Dysregulated Inflammatory Response Research Articles

The alarmin IL-33 promotes regulatory T-cell function in the intestine.

Foxp3+ regulatory T cells are abundant in the intestine where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function1; however, key host factors controlling the Treg response in the intestine are poorly understood. IL-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites2 where it functions as an endogenous danger signal or alarmin following tissue damage3. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease (IBD) patients4-7 suggesting a role for this cytokine in the pathogenesis of IBD. In the intestine, both protective and pathologic roles for IL-33 have been described in murine models of acute colitis8-11 but its contribution to chronic inflammation remains ill defined. Here we show that the IL-33 receptor ST2 is preferentially expressed on colonic Treg (cTreg) cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signaling into T cells stimulates Treg responses in several ways. Firstly, it enhances transforming growth factor-β1 (TGF-β1) mediated differentiation of Treg cells and secondly, it provides a necessary signal for Treg accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of IBD, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.

Cod liver oil in sodium nitrite induced hepatic injury: Does it have a potential protective effect?

ObjectivesExposure to sodium nitrites, a food additive, at high levels has been reported to produce reactive nitrogen and oxygen species that cause dysregulation of inflammatory responses and tissue injury. In this work, we examined the impact of dietary cod liver oil on sodium nitrite-induced inflammation in rats.MethodsThirty-two adult male Sprague-Dawely rats were treated with 80 mg/kg sodium nitrite in presence/absence of 5 ml/kg cod liver oil. Liver sections were stained with hematoxylin/eosin. We measured hepatic tumor necrosis factor (TNF)-α, interleukin-1 beta (IL)-1β, C-reactive protein (CRP), transforming growth factor (TGF)-β1, and caspase-3.ResultsCod liver oil reduced sodium nitrite-induced hepatocyte damage. In addition, cod liver oil results in reduction of hepatic TNF-α, IL-1β, CRP, TGF-β1, and caspase-3 when compared with the sodium nitrite group.DiscussionCod liver oil ameliorates sodium nitrite-induced hepatic injury via multiple mechanisms including blocking sodium nitrite-induced elevation of inflammatory cytokines, fibrosis mediators, and apoptosis markers.

CD84 is markedly up-regulated in Kawasaki disease arteriopathy

The major goals of Kawasaki disease (KD) therapy are to reduce inflammation and prevent thrombosis in the coronary arteries (CA), but some children do not respond to currently available non-specific therapies. New treatments have been difficult to develop because the molecular pathogenesis is unknown. In order to identify dysregulated gene expression in KD CA, we performed high-throughput RNA sequencing on KD and control CA, validated potentially dysregulated genes by real-time reverse transcription-polymerase chain reaction (RT-PCR) and localized protein expression by immunohistochemistry. Signalling lymphocyte activation molecule CD84 was up-regulated 16-fold (P < 0·01) in acute KD CA (within 2 months of onset) and 32-fold (P < 0·01) in chronic CA (5 months to years after onset). CD84 was localized to inflammatory cells in KD tissues. Genes associated with cellular proliferation, motility and survival were also up-regulated in KD CA, and immune activation molecules MX2 and SP140 were up-regulated in chronic KD. CD84, which facilitates immune responses and stabilizes platelet aggregates, is markedly up-regulated in KD CA in patients with acute and chronic arterial disease. We provide the first molecular evidence of dysregulated inflammatory responses persisting for months to years in CA significantly damaged by KD.

Oxidative stress modulates the expression of genes involved in cell survival in ΔF508 cystic fibrosis airway epithelial cells.

Although cystic fibrosis (CF) pathophysiology is explained by a defect in CF transmembrane conductance regulator (CFTR) protein, the broad spectrum of disease severity is the consequence of environmental and genetic factors. Among them, oxidative stress has been demonstrated to play an important role in the evolution of this disease, with susceptibility to oxidative damage, decline of pulmonary function, and impaired lung antioxidant defense. Although oxidative stress has been implicated in the regulation of inflammation, its molecular outcomes in CF cells remain to be evaluated. To address the question, we compared the gene expression profile in NuLi-1 cells with wild-type CFTR and CuFi-1 cells homozygous for ΔF508 mutation cultured at air-liquid interface. We analyzed the transcriptomic response of these cell lines with microarray technology, under basal culture conditions and after 24 h oxidative stress induced by 15 μM 2,3-dimethoxy-1,4-naphtoquinone. In the absence of oxidative conditions, CuFi-1 gene profiling showed typical dysregulated inflammatory responses compared with NuLi-1. In the presence of oxidative conditions, the transcriptome of CuFi-1 cells reflected apoptotic transcript modulation. These results were confirmed in the CFBE41o- and corrCFBE41o- cell lines as well as in primary culture of human CF airway epithelial cells. Altogether, our data point to the influence of oxidative stress on cell survival functions in CF and identify several genes that could be implicated in the inflammation response observed in CF patients.

CD4+CD25 high FOXP3+ Regulatory T Cells Correlate with FEV1 in North Indian Children with Cystic Fibrosis

Cystic fibrosis (CF) lung disease is characterized by dysregulated inflammatory response in the airways. CD4+CD25+ regulatory T cells play a crucial role in maintaining the immune homeostasis. However their role in the disease pathogenesis of CF remains unexplored. Aim: To determine the percentage of circulating CD4+CD25high, FoxP3+ T cell expression in children with CF and controls. Furthermore to evaluate the relationship between CD4+CD25high, FOXP3 T cell % and the clinical status of the disease (lung function). Methods: CD4+CD25+, intracellular FoxP3 expression in peripheral blood were estimated using flowcytometry in 20 children with CF and 10 healthy controls. Spirometry was carried out according to the standard guidelines. Results: We observed a significant difference in CD4+CD25+T cell% in children with CF (5.2 ± 1.2) versus controls (6.8 ± 1.4, p < 0.05), CD4+CD25highTcell% in CF (1.72 ± 0.36) versus controls (2.59 + 0.42, p < 0.003). Similarly a significant difference was observed in FoxP3 T cell% CF: (60.7 ± 6.19) versus controls (76.8 ± 5.16), p < 0.001. A significant positive correlation between FoxP3 T cell% and FEV1 in children with CF(r = 0.822, p < 0.01) was observed.CD4+CD25high T cell% correlated positively with FEV1 (r = 0.742, p < 0.01). Conclusion: Our findings report the first evidence of a decreased expression of circulating CD4+CD25high FoxP3+ T cells in children with CF. Furthermore circulating CD4+ CD25high, FOXP3+ T cell percentage correlated with FEV1.

Epidemiology and Natural History of IBD in the Paediatric Age.

The inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract characterised by episodes of relapse and remission. Although the aetiology of IBD is not fully elucidated, it is thought to be driven by a combination of genetic susceptibility, environmental triggers, and alterations in the gut microbiome that stimulate a dysregulated inflammatory response. The two main forms of IBD, Crohn's disease (CD) and ulcerative colitis (UC), are diagnosed on the basis of clinical suspicion and laboratory, radiological, endoscopic, and histological findings. It is not always possible to classify patients as having one of these two forms using the diagnostic tools available, with the term inflammatory bowel disease-unclassified (IBD-U) currently used to categorize this subgroup presenting with chronic intestinal inflammation with features of both diseases; many children persist with this diagnosis into adult life. In contrast, the term indeterminate colitis is given to the histopathological description of intestinal inflammation involving bowel resection material. Both CD and UC can present throughout the age range, including infancy, childhood, and adolescence. The number patients diagnosed with IBD, including childhood, has dramatically increased worldwide over the past 20 years. The reasons behind the rising incidence worldwide are not entirely clear. The current mean prevalence of IBD in the general population of Western countries is estimated at 1/1,000 inhabitants. At present, Scandinavia, Canada, and Scotland have the highest incidences of paediatric IBD worldwide; however, the reason for these high rates remains elusive. Although there are only few epidemiological data available regarding developing countries, the incidence and prevalence of IBD seem to be increasing over the past few decades practically in all regions of the world, indicating its emergence as a global disease. The changing epidemiology of IBD across time and between geographic areas suggests that environmental factors are likely playing a major role in modifying disease expression. The rising incidence of IBD in developing nations may be linked to industrialization and a Western lifestyle, especially diet. Insight into the worldwide epidemiology of this disease is, thus, important to identify geographic patterns and time trends. Recent findings will also make it possible to estimate the global public health burden so that health care resources can be allocated and research can be targeted in specific geographic regions. Information about environmental factors hypothetically affecting the incidence and prevalence of this disease may, finally, lead to preventative interventions where possible. Although less prevalent in infants and in very young children, a number of case reports and small population studies have documented disease onset at very early ages. Underlying immune deficiency and monogenic disorders have been identified in a small subgroup of those diagnosed under the age of 2. An intestinal IBD-like pattern has been found to be associated in these cases with systemic immunodeficiency, within a complex scenario which can even lead to severe life-threatening events. Consequently those under the age of 6 should always have thorough investigation of other aetiologies before a diagnosis of IBD is given. Assessing the incidence of IBD is complicated, as epidemiological investigations have often ignored cases of IBD-U although they are considered as a distinct disease subtype of IBD. IBD can also be difficult to recognize, particularly in children when extraintestinal symptoms and signs (such as iron deficiency, skin lesions, and liver pathology) are predominant and in third world countries where medical services are lacking. The aim of this special issue is to review the current levels of knowledge with regard to IBD epidemiology worldwide and to examine its natural history in paediatric patients. The main topics of the issue include the most up-to-date definitions and classifications of paediatric IBD, the epidemiology of IBD worldwide, the epidemiology and natural history of paediatric IBD, and the disease burden within the general and paediatric populations. We hope that readers of this special issue on paediatric IBD will not only find accurate data and updated reviews, but also consider the questions yet to be resolved such as disease distribution worldwide, its classification, and its impact on the healthcare system. Graziella Guariso Marco Gasparetto Andrew S. Day Paul Henderson

Inflammatory Response to Escherichia coli Urinary Tract Infection in the Neurogenic Bladder of the Spinal Cord Injured Host

Urinary tract infections cause significant morbidity in patients with spinal cord injury. An in vivo spinal cord injured rat model of experimental Escherichia coli urinary tract infection mimics human disease with enhanced susceptibility to urinary tract infection compared to controls. We hypothesized that a dysregulated inflammatory response contributes to enhanced susceptibility to urinary tract infection. Spinal cord injured and sham injured rats were inoculated transurethrally with E. coli. Transcript levels of 84 inflammatory pathway genes were measured in bladder tissue of each group before infection, 24 hours after infection and after 5 days of antibiotic therapy. Before infection quantitative polymerase chain reaction array revealed greater than twofold up-regulation in the proinflammatory factor transcripts slc11a1, ccl4 and il1β, and down-regulation of the antimicrobial peptides lcn2 and mpo in spinal cord injured vs control bladders. At 24 hours after infection spinal cord injured bladders showed an attenuated innate immune response with decreased expression of il6, slc11a1, il1β and lcn2, and decreased il10 and slpi expression compared to controls. Despite clearance of bacteriuria with antibiotics spinal cord injured rats had delayed induction of il6 transcription and a delayed anti-inflammatory response with decreased il10 and slpi transcript levels relative to controls. Spinal cord injured bladders fail to mount a characteristic inflammatory response to E. coli infection and cannot suppress inflammation after infection is eliminated. This may lead to increased susceptibility to urinary tract infection and persistent chronic inflammation through neural mediated pathways, which to our knowledge remain to be defined.

O-037 Modulation of Inflammatory Processes in DSS-induced Colitis Models versus Gastrointestinal Acute Radiation Syndrome with AVX-470m, an Oral Polyclonal Anti-TNF Antibody

Development of improved therapies for inflammatory bowel disease (IBD) requires animal models that elucidate underlying mechanisms of disease. Acute radiation syndrome (ARS) has devastating consequences in the gastrointestinal (GI) tract driven in part by cytokine-mediated inflammation that closely resembles the pathophysiology of IBD. Tumor Necrosis Factor (TNF) is central to the dysregulated inflammatory response in IBD, and is strongly implicated in GI ARS. In this study AVX-470 m, a bovine polyclonal neutralizing antibody for murine TNF, is used to characterize the pathogenesis of GI damage in models of GI ARS and IBD. Colitis was induced in C57BL/6 mice by including 3% DSS in drinking water for 5 days. Other C57BL/6 mice were irradiated with 15.9 Gy (∼LD80/30) from a 60Co gamma source, with partial bone marrow shielding. Animals were dosed BID with AVX-470 m (10 mg/day) or saline by oral gavage for up to 14 days. In colon and jejunum tissues, relative mRNA expression levels of cytokines and immune markers was measured by qPCR (Taqman), and protein expression was analyzed by immunohistochemistry (IHC) in paraffin embedded, formalin fixed tissue sections. Both mRNA and protein levels of TNF were increased in colon and jejunum tissue, respectively, in the colitis and GI ARS models. IL-1β, IL-6, MMP9, ICAM-1, and TNFR2 mRNA levels were increased in both models, but IL12p40 was increased only in the colitis model, and no change in TNFR1 mRNA levels was detected in either model. Protein expression of MPO was increased in both the colitis and GI ARS models. These data show a remarkable correlation of inflammatory responses between these 2 models of GI injury. In contrast, CD68 and CD3 protein were increased in colon tissue in the colitis model, but neither protein was detected in jejunum in the GI ARS model, suggesting a reduced T-cell component in GI ARS, perhaps due to destruction of these cells by the high levels of ionizing radiation. In both colitis and GI ARS models, treatment with AVX-470 m resulted in a significant decrease in TNF mRNA and protein expression in colon and jejunum tissues, respectively. AVX-470 m also decreased MPO protein expression, and reduced MMP9 mRNA expression, in both models. In the colitis model, IL-6 mRNA levels were decreased by AVX-470 m treatment in colon tissue, while in the GI ARS model IL-6 mRNA levels were transiently increased in jejunum tissue. No change in mRNA levels for ICAM-1 or TNFR1 were seen in either model following AVX-470 m treatment. These studies show that inflammatory responses in colitis and GI ARS models share a common TNF-mediated neutrophilic component in the colon and jejunum, respectively, but differ with respect to immune cell involvement in response to injury. Further studies will reveal whether these differences reflect variability in timing, tissue localization, or response to the different insults. The fact that AVX-470 m is effective in both models highlights the central role of TNF in inflammation in the GI tract, and supports the therapeutic potential of an oral anti-TNF antibody as a gut-targeted treatment for multiple GI inflammatory diseases.

Open questions: a few that need answers in immunology

The cells of the immune system fall into two broad categories - innate and adaptive - with the cells of the innate immune system providing frontline defense by means of invariant receptors to conserved microbial components, and the B and T lymphocytes of the adaptive immune system, with highly variable somatically diversified receptors, providing reinforcement after selective proliferation in response to specific antigen. While this principle still holds, the ‘old’ view of these systems as developmentally separate and functionally distinct has been eroded, most recently and dramatically by the discovery of a whole new group of innate lymphoid cell subsets. Another development has been the increasing emphasis on studying immune responses in vivo in interaction with stromal components that are beginning to be seen as essential contributors to the development of immune responses, rather than just as matrix or scaffold components in lymphoid organs or non-lymphoid peripheral tissues. A major focus now is on immune defense at epithelial barriers and homeostatic coexistence with a healthy microbiota, as it is becoming increasingly clear that intestinal dysbiosis strongly influences immune responses even at distal sites. However, whether dysbiosis is a cause or consequence of dysregulated inflammatory responses remains to be unraveled. I outline below some of the open questions raised by these developments.

Adjunctive treatment of severe sepsis

Adjunctive treatment of severe sepsis

IntracellularShigellaremodels its LPS to dampen the innate immune recognition and evade inflammasome activation

LPS is a potent bacterial effector triggering the activation of the innate immune system following binding with the complex CD14, myeloid differentiation protein 2, and Toll-like receptor 4. The LPS of the enteropathogen Shigella flexneri is a hexa-acylated isoform possessing an optimal inflammatory activity. Symptoms of shigellosis are produced by severe inflammation caused by the invasion process of Shigella in colonic and rectal mucosa. Here we addressed the question of the role played by the Shigella LPS in eliciting a dysregulated inflammatory response of the host. We unveil that (i) Shigella is able to modify the LPS composition, e.g., the lipid A and core domains, during proliferation within epithelial cells; (ii) the LPS of intracellular bacteria (iLPS) and that of bacteria grown in laboratory medium differ in the number of acyl chains in lipid A, with iLPS being the hypoacylated; (iii) the immunopotential of iLPS is dramatically lower than that of bacteria grown in laboratory medium; (iv) both LPS forms mainly signal through the Toll-like receptor 4/myeloid differentiation primary response gene 88 pathway; (v) iLPS down-regulates the inflammasome-mediated release of IL-1β in Shigella-infected macrophages; and (vi) iLPS exhibits a reduced capacity to prime polymorfonuclear cells for an oxidative burst. We propose a working model whereby the two forms of LPS might govern different steps of the invasive process of Shigella. In the first phases, the bacteria, decorated with hypoacylated LPS, are able to lower the immune system surveillance, whereas, in the late phases, shigellae harboring immunopotent LPS are fully recognized by the immune system, which can then successfully resolve the infection.

Targeting inflammatory pathways in myocardial infarction

Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signalling and triggering an intense inflammatory reaction. Infiltrating leucocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels, the geometric, functional and molecular alterations associated with postinfarction remodelling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the postinfarction inflammatory reaction may be crucial to protect the myocardium from dilative remodelling and progressive dysfunction. Inhibition and resolution of postinfarction inflammation involve mobilization of inhibitory mononuclear cell subsets and require activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the postinfarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischaemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodelling. Given the pathophysiologic complexity of postinfarction remodelling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and monocyte chemoattractant protein-1) may be effective in patients with defective resolution of postinfarction inflammation who exhibit progressive dilative remodelling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies.

Epigenetics in sepsis: targeting histone deacetylases

Severe sepsis and septic shock are lethal complications of infection, characterised by dysregulated inflammatory and immune responses. Our understanding of the pathogenesis of sepsis has improved markedly in recent years, but unfortunately has not been translated into efficient treatment strategies. Epigenetic mechanisms such as covalent modification of histones by acetylation are master regulators of gene expression under physiological and pathological conditions, and strongly impact on inflammatory and host defence responses. Histone acetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs), which affect gene expression also by targeting non-histone transcriptional regulators. Numerous HDAC inhibitors (HDACi) are being tested in clinical trials, primarily for the treatment of cancer. We performed the first comprehensive study of the impact of HDACi on innate immune responses in vitro and in vivo. We showed that HDACi act essentially as negative regulators of the expression of critical immune receptors and antimicrobial pathways in innate immune cells. In agreement, HDACi impaired phagocytosis and killing of bacteria by macrophages, and increased susceptibility to non-severe bacterial and fungal infections. Strikingly, proof-of-principle studies demonstrated that HDACi protect from lethal toxic shock and septic shock. Overall, our observations argue for a close monitoring of the immunological and infection status of patients treated with HDACi, especially immunocompromised cancer patients. They also support the concept of pharmacological inhibitors of HDACs as promising drugs to treat inflammatory diseases, including sepsis.

Pregnane X receptor regulates the innate inflammatory response against intracellular bacterial infection (P4209)

Abstract Pregnane X receptor (PXR) is a member of the nuclear receptor family and is primarily expressed in stromal cells of liver and intestine. It’s well established that PXR regulates the metabolism of xenobiotics. Here we demonstrate that PXR signaling specifically in hematopoietic cells is also essential for regulating innate antimicrobial immune responses. Compared to wild type mice, Pxr-/- animals exhibited significantly higher inflammatory response to intracellular bacteria Listeria Monocytogenes (LM) infection. However, strikingly, despite the more robust innate immune response, Pxr-/- mice were unable to control LM infection. Our data demonstrated that the inflammatory monocyte response was significantly reduced in Pxr-/- mice, and these monocytes produced elevated amounts of TNF-α and reactive oxygen species that are known to induce cell death. We propose that the dysregulated inflammatory response in Pxr-/- monocytes results in their increased cell death and thus elevated bacterial burden. Surprisingly, increased activation of the TLR pathway in Pxr-/- mice was the singular determinant of the susceptibility since Pxr-/-Tlr4-/- mice were efficient in clearing LM. In conclusion, our study for the first time defines a novel role of PXR as a critical negative regulator of the innate immune response. Our results also illustrate the need for exquisite fine tuning and balance of the innate inflammatory pathways to ensure the clearance of an intracellular pathogen.

The male excess in sudden infant deaths

The peak age at which sudden infant death syndrome (SIDS) occurs corresponds to the developmental period in which infants are dependent on their innate responses to infection. There is a growing body of evidence indicating that dysregulation of inflammatory responses might contribute to the physiological changes leading to these sudden deaths. This study examined the effects of three important risk factors for SIDS on inflammatory responses: cigarette smoke, virus infection and male sex. Cytokine responses of peripheral monocytic blood cells of healthy, non-smoking males and females to endotoxin were measured. Surrogates for virus infection or cigarette smoke were assessed using IFN-γ or water-soluble cigarette smoke extract (CSE). For most conditions, cells from males had lower pro-inflammatory cytokine responses than those of females. An opposite trend was observed for IL-10. Significantly lower levels of some cytokines were noted for cells from male donors exposed to CSE. In females, there were significant correlations between testosterone levels and levels of pro-inflammatory cytokines, but none for males. Testosterone levels in females correspond to those among male infants in the age range at greatest risk of SIDS. The effects of the testosterone surge in male infants need to be examined in relation to changes in cortisol levels that occur during the same period of infant development.

Cancer surgery induces inflammation, immunosuppression and neo-angiogenesis, but is it influenced by analgesics?

Surgery remains a main part of the treatment of most solid tumors. Paradoxically, rapid disease progression may be a consequence of surgery in patients presenting with a dysregulated inflammatory response, and increased angiogenesis consequent to a suppressed antitumoral immune response. Physicians taking care of cancer patients should be aware of the important findings that indicate that analgesic techniques could play a role in these phenomena.

Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis

BackgroundSepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage.MethodsAnaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines.ResultsMitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001).ConclusionsAntioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.

Resolution of Inflammation: Leukocytes and Molecular Pathways as Potential Therapeutic Targets

Inflammation is the principal defense mechanism against invading pathogens and host injury. Neutralization and elimination of the offending insult ideally prompts resolution of inflammation and restoration of tissue homeostasis. Excessive or dysregulated inflammatory responses together with impaired repair processes results in non-resolving inflammation and persisting tissue damage, which is now considered as a critical component of many chronic human diseases. Ground-breaking work during the past decade has led to the recognition that resolution of inflammation is a tightly controlled active process that involves generation of a new class of lipid mediators, proteins, and autacoids. These endogenous molecules possess overlapping but not fully identical biological properties and may act simultaneously or sequentially to regulate processes that are essential for timely and complete resolution of inflammation. Among these mechanisms are sequestering and suppression of generation of pro-inflammatory cytokines, inhibition of inflammatory cell trafficking into inflamed sites, promotion of neutrophil apoptosis, and macrophage polarization into M2 (alternatively activated or pro-resolution) phenotype, and facilitation of removal of apoptotic neutrophils and other cell types via efferocytosis and tissue repair. During the past years much progress has been made in the identification and characterization of pro-resolution mediators and signaling circuits. Of these, protein mediators, such as annexin A1, and novel classes of lipid mediators, including arachidonic acid-derived lipoxins, and omega-3 polyunsaturated fatty acid-derived resolvins, protectins, and maresins exhibit dual anti-inflammatory and pro-resolution properties. Extensive research has characterized biosynthetic pathways, G-protein-coupled receptors, downstream intracellular signaling pathways, and identified several microRNAs that are involved in the regulation of pro-resolving molecular and cellular circuits. While in inflamed sites neutrophils interact with other cells in their immediate vicinity to produce these lipid mediators, eosinophil granulocytes can also generate pro-resolving mediators from omega-3 polyunsaturated fatty acids, indicating an important role for this type of leukocytes in inflammatory resolution. Resolvins facilitate macrophage polarization into the M2 phenotype. Lipoxins and resolvins interfere with β2 integrin-mediated outside in signaling that in addition to governing leukocyte trafficking also modulates neutrophil apoptosis, another control point in resolving inflammation. Data emerging from a variety of experimental models demonstrated that resolvins and protectins limit adaptive immunity in asthma, attenuate adipose tissue inflammation and metabolic dysfunctions, including type-2 diabetes mellitus-associated insulin resistance and non-alcoholic fatty acid liver disease, and protect the kidney against diabetic nephropathy. The glucocorticoid-regulated protein annexin A1 may act in concert with lipoxins to limit inflammation underlying myocardial ischemia/reperfusion, arthritis, multiple sclerosis, and sepsis. Altering local adenosine signaling affects leukocyte activation and trafficking, and may restore tissue homeostasis in liver injury and rheumatoid arthritis. The nuclear proteins proliferating cell nuclear antigen (PCNA) and myeloid nuclear differentiation antigen (MNDA) play opposing roles in modulating neutrophil apoptosis in patient with sepsis. Targeting the complement C5a receptors C5Ra and C5L2 may attenuate excessive inflammation in sepsis and autoimmune diseases. Intracellular molecular mechanisms have also been implicated in dampening inflammation. The NOD-like receptors NOD1 and NOD2 recognize intracellular pathogens and activate transcriptional responses that would lead to restriction of infection. Suppression of IFNγ production in T lymphocytes by allopurinol may attenuate cell-mediated inflammatory diseases. This Research Topic focuses on articles that discuss the molecular mechanisms governing the function and fate of leukocytes during inflammation and identify potential targets for development of innovative therapeutic approaches for the treatment of inflammatory pathologies based on mimicking and/or activating endogenous pro-resolution mechanisms.

Oxidative stress markers in intestinal mucosa of Tunisian inflammatory bowel disease patients

Background/Aims:Inflammatory bowel diseases (IBDs), Crohn's disease (CrD) and ulcerative colitis (UC), are chronic gastrointestinal inflammatory disorders. The precise etiology of IBD remains unclear, and it is thought that interactions among various factors, including, genetic factors, the host immune system and environmental factors, cause disruption of intestinal homeostasis, leading to dysregulated inflammatory responses of the gut. As inflammation is intimately related to formation of reactive intermediates, including, reactive oxygen species, oxidative stress has been proposed as a mechanism underlying the pathophysiology of IBD. The purpose of this study is to examine the lipid peroxidation, protein oxidation and anti-oxidative profile in Tunisian IBD.Materials and Methods:Malondialdehyde (MDA), conjugated dienes (CD), protein thiol levels, as well as the catalase (CAT) activity were evaluated in intestinal biopsies of 17 patients affected by IBD (12 CrD and 5 UC) and 12 healthy control individuals.Results:Oxidative stress was confirmed in these two types of disease biopsies as compared to controls. MDA and CD levels were significantly increased in both UC and CrD patients’ biopsies as compared to controls’ biopsies (P < 0.001). CAT activity was similar in UC and CrD biopsies’ and was not significantly increased in IBD patients’ biopsies compared with controls’ biopsies (P > 0.05). Anon-significant decrease in thiol (SH) level was observed in both UC and CrD patients’ biopsies compared with controls’ biopsies (P > 0.05).Conclusion:Increased levels of MDA and CD in IBD patients’ biopsies underline the implication of oxidative stress in the physiopathology of IBD.

A multiscale modeling approach to inflammation: A case study in human endotoxemia

Inflammation is a critical component in the body’s response to injury. A dysregulated inflammatory response, in which either the injury is not repaired or the inflammatory response does not appropriately self-regulate and end, is associated with a wide range of inflammatory diseases such as sepsis. Clinical management of sepsis is a significant problem, but progress in this area has been slow. This may be due to the inherent nonlinearities and complexities in the interacting multiscale pathways that are activated in response to systemic inflammation, motivating the application of systems biology techniques to better understand the inflammatory response. Here, we review our past work on a multiscale modeling approach applied to human endotoxemia, a model of systemic inflammation, consisting of a system of compartmentalized differential equations operating at different time scales and through a discrete model linking inflammatory mediators with changing patterns in the beating of the heart, which has been correlated with outcome and severity of inflammatory disease despite unclear mechanistic underpinnings. Working towards unraveling the relationship between inflammation and heart rate variability (HRV) may enable greater understanding of clinical observations as well as novel therapeutic targets.