blood measurements. Systemic inflammation may be present in patients with severe or very severe COPD.

Biomarkers of Systemic Inflammation in Stable and Exacerbation Phases of COPD

Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-alpha and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-alpha and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.

Hyperleptinaemia and chronic inflammation after peritonitis predicts poor nutritional status and mortality in patients on peritoneal dialysis

The serum leptin level is elevated in patients undergoing peritoneal dialysis (PD) and associated with a loss of lean body mass. The nutritional status of PD patients may further be worsened following peritonitis. We investigated the association between hyperleptinaemia, inflammation and malnourishment in PD-related peritonitis. We conducted a prospective study on PD patients who developed peritonitis. Blood samples were obtained as baseline (D0) before the onset of peritonitis, and once peritonitis developed, leptin, adiponectin (ADPN) and other inflammatory markers were collected, on day 1 (D1), day 7 (D7) and day 42 (D42) of peritonitis. Patients were followed-up for any censor event or 1 year after peritonitis. Forty-two patients with a mean age of 62.9+/-13.2 years were recruited. Fourteen (33.3%) were diabetic. The serum leptin levels increased significantly from baseline to day 1 and 7, but fell back to the premorbid state at day 42. In contrast, the ADPN level decreased from a baseline value of 15.60+/-10.4 microg/ml to 13.01+/-8.1 microg/ml on day 1 (P=0.01) but rose to 14.39+/-8.9 microg/ml on day 7 (P=0.28) and 13.87+/-7.9 microg/ml on day 42 (P=0.21). High-sensitivity C-reactive protein (hs-CRP) increased significantly from baseline to day 1, 7 and even at day 42. The lean body mass (LBM) and nutritional markers decreased significantly after peritonitis. For patients with high hs-CRP (>3.0 mg/l) at day 42, there was a higher mortality rate than for those with lower hs-CRP (<3.0 mg/l, P=0.02), even if they were in clinical remission of peritonitis. Our study confirmed an increase in serum leptin during acute peritonitis and a prolonged course of systemic inflammation after apparent clinical remission of peritonitis. These factors related to the persistent chronic inflammation may contribute to the development of malnourishment and poor survival rate.

Inflammatory changes, recovery and recurrence at COPD exacerbation

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased airway and systemic inflammation, though relationships between exacerbation recovery, recurrent exacerbation and inflammation have not been previously reported. In the present study, inflammatory changes at COPD exacerbations were related to clinical nonrecovery and recurrent exacerbations within 50 days. Serum interleukin (IL)-6, C-reactive protein (CRP), sputum IL-6 and IL-8 were measured in 73 COPD patients when stable, at exacerbation and at 7, 14 and 35 days post-exacerbation. In 23% of patients, symptoms did not recover to baseline by day 35. These patients had persistently higher levels of serum CRP during the recovery period. A total of 22% of the patients who had recurrent exacerbations within 50 days had significantly higher levels of serum CRP at day 14, compared with those without recurrences: 8.8 mg.L(-1) versus 3.4 mg.L(-1). Frequent exacerbators had a smaller reduction in systemic inflammation between exacerbation onset and day 35 compared with infrequent exacerbators. Nonrecovery of symptoms at chronic obstructive pulmonary disease exacerbation is associated with persistently heightened systemic inflammation. The time course of systemic inflammation following exacerbation is different between frequent and infrequent exacerbators. A high serum C-reactive protein concentration 14 days after an index exacerbation may be used as a predictor of recurrent exacerbations within 50 days.

Procalcitonin amplifies inducible nitric oxide synthase gene expression and nitric oxide production in vascular smooth muscle cells.

Elevated procalcitonin concentrations are found in the course of systemic inflammation caused by bacterial insults, for example, sepsis and septic shock. However, the source of procalcitonin and its role in the inflammatory process are still unknown. In clinical studies, procalcitonin concentrations reflected the severity of sepsis and were predictive of mortality, suggesting that an increased procalcitonin synthesis is detrimental for the host. In contrast, and data report anti-inflammatory effects of procalcitonin that rather may represent a benefit for the septic patient. Prospective, controlled, cell culture study. University research laboratories. WKY rats. We investigated whether procalcitonin affects one principal mediator of sepsis, inducible nitric oxide synthase-derived nitric oxide, taking into account the typical 3-hr delay of procalcitonin increase following a bacterial challenge. Vascular smooth muscle cells were incubated with lipopolysaccharide (10 microg/mL), tumor necrosis factor-alpha (500 units/mL), interferon-gamma (100 units/mL), and procalcitonin (1, 10, 100, and 1000 ng/mL). Cells were preincubated with lipopolysaccharide for 90 mins followed by the addition of tumor necrosis factor-alpha/interferon-gamma. In a second set of experiments, procalcitonin was added to these proinflammatory agonists 3 hrs after lipopolysaccharide application. Although no inducible nitric oxide synthase complementary DNA was detectable in unstimulated controls and following single application of procalcitonin, inducible nitric oxide synthase gene expression was induced in cells treated with lipopolysaccharide plus tumor necrosis factor-alpha/interferon-gamma for a total incubation time of 24 hrs. When vascular smooth muscle cells were incubated with procalcitonin in addition to lipopolysaccharide plus tumor necrosis factor-alpha/interferon-gamma, a further stimulation of inducible nitric oxide synthase transcription rate could be detected. These results provide evidence that procalcitonin acts as a modulator that augments the inflammatory response triggered by agonists like lipopolysaccharide, tumor necrosis factor-alpha, and interferon-gamma. Although not effective as a single stimulus, it might contribute to the detrimental outcome following excessive activation of the inflammatory cascade.

A prospective study of inflammation markers in patients at risk of indirect acute lung injury.

Systemic inflammation triggered by insults like sepsis and acute pancreatitis may play a role in development of indirect acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Because little is known about the course of systemic inflammation on the days preceding diagnosis of ARDS, we prospectively monitored immune inflammatory status in 52 patients at risk and we assessed the presence of ALI and ARDS on day 7 after admission to the intensive care unit. On admission, serum interleukin (IL) 8, IL-6, and soluble IL-2 receptor concentrations were significantly higher in patients with subsequent ALI (n = 18) than in patients without ALI (n = 30). During a 4-day follow-up, IL-8 and IL-6 levels of ALI patients remained high and those of non-ALI patients decreased. None of the markers discriminated ARDS patients (n = 9) from non-ARDS ALI patients (n = 9). Among 11 patients with acute pancreatitis, ALI patients had significantly higher IL-8, IL-6, and phagocyte CD11b expression levels than did non-ALI patients, whereas among 14 patients with massive transfusion, respective findings in ALI and non-ALI patients were comparable. Results give credence to the view that systemic inflammation plays a role in development of ALI triggered by pancreatitis, but not in that by massive transfusion. This finding, if confirmed in studies with sufficient statistical power, suggests that the patients with massive transfusion do not necessarily benefit from novel biotherapies aimed at altering the course of systemic inflammation.

Procalcitonin, soluble interleukin-2 receptor, and soluble E-selectin in predicting the severity of acute pancreatitis.

To investigate whether marker(s) of systemic inflammation detect, at an early stage of acute pancreatitis, patients who may ultimately develop severe disease. Prospective study. University hospital emergency unit. Thirty patients with mild acute pancreatitis (SEV0 group) and 27 with severe acute pancreatitis. Of the latter, 11 did not develop organ failure (SEV1 group), whereas the other 16 patients developed acute respiratory failure and 9 of them also developed renal failure (SEV2 group). Blood samples were collected at admission to the hospital (T0), and at 12 hrs (T12) and 24 hrs (T24 after admission. The plasma concentrations of procalcitonin (PCT), soluble E-selectin (sE-selectin), soluble interleukin-2 receptor (sIL-2R), and the serum concentration of C-reactive protein (CRP) were monitored. PCT levels at T0 were significantly higher in the SEV1 group (median 0.4 ng/mL, range 0.2-2.3) and the SEV2 group (0.8 ng/mL, 0.2-73.5) than in the SEV0 group (0.3 ng/mL, 0.1-3, p < .05 and p < .001, respectively). At T12, PCT level in the SEV2 group was significantly higher than that in the SEV1 group (2.2 ng/mL, 0.2-86.6 vs. 0.4 ng/mL, 0.3-2.8, p = .05), as it also was at T24 (2.2 ng/mL, 0.4-73.3 vs. 0.5 ng/mL, 0.3-4, p < .01). Among SEV2 patients, PCT concentration correlated negatively with the time elapsed between admission and the diagnosis of organ failure. At T12, sIL-2R levels of the SEV1 group (1,011 U/mL, range 334-2,211) and the SEV2 group (1,495 U/ml, range 514-4,526) both differed significantly from the SEV0 group (636 U/ml, range 356-1,678, p < .05 and p < .001, respectively) as they also did at T24. Although CRP level in the SEV1 group at T12 did not differ from the SEV0 group, the difference between SEV2 (272 microg/mL, range 46-462) and SEV0 was significant (53 microg/mL, range 5-243, p < 0.01). sE-selectin levels did not differ between groups. At admission to hospital, concentrations of PCT, but not those of CRP, sE-selectin, or sIL-2R, are higher in patients with severe acute pancreatitis than in patients with mild pancreatitis. PCT test had sensitivity of 94% and specificity of 73% for development of organ failure. PCT may be useful to identify the patients who benefit from novel therapies aimed at modifying the course of systemic inflammation.