Strong Systemic Inflammatory Response Research Articles

Assessment of Micronuclei Frequency in the Peripheral Blood of Adult and Pediatric Patients Receiving Fractionated Total Body Irradiation

The cytokinesis-block micronucleus (CBMN) assay is an established method for assessing chromosome damage in human peripheral blood lymphocytes resulting from exposure to genotoxic agents such as ionizing radiation. The objective of this study was to measure cytogenetic DNA damage and hematology parameters in vivo based on MN frequency in peripheral blood lymphocytes (PBLs) from adult and pediatric leukemia patients undergoing hematopoietic stem cell transplantation preceded by total body irradiation (TBI) as part of the conditioning regimen. CBMN assay cultures were prepared from fresh blood samples collected before and at 4 and 24 h after the start of TBI, corresponding to doses of 1.25 Gy and 3.75 Gy, respectively. For both age groups, there was a significant increase in MN yields with increasing dose (p < 0.05) and dose-dependent decrease in the nuclear division index (NDI; p < 0.0001). In the pre-radiotherapy samples, there was a significantly higher NDI measured in the pediatric cohort compared to the adult due to an increase in the percentage of tri- and quadri-nucleated cells scored. Complete blood counts with differential recorded before and after TBI at the 24-h time point showed a rapid increase in neutrophil (p = 0.0001) and decrease in lymphocyte (p = 0.0006) counts, resulting in a highly elevated neutrophil-to-lymphocyte ratio (NLR) of 14.45 ± 1.85 after 3.75 Gy TBI (pre-exposure = 4.62 ± 0.49), indicating a strong systemic inflammatory response. Correlation of the hematological cell subset counts with cytogenetic damage, indicated that only the lymphocyte subset survival fraction (after TBI compared with before TBI) showed a negative correlation with increasing MN frequency from 0 to 1.25 Gy (r = −0.931; p = 0.007). Further, the data presented here indicate that the combination of CBMN assay endpoints (MN frequency and NDI values) and hematology parameters could be used to assess cytogenetic damage and early hematopoietic injury in the peripheral blood of leukemia patients, 24 h after TBI exposure.

Platelet P2Y12 signalling pathway in the dysregulated immune response during sepsis.

Sepsis is a complicated pathological condition in response to severe infection. It is characterized by a strong systemic inflammatory response, where multiple components of the immune system are involved. Currently, there is no treatment for sepsis. Blood platelets are known for their role in haemostasis, but they also participate in inflammation through cell-cell interaction and the secretion of inflammatory mediators. Interestingly, an increase in platelet activation, secretion, and aggregation with other immune cells (such as monocytes, T-lymphocytes and neutrophils) has been detected in septic patients. Therefore, antiplatelet therapy in terms of P2Y12 antagonists has been evaluated as a possible treatment for sepis. It was found that blocking P2Y12 receptors decreased platelet marker expression and limited attachment to immune cells in some studies, but not in others. This review addresses the role of platelets in sepsis and discusses whether antagonizing P2Y12 signalling pathways can alter the disease outcome. Challenges in studying P2Y12 antagonists in sepsis also are discussed. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

TLR2 and TLR4 in colorectal cancer: relationship to tumor necrosis and markers of systemic inflammation.

In colorectal cancer (CRC), systemic inflammation is associated with poor prognosis, but the underlying mechanisms are not fully characterized. Tumor necrosis may contribute to systemic inflammation by inducing interleukin (IL)-6 signaling, and proinflammatory cytokines such as IL-6 and IL-8, and matrix metalloproteinase (MMP)-8 also are linked to adverse CRC outcomes. Because Toll-like receptors (TLRs) are important mediators of inflammatory responses, we investigated the roles of TLR2 and TLR4 in CRC-associated systemic inflammatory responses, especially tumor necrosis. In 118 patients with CRC, extensive tumor necrosis was associated with low TLR4 expression in tumor cells. Tumor cell TLR4 expression was inversely correlated with serum IL-6 and MMP-8 levels, blood total leukocyte and neutrophil counts, and serum C-reactive protein levels. Tumor cell TLR2 expression was not significantly associated with necrosis or systemic inflammation, but low expression in normal mucosa was linked to high serum MMP-8 and IL-8. These findings indicate that tumor necrosis is associated with low TLR4 expression in cancer cells and that low TLR4 expression correlates with a strong systemic inflammatory response. The low TLR2 expression in normal mucosa and its association with systemic inflammation suggest that the normal mucosa may reflect or contribute to the systemic inflammatory response.

Sympathetic nerves control bacterial clearance

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection.

Association of Brain-Dead Donors' Terminal Inflammation With Delayed Graft Function in Kidney Transplant Recipients

BackgroundSystemic inflammation affects kidney function in a wide range of diseases. Even in kidney transplant recipients, higher levels of C-reactive protein (CRP) are invariably associated with both worse short- and long-term graft outcomes. However, little is known about systemic inflammation in kidney donors and, notably, brain death causes a strong systemic inflammatory response. ObjectiveTo analyze the role of systemic inflammation of brain-dead donors on short-term kidney graft outcomes (ie, delayed graft function [DGF], defined as the need of dialysis during the first week after transplantation). Materials and methodsRetrospective analysis of clinical and biochemical characteristics of all brain-dead kidney donors generated in the Hospital Clínic of Barcelona in the 2006 to 2015 period (n = 194). Donors who were tested for CRP in the 24 hours before BD declaration were included (n = 97, 50% of initial population). Clinical and biochemical features of their respective recipients (n = 165) were analyzed, comparing recipients who developed DGF (n = 30) with recipients who did not (n = 135). ResultsDonors whose recipients later developed DGF had much higher CRP values (10.58 [5.1-18.21] vs 4.81 [1.42-12.2] mg/dL, P = .025). Other characteristics associated with the development of DGF were renal biopsy score and recipient dialysis vintage (P = .025 and P = .002, respectively). In logistic regression analysis, PCR maintained significance in the non–expanded criteria donor (ECD) group (odds ratio [OR], 1.102; P = .027), but it lost significance in the ECD group (P = .67). ConclusionsTerminal donor CRP was associated with DGF in kidney transplant recipients and proved to be mostly significant in younger donors.

Hypoxia-induced inflammation and purinergic signaling in cross clamping the human aorta.

Open aortic surgery evokes a systemic inflammatory response and is associated with high morbidity and mortality. Purinergic signaling has been shown to be crucial for maintaining vascular integrity and attenuating inflammation related to hypoxia. The involvement of purinergic signaling in cross clamping of major human arteries is unknown. Our aim was to compare systemic inflammatory responses and hypoxia-induced purinergic signaling in patients undergoing either open infra-renal abdominal aortic repair or infra-inguinal revascularization. Pre- and 24 h post-operative blood samples were gathered from 6 patients undergoing aortic clamping and 6 similar patients undergoing common femoral artery cross-clamping. Using Biorad Multipex™ 21- and 27-panels 48 different cytokines, chemokines and growth factors were analyzed, in addition to circulating levels of ATP, ADP, CD39, CD73 and HIF-1α, and compared between the groups. Several inflammatory cytokines were elevated from baseline levels after aortic clamping, but not after femoral cross clamping. Most pronoun rises were seen in IL-6 (667 %, P = 0.016) and HGF (760 %, P = 0.016). HIF-1α values showed a steady increase after clamping of either artery unless the subject underwent blood transfusion. Despite an adequate increase in HIF-1α CD39 and CD73 activity decreased significantly after aortic clamping (P = 0.047 and P = 0.016, respectively). Aortic clamping is associated with a clear and strong systemic inflammatory response and impaired repair mechanisms in terms of purinergic signaling. Patients undergoing open aorta repair could benefit from pre-operative medical therapy, which enhances CD73 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1651-x) contains supplementary material, which is available to authorized users.

Central role of neutrophil in the pathogenesis of severe acute pancreatitis.

Severe acute pancreatitis (SAP) is an acute abdominal disease with the strong systemic inflammatory response, and rapidly progresses from a local pancreatic damage into multiple organ dysfunction. For many decades, the contributions of neutrophils to the pathology of SAP were traditionally thought to be the chemokine and cytokine cascades that accompany inflammation. In this review, we focus mainly on those recently recognized aspects of neutrophils in SAP processes. First, emerging evidence suggests that therapeutic interventions targeting neutrophils significantly lower tissue damage and protect against the occurrence of pancreatitis. Second, trypsin activation promotes the initial neutrophils recruitment into local pancreas, and subsequently neutrophils infiltration in turn triggers trypsin production. Finally, neutrophils have the unique ability to release neutrophil extracellular traps even in the absence of pathogens.

Poloxamer 188 as a Supplement to Barium Cross-Linked Ultra-High Viscosity Alginate for Immunoisolation of Transplanted Islet Cells

Transplantation of Langerhans islets is a potential cure for diabetes mellitus. The main problem for routine clinical use remains the prevention of rejection without drastic side effects. Immuno-isolation is an experimental strategy to prevent graft rejection by separating the transplanted cells from the host immune system using a barrier device. The aim of the current study was to improve the physical features of encapsulated islets in a barium cross-linked ultra-high viscosity alginate by adding Poloxamer 188 (P188). Empty alginate capsules, and especially encapsulated islets, could be easily generated using UHV-P188 alginate because of its anti-foaming properties. Diabetic mice were used for evaluation of biocompatibility and graft function. Biocompatibility testing with empty capsules showed no inflammatory reaction or fibrotic overgrowth. The capsules remained intact in the intraperitoneal and intramuscular implant sites over a period of 4 weeks. Transplantation of encapsulated islets, however, led to a strong systemic inflammatory response with fibrotic overgrowth of the islet-containing capsules but no graft failure. This finding likely reflected the complementactivating property of P188. Our results clearly showed that the complex interaction of additives, xenogeneic tissue, and alginate with the host immune system could not be predicted by the behavior of the individual components. Furthermore, the mouse model described herein was an excellent tool to evaluate the physico-chemical properties and the in vivo biocompatibility and functionality of various additives. Our results will improve the biomaterials used for alginate microbeads in a clinical setting in the future.

Influenza pneumonia among adolescents and adults: a concurrent comparison between influenza A (H1N1) pdm09 and A (H3N2) in the post‐pandemic period

IntroductionComparisons of the characteristics between the influenza A (H1N1) pdm09 and common seasonal influenza are important for both clinical management and epidemiological studies. However, the differences between pandemic and seasonal influenza during the post-pandemic period are poorly understood.ObjectivesThe aim of our research was to investigate clinical and immune response differences between patients with influenza A (H1N1) pdm09 pneumonia and seasonal influenza A (H3N2) pneumonia in the post-pandemic period.MethodsDuring the first flu season in post-pandemic period, patients from Beijing Network for Adult Community-Acquired Pneumonia present A (H1N1) pdm09 or A (H3N2) influenza were compared concurrently in the aspects of clinical characteristics and inflammatory profile in acute phase.ResultPatients with A (H1N1) pdm09 influenza pneumonia showed a close mean age to A (H3N2) pneumonia (51 ± 20 vs 53 ± 16, mean ± standard deviation, years) but tended to have more underlying diseases (32.8% vs 10%, P = 0.036). Although clinical characteristics were similar, no statistical difference were found in pneumonia severity index (PSI) score or intensive care unit admission rate or mortality, patients in A (H1N1) pdm09 cohort present higher levels of aspartate aminotransferase, lactase dehydrogenase (P = 0.006, 0.018, respectively) in blood and also longer duration of fever than A (H3N2) cohort. Levels of interleukin (IL)-10 and IL-12 (p70) were higher in A (H1N1) pdm09 cohort (P = 0.031, 0.047, respectively).ConclusiosDuring the first post-pandemic flu season, patients with the A (H1N1) pdm09 pneumonia showed similar clinical characteristics but slightly higher disease severity and stronger systemic inflammatory response than A (H3N2) pneumonia.

Necro-inflammatory response of pancreatic acinar cells in the pathogenesis of acute alcoholic pancreatitis.

The role of pancreatic acinar cells in initiating necro-inflammatory responses during the early onset of alcoholic acute pancreatitis (AP) has not been fully evaluated. We investigated the ability of acinar cells to generate pro- and anti-inflammatory mediators, including inflammasome-associated IL-18/caspase-1, and evaluated acinar cell necrosis in an animal model of AP and human samples. Rats were fed either an ethanol-containing or control diet for 14 weeks and killed 3 or 24 h after a single lipopolysaccharide (LPS) injection. Inflammasome components and necro-inflammation were evaluated in acinar cells by immunofluorescence (IF), histology, and biochemical approaches. Alcohol exposure enhanced acinar cell-specific production of TNFα, IL-6, MCP-1 and IL-10, as early as 3 h after LPS, whereas IL-18 and caspase-1 were evident 24 h later. Alcohol enhanced LPS-induced TNFα expression, whereas blockade of LPS signaling diminished TNFα production in vitro, indicating that the response of pancreatic acinar cells to LPS is similar to that of immune cells. Similar results were observed from acinar cells in samples from patients with acute/recurrent pancreatitis. Although morphologic examination of sub-clinical AP showed no visible signs of necrosis, early loss of pancreatic HMGB1 and increased systemic levels of HMGB1 and LDH were observed, indicating that this strong systemic inflammatory response is associated with little pancreatic necrosis. These results suggest that TLR-4-positive acinar cells respond to LPS by activating the inflammasome and producing pro- and anti-inflammatory mediators during the development of mild, sub-clinical AP, and that these effects are exacerbated by alcohol injury.

New insights into the pathogenesis of pancreatitis

In this article, we review important advances in our understanding of the mechanisms of pancreatitis. The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.

Characterization of peri-infarct zone by CMR is a robust predictor of major adverse events and is strongly associated with systemic inflammatory response post-myocardial infarction

While previous studies suggest that the peri-infarct zone (PIZ) may be an important arrhythmogenic substrate and may be associated with an unfavorable outcome post-MI, to date, there is no convincing mechanistic explanation to support that relationship. Systemic inflammatory response (SIR) in the acute phase post-MI has also been associated an adverse prognosis.Furthermore, a strong SIR may lead to greater heterogeneity of the infarcted myocardium. We hypothesized that the PIZ extent would be associated with the severity of the post-MI SIR. We further sought to determine if prognostic information provided by PIZ extent and SIR would complement classical markers of adverse outcome post-MI.

Association between increased CCL2 (MCP-1) expression in lesions and persistence of disease activity in giant-cell arteritis*

Patients with giant-cell arteritis (GCA) usually respond dramatically to corticosteroid treatment. However, recurrences are frequent and corticosteroid requirements are highly variable among patients. The aim of our study was to identify genes potentially involved in disease persistence. Gene expression was explored with cDNA arrays in temporal artery biopsies from six GCA patients with relapsing disease and six patients who easily achieved sustained remission. Differentially expressed genes of interest were subsequently analysed by quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry in temporal artery biopsies from 35 patients with biopsy-proven GCA and nine controls. CCL2 (MCP-1) was up-regulated in temporal artery samples from relapsing individuals. In the extended series of patients, CCL2 mRNA concentration in lesions was significantly higher than in controls (31 +/- 15.6 vs 0.44 +/- 0.10, P = 0.0001). In addition, CCL2 was more abundant in patients who experienced two or more relapses during the first year compared with those who endured sustained remission (127 +/- 82 vs 11 +/- 5.5, P = 0.0233) and correlated with the cumulated prednisolone dose (R = 0.533, P = 0.0024). CCL2 mRNA concentration correlated with IL-1beta (R = 0.45, P = 0.02), tumour necrosis factor-alpha (TNF-alpha) (R = 0.47, P = 0.013) and IL-6 (R = 0.52, P = 0.0053) mRNA. However, circulating CCL2 determined by ELISA was decreased in patients with strong systemic inflammatory response, suggesting that reduction in circulating CCL2 may reinforce the local gradient in lesions. Increased CCL2 (MCP-1) expression in lesions is associated with persistence of disease activity in GCA.

Airborne occupational exposure, ABO phenotype, and risk of obesity

We have previously found a quite strong interplay between occupational airborne pollutants, ABO phenotypes, and risk of ischaemic heart disease (IHD), with long-term exposure being associated with a significantly increased risk among men with phenotype O, and not among men with other ABO phenotypes. We suggested that the biological pathway could be a stronger systemic inflammatory response in men with blood group O. Several inflammatory mediators likely to increase the risk of IHD have recently been linked also to obesity, suggesting that long-term exposure to airborne pollutants might play a role in the aetiology of obesity. Accordingly, we tested the hypothesis that long-term occupational exposure to airborne pollutants would be more strongly associated with obesity in men with phenotype O than in men with other ABO phenotypes. Cross-sectional exposure-response study taking into account potential confounders. The Copenhagen Male Study. A total of 3290 men aged 53-74 y. Prevalence of obesity (BMI > or =30 (kg/m2)). Overall, no differences were found in the prevalence of obesity between men with the O phenotype (n=1399) and men with other phenotypes (n=1891), 8.6 and 9.0%. However, only among men with the O phenotype was long-term occupational exposure (at least 5 y of frequent exposure) to various respirable airborne pollutants: dust, asbestos, soldering fumes, welding fumes, organic solvents, fumes from lacquer, paint or varnish, toxic components, breath irritants, stench or strongly smelling products, and irritants (other than breath irritants or contagious components) associated with an increased prevalence of obesity. Statistically, the strongest univariate associations were found for asbestos exposure, welding fumes, and breath irritants. Odds ratios (95% confidence limits) for these factors were 3.7 (1.8-7.6), 2.7 (1.6-4.4), and 2.6 (1.5-4.4), respectively. This particular relationship of airborne exposures with obesity in men with phenotype O was supported in multivariate analysis including interaction terms and taking into account a number of potential confounders. In contrast, no gene-environment interactions with obesity were found with respect to ABO phenotypes and a number of nonrespirable exposures. The finding of a quite strong interplay between long-term exposure to airborne pollutants, ABO phenotypes, and risk of obesity may open up new possibilities for clarifying mechanisms underlying the global obesity epidemic.

Preoperative optimization of the high-risk surgical patient

After major surgery there is a significant risk of major complications and even death, particularly in the elderly and patients with significant cardiorespiratory disease. In the UK, recent large audits have shown a 30-day mortality rate of 5.6% for elective colorectal cancer surgery, 62 19.3% for emergency colorectal surgery, 62 7.3% for elective infrarenal aortic aneurysm and aorto-iliac occlusive disease surgery, 4 9‐15% for oesophagectomy and 13‐15% for elective gastrectomy. 34 Major surgery generates a strong systemic inflammatory response that in turn leads to an increase in oxygen requirement from an average of 110 ml min ‐1 m ‐2 at rest to an average of 170 ml min ‐1 m ‐2 in the postoperative period. 43 55 This substantial increase in oxygen demand is normally met by increases in cardiac output and tissue oxygen extraction. Most patients can meet the increased oxygen demand by increasing cardiac output and will usually do well after surgery. However, there remains a group who may not have the physiological reserve to increase cardiac output to the required level and this group of patients is at higher risk of complications after surgery. Trials have identified high-risk patients and implemented strategies before surgery to increase oxygen delivery (DO2) to the levels that major surgery demands. 15 30 55 67 Although some of these trials have demonstrated an improvement in outcome, the strategy remains controversial. The exact mechanisms that lead to postoperative complications are not completely understood, but an understanding of the existing knowledge on the pathogenesis of postoperative morbidity and mortality will help the clinician understand the rationale for increasing DO2 and tissue perfusion in the high-risk surgical patient. In this paper we review the role of inadequate tissue perfusion and DO2 in the development of complications after major surgery, the results of trials of preoperative interventions that aim to improve cardiac function and hence DO2, developments in the identification of patients who are most likely to benefit from these interventions and the role of fluids and inotropes in optimization strategies.

Tissue production of pro-inflammatory cytokines (IL-1 , TNF and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis

To investigate proinflammatory cytokine expression in temporal arteries from patients with giant-cell arteritis (GCA) and to analyse its relationship with the intensity of the initial systemic inflammatory reaction and response to corticosteroid therapy. Quantification of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) mRNA by real-time quantitative PCR in temporal artery samples from 36 patients with biopsy-proven GCA and 11 controls. Immunohistochemical detection of IL-1beta, TNFalpha, and IL-6 in temporal artery sections from 74 patients with GCA and 15 controls. Clinical and biochemical parameters of inflammation as well as the time (weeks) required to reach a maintenance prednisone dose <10 mg/day were recorded. IL-1beta (13.8 +/- 2.5 vs 5.4 +/- 1.3 relative units, P = 0.012) and IL-6 transcripts (34 +/- 13.7 vs 7.8 +/- 4.5 relative units, P = 0.034) were significantly more abundant in patients with a strong systemic inflammatory response compared with those with no inflammatory parameters. Immunohistochemical scores for IL-1beta (2.7 +/- 0.3 vs 1.9 +/- 0.2, P = 0.018), TNFalpha (3.2 +/- 0.2 vs 2.4 +/- 0.3, P = 0.028) and IL-6 (3 +/- 0.2 vs 2.1 +/- 0.3, P = 0.023) were also significantly higher in patients with strong systemic inflammatory reaction. A significant correlation was found between the amount of tissue TNFalpha mRNA and the time required to reach a maintenance dose of prednisone <10 mg/day (r = 0.586, P = 0.001). GCA patients with a strong systemic inflammatory response, who have been previously shown to be more resistant to corticosteroid therapy, have elevated tissue expression of proinflammatory cytokines IL-1beta, TNFalpha and IL-6. High production of TNFalpha is associated with longer corticosteroid requirements.