An outbreak of livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) clonal complex 398 in a regional burns centre.

BACKGROUND: Meticillin-resistant Staphylococcus aureus (MRSA) outbreaks have been reported previously in burns centres with resulting mortality and morbidity. This article describes the first human-associated outbreak in the UK caused by a strain of mupirocin-resistant (MuR) livestock-associated MRSA clonal complex 398 (LA-MRSA CC398) in an adult burns centre. The centre historically had a very low prevalence of MRSA infections. AIM: To describe the clinical and epidemiological context of how the outbreak was identified and contained using a range of infection prevention and control (IPC) measures guided by both traditional and genetic methods. METHODS: A cluster of MuR-MRSA led to an outbreak investigation. Cases were detected via retrospective search and real-time laboratory surveillance. Isolates were sent continuously for whole-genome sequencing (WGS). A live timeline of cases and interventions was produced throughout the period. FINDINGS: The outbreak consisted of 12 cases (seven males and five females) aged between 22 and 70 years. Patients were identified between May and October 2020. All patients were colonized rather than infected. The strain acquired the plasmid bearing MupA while colonizing the index case before dissemination. The index case was found to be a chicken farmer. This outbreak was eventually controlled using IPC measures, audits, and blind staff decolonization guided by insight from WGS. CONCLUSION: It was not possible to determine how the strain entered the centre, or if a staff carrier was involved. The outbreak demonstrated the potential for continued transmissions for months despite active surveillance and stringent control measures.

Textural pattern classification for oral squamous cell carcinoma.

Despite being an area of cancer with highest worldwide incidence, oral cancer yet remains to be widely researched. Studies on computer-aided analysis of pathological slides of oral cancer contribute a lot to the diagnosis and treatment of the disease. Some researches in this direction have been carried out on oral submucous fibrosis. In this work an approach for analysing abnormality based on textural features present in squamous cell carcinoma histological slides have been considered. Histogram and grey-level co-occurrence matrix approaches for extraction of textural features from biopsy images with normal and malignant cells are used here. Further, we have used linear support vector machine classifier for automated diagnosis of the oral cancer, which gives 100% accuracy.

An exploration of how to define and measure the evolution of behavior, learning, memory and mind across the full phylogenetic tree of life.

There are probably few terms in evolutionary studies regarding neuroscience issues that are used more frequently than 'behavior', 'learning', 'memory', and 'mind'. Yet there are probably as many different meanings of these terms as there are users of them. Further, investigators in such studies, while recognizing the full phylogenetic spectrum of life and the evolution of these phenomena, rarely go beyond mammals and other vertebrates in their investigations; invertebrates are sometimes included. What is rarely taken into consideration, though, is that to fully understand the evolution and significance for survival of these phenomena across phylogeny, it is essential that they be measured and compared in the same units of measurement across the full phylogenetic spectrum from aneural bacteria and protozoa to humans. This paper explores how these terms are generally used as well as how they might be operationally defined and measured to facilitate uniform examination and comparisons across the full phylogenetic spectrum of life. This paper has 2 goals: (1) to provide models for measuring the evolution of 'behavior' and its changes across the full phylogenetic spectrum, and (2) to explain why 'mind phenomena' cannot be measured scientifically at the present time.

Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro.

There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca(2+) concentrations during diastole, together with the appearance of spontaneous Ca(2+) transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na(+)/K(+)-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca(2+) concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na(+)/Ca(2+) exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis-induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E' septal annulus, E/E' septal annulus, left ventricular diastolic volume). We also found in CMs from septic mice the presence of defective current densities for Ik1, l-type calcium channel, and Na(+)/Ca(2+) exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.

Daptomycin for the treatment of osteomyelitis and orthopaedic device infections: real-world clinical experience from a European registry.

Osteomyelitis is a serious infection predominantly caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Orthopaedic device-related infections are complex and require a careful combination of surgical intervention and antimicrobial therapy. Daptomycin, a cyclic lipopeptide, effectively penetrates soft tissue and bone and demonstrates rapid concentration-dependent bactericidal activity against Gram-positive pathogens. This retrospective, non-interventional study evaluated clinical outcomes in patients with osteomyelitis or orthopaedic device infections treated with daptomycin from the European Cubicin® Outcomes Registry and Experience (EU-CORE(SM)) study. Patients were treated between January 2006 and April 2012, with follow-up to 2014. Clinical outcomes were assessed as success (cured or improved), failure or non-evaluable. Of 6,075 patients enrolled, 638 (median age, 63.5 years) had primary infections of osteomyelitis or orthopaedic device infections, 224 had non-prosthetic osteomyelitis, 208 had osteomyelitis related to a permanent or temporary prosthetic device, and 206 had orthopaedic device infections. The most commonly isolated pathogen was S. aureus (214 [49.1 %]; 24.8 % were MRSA). Overall, 455 (71.3 %) patients had received previous antibiotic therapy. Patients underwent surgical interventions, including tissue (225 [35.3 %]) and bone (196 [30.7 %]) debridement, as part of their treatment. Clinical success rates were 82.7 % and 81.7 % in S. aureus and coagulase-negative staphylococcal infections. Adverse events (AEs) and serious AEs assessed as possibly related to daptomycin were observed in 6.7 % and 1.9 % of patients, respectively. Daptomycin was discontinued by 5.5 % of patients due to AEs and 10 (1.6 %) deaths were reported. In conclusion, daptomycin was effective and safe in patients with osteomyelitis or orthopaedic device infections.

Effects of fluoroquinolone restriction (from 2007 to 2012) on resistance in Enterobacteriaceae: interrupted time-series analysis.

BACKGROUND: Antibiotic stewardship is a key component in the effort to reduce healthcare-associated infections. AIM: To describe the implementation and analyse the impact of fluoroquinolone restriction on resistance in Enterobacteriaceae, focusing on urinary isolates of extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli, which were historically almost universally resistant to fluoroquinolones. METHODS: ESBL-producing E. coli hospital and community isolates, obtained between April 2009 and March 2012 from consecutive non-duplicate urine samples, were included in an interrupted time-series analysis based on a Poisson distribution model. Periods before and after fluoroquinolone restriction were compared. The trend in fluoroquinolone resistance in all urinary isolates of Enterobacteriaceae (N ≈ 20,000 per year) and blood culture isolates of E. coli (N ≈ 350) between 2009 and 2013 were also analysed. FINDINGS: A large decline in the percentage of ciprofloxacin-resistant ESBL-producing urinary E. coli isolates was observed in both hospital (risk ratio: 0.473; 95% confidence interval: 0.315-0.712) and community settings (0.098; 0.062-0.157). The decline was also marked in all urinary isolates of Enterobacteriaceae and E. coli isolates from blood cultures. CONCLUSION: We conclude that reducing fluoroquinolone usage to a level of ≤2 defined daily doses per 100 occupied bed-days in hospital sufficiently removed selection pressure to allow resistant Enterobacteriaceae ­ specifically, the UK endemic strains of ESBL-producing E. coli ­ to revert back to fluoroquinolone susceptibility within a short span of four months. This was accompanied with a concomitant reduction in overall ESBL burden.

Effects of fluoroquinolone restriction (from 2007 to 2012) on Clostridium difficile infections: interrupted time-series analysis.

BACKGROUND: Antimicrobial stewardship is a key component in the reduction of healthcare-associated infections, particularly Clostridium difficile infection (CDI). We successfully restricted the use of cephalosporins and, subsequently, fluoroquinolones. From an endemically high level of >280 cases per year in 2007-08, the number of CDIs reduced to 72 cases in 2011-12. AIM: To describe the implementation and impact of fluoroquinolone restriction on CDI. METHODS: This was an interrupted time-series analysis pre and post fluoroquinolone restriction for 60 months based on a Poisson distribution model. FINDINGS: In June 2008, fluoroquinolone consumption halved to about 5 defined daily doses (DDD) per 100 occupied bed-days (OBD). This was followed by a significant fall in CDI number [rate ratio (RR): 0.332; 95% confidence interval (CI): 0.240-0.460] which remained low over the subsequent months. Subsequently, fluoroquinolone consumption was further reduced to about 2 DDD/100 OBD in June 2010 accompanied by further reduction in CDI rate (RR: 0.394; 95% CI: 0.199-0.781). In a univariate Poisson model the CDI rate was associated with fluoroquinolone usage (RR: 1.086; 95% CI: 1.077-1.094). CONCLUSION: We conclude that in an environment where cephalosporin usage is already low, the reduction in fluoroquinolone usage was associated with an immediate, large, and significant reduction in CDI cases.

A matched case control study of risk indicators of breast cancer in assam, India.

Breast cancer is the leading cause of cancer death among women worldwide especially in a developing country like India. It also occupies the highest place with relative proportion 17.5% in the Hospital Based Cancer Registry in progress in the Dr. B. Borooah Cancer Research Institute. Dr. B. Borooah Cancer Research Institute is the Regional Cancer Care Center for entire North East region of India. With this background a matched case control study of 100 cases of breast cancer and 100 controls was carried out to investigate the role of different Socio economic, Female Reproductive and Life style related factors and to understand the etiology of breast cancer in Assam. Controls are matched to the cases by age at diagnosis (±5 years), family income and place of residence with matching ratio 1:1. Data were collected using questionnaire and then conditional logistic regression analysis is used to estimate the odd ratios for several factors. Study revealed that breast cancer occurrence has statistical association with the factors chewing habits (p=0.003), number of children (p=0.080), age at marriage (p=0.014), age at first child birth (p=0.007), age at menarche (p=0.010).

Role of extracellular histones in the cardiomyopathy of sepsis.

The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca(2+)]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains-containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca(2+)]i, as well as defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.

Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3.

Severe sepsis and septic shock are leading causes of morbidity and mortality worldwide. Infection-associated inflammation promotes the development and progression of adverse outcomes in sepsis. The effects of heterodimeric IL-27 (p28/EBI3) have been implicated in the natural course of sepsis, whereas the molecular mechanisms underlying the regulation of gene expression and release of IL-27 in sepsis are poorly understood. We studied the events regulating the p28 subunit of IL-27 in endotoxic shock and polymicrobial sepsis following cecal ligation and puncture. Neutralizing Abs to IL-27(p28) improved survival rates, restricted cytokine release, and reduced bacterial burden in C57BL/6 mice during sepsis. Genetic disruption of IL-27 signaling enhanced the respiratory burst of macrophages. Experiments using splenectomized mice or treatment with clodronate liposomes suggested that macrophages in the spleen may be a significant source of IL-27(p28) during sepsis. In cultures of TLR4-activated macrophages, the frequency of F4/80(+)CD11b(+)IL-27(p28)(+) cells was reduced by the addition of IL-10. IL-10 antagonized both MyD88-dependent and TRIF-dependent release of IL-27(p28). Genetic deletion of STAT3 in Tie2-Cre/STAT3flox macrophages completely interrupted the inhibition of IL-27(p28) by IL-10 after TLR4 activation. In contrast, IL-10 remained fully active to suppress IL-27(p28) with deletion of SOCS3 in Tie2-Cre/SOCS3flox macrophages. Blockade of IL-10R by Ab or genetic deficiency of IL-10 resulted in 3-5-fold higher concentrations of IL-27(p28) in endotoxic shock and polymicrobial sepsis. Our studies identify IL-10 as a critical suppressing factor for IL-27(p28) production during infection-associated inflammation. These findings may be helpful for a beneficial manipulation of adverse IL-27(p28) release during sepsis.

Anthrax lethal factor inhibitors as potential countermeasure of the infection.

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).

Induction of M2 regulatory macrophages through the ß2-adrenergic receptor with protection during endotoxemia and acute lung injury.

The main drivers of acute inflammation are macrophages, which are known to have receptors for catecholamines. Based on their function, macrophages are broadly categorized as having either M1 (proinflammatory) or M2 phenotypes (anti-inflammatory). In this study, we investigated catecholamine-induced alterations in the phenotype of activated macrophages. In the presence of lipopolysaccharide (LPS), mouse peritoneal macrophages acquired an M1 phenotype. However, the copresence of LPS and either epinephrine or norepinephrine resulted in a strong M2 phenotype including high levels of arginase-1 and interleukin-10, and a reduced expression of M1 markers. Furthermore, epinephrine enhanced macrophage phagocytosis and promoted type 2 T-cell responses in vitro, which are known features of M2 macrophages. Analysis of M2 subtype-specific markers indicated that LPS and catecholamine-cotreated macrophages were not alternatively activated but were rather of the regulatory macrophage subtype. Interestingly, catecholamines signaled through the ß2-adrenergic receptor but not the canonical cAMP/protein kinase A signaling pathway. Instead, the M2 pathway required an intact phosphoinositol 3-kinase pathway. Blockade of the ß2-adrenergic receptor reduced survival and enhanced injury in mouse models of endotoxemia and LPS-induced acute lung injury, respectively. These results demonstrate a role for the ß2-adrenergic receptor in promoting the M2 macrophage phenotype.

Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury.

Proinflammatory mediators trigger intensive postischemic inflammatory remodeling of the blood-brain barrier (BBB) including extensive brain endothelial cell surface and junctional complex changes. Junctional adhesion molecule-A (JAM-A) is a component of the brain endothelial junctional complex with dual roles: paracellular route occlusion and regulating leukocyte docking and migration. The current study examined the contribution of JAM-A to the regulation of leukocyte (neutrophils and monocytes/macrophages) infiltration and the postischemic inflammatory response in brain ischemia/reperfusion (I/R injury). Brain I/R injury was induced by transient middle cerebral artery occlusion (MCAO) for 30min in mice followed by reperfusion for 0-5days, during which time JAM-A antagonist peptide (JAM-Ap) was administered. The peptide, which inhibits JAM-A/leukocyte interaction by blocking the interaction of the C2 domain of JAM-A with LFA on neutrophils and monocytes/macrophages, attenuated I/R-induced neutrophil and monocyte infiltration into brain parenchyma. Consequently, mice treated with JAM-A peptide during reperfusion had reduced expression (~3-fold) of inflammatory mediators in the ischemic penumbra, reduced infarct size (94±39 vs 211±38mm3) and significantly improved neurological score. BBB hyperpermeability was also reduced. Collectively, these results indicate that JAM-A has a prominent role in regulating leukocyte infiltration after brain I/R injury and could be a new target in limiting post-ischemic inflammation.

Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury.

We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of acute lung injury (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all models requiring availability of both C5a receptors (C5aR and C5L2) for full development of ALI. Ligation of C5aR and C5L2 with C5a triggered the appearance of histones (H3 and H4) in bronchoalveolar lavage fluid (BALF). BALF from humans with ALI contained H4 histone. Histones were absent in control BALF from healthy volunteers. In mice with ALI, in vivo neutralization of H4 with IgG antibody reduced the intensity of ALI. Neutrophil depletion in mice with ALI markedly reduced H4 presence in BALF and was highly protective. The direct lung damaging effects of extracellular histones were demonstrated by airway administration of histones into mice and rats (Sprague-Dawley), which resulted in ALI that was C5a receptor-independent, and associated with intense inflammation, PMN accumulation, damage/destruction of alveolar epithelial cells, together with release into lung of cytokines/chemokines. High-resolution magnetic resonance imaging demonstrated lung damage, edema and consolidation in histone-injured lungs. These studies confirm the destructive C5a-dependent effects in lung linked to appearance of extracellular histones.

Incidence of bla NDM-1 gene in Escherichia coli isolates at a tertiary care referral hospital in Northeast India.

PURPOSE: Increasing reports on New Delhi metallo-ß-lactamase-1 (NDM-1) producing Escherichia coli constitute a serious threat to global health since it is found to be highly resistant to most of the currently available antibiotics including carbapenems. This study has been performed to find out the incidence blaNDM-1 in E. coli isolates recovered from the various clinical samples at a tertiary care referral hospital in Northeast India. MATERIALS AND METHODS: A total of 270 non-duplicated E. coli isolates were recovered from the various clinical samples at a tertiary care referral hospital in Northeast India. All isolates with reduced susceptibility to meropenem or ertapenem (diameter of zones of inhibition, ≤ 21 mm) were further phenotypically confirmed for carbapenemase production by modified Hodge test. All screened isolates were also subjected to the polymerase chain reaction detection of blaNDM-1 gene and additional bla genes coding for transmission electron microscopy, SHV, CTX-M, and AmpC. RESULTS: Out of 270 E. coli isolates, 14 were screened for carbapenemase production on the basis of their reduced susceptibility to meropenem or ertapenem. All screened isolates were found to be positive for blaNDM-1 . Each of the blaNDM-1 possessing isolate was also positive for two or more additional bla genes, such as blaTEM , blaCTX-M and blaAmpC . Phylogenetic analysis showed very less variation in blaNDM-1 gene with respect to blaNDM-1 possessing E. coli isolates from other parts of India and abroad. CONCLUSIONS: Our findings highlight the incidence of blaNDM-1 in E. coli isolates with a reduced susceptibility to meropenem or ertapenem.

The interaction between C5a and both C5aR and C5L2 receptors is required for production of G-CSF during acute inflammation.

The complement activation product, C5a, is a key factor for regulation of inflammatory responses. C5a and C5adesArg bind to their receptors, C5aR and C5L2, but the functional roles of C5L2 remain controversial. We screened the patterns of 23 inflammatory mediators in cultures of LPS-activated mouse peritoneal elicited macrophages (PEMs) in the presence or absence of recombinant mouse C5a. Production of most mediators studied was suppressed by C5a, whereas G-CSF production was enhanced. G-CSF gene expression and secretion from PEMs was amplified two- to threefold by C5a in a dose- and time-dependent fashion. The degradation product C5adesArg promoted lower levels of G-CSF. The effects of C5a on G-CSF were associated with activation of PI3K/Akt and MEK1/2 signaling pathways. C5a did not enhance G-CSF production in cultures of PEMs from either C5aR- or C5L2-deficient mice, indicating that both C5a receptors are indispensable for mediating the effects of C5a in the production of G-CSF. Finally, G-CSF levels in plasma during polymicrobial sepsis after cecal ligation and puncture were substantially lower in C5aR- or C5L2-deficient mice as compared with that in C57BL/6J WT mice. These findings elucidate the functional characteristics of the C5L2 receptor during the acute inflammatory response.

Changes and regulation of the C5a receptor on neutrophils during septic shock in humans.

During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.

CD11c+ alveolar macrophages are a source of IL-23 during lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is a severe pulmonary disease causing high numbers of fatalities worldwide. Innate immune responses are an integral part of the pathophysiologic events during ALI. Interleukin 23 (IL-23) is a proinflammatory mediator known to direct the inflammatory responses in various settings of infection, autoimmunity, and cancer. Interleukin 23 has been associated with proliferation and effector functions in T(H)17 cells. Surprisingly, little is known about production of IL-23 during ALI. In this study, we found expression of mRNA for IL-23p19 to be 10-fold elevated in lung homogenates of C57BL/6 mice after lipopolysaccharide (LPS)-induced ALI. Likewise, concentrations of IL-23 significantly increased in bronchoalveolar lavage fluids. Experiments with IL-23-deficient mice showed that endogenous IL-23 was required for production of IL-17A during LPS-ALI. CD11c-diphtheria toxin receptor transgenic mice were used to selectively deplete CD11c cells, the data suggesting that IL-23 production is dependent at least in part on CD11c cells during ALI. No alterations of IL-23 levels were observed in Rag-1-deficient mice as compared with wild-type C57BL/6 mice following ALI. The mouse alveolar macrophage cell line, MH-S, as well as primary alveolar macrophages displayed abundant surface expression of CD11c. Activation of these macrophages by LPS resulted in release of IL-23 in vitro. Our findings identify CD11c macrophages in the lung are likely an important source of IL-23 during ALI, which may be helpful for better understanding of this disease.

Regulation of IL-17 family members by adrenal hormones during experimental sepsis in mice.

Severe sepsis is a life-threatening disease that causes major morbidity and mortality. Catecholamines and glucocorticoids often have been used for the treatment of sepsis. Several recent studies have suggested a potential role of IL-17 during the development and progression of sepsis in small animal models. In this study, the cross-talk of catecholamines and glucocorticoids with members of the IL-17 family was investigated during sepsis in C57BL/6 mice. The concentrations in plasma of IL-17A, IL-17F, and the IL-17AF heterodimer all were increased greatly in mice after endotoxemia or cecal ligation and puncture as compared with sham mice. Surprisingly, when compared with IL-17A (487 pg/mL), the concentrations of IL-17F (2361 pg/mL) and the heterodimer, IL-17AF (5116 pg/mL), were much higher 12 hours after endotoxemia. After surgical removal of the adrenal glands, mice had much higher mortality after endotoxemia or cecal ligation and puncture. The absence of endogenous adrenal gland hormones (cortical and medullary) was associated with 3- to 10-fold higher concentrations of IL-17A, IL-17F, IL-17AF, and IL-23. The addition of adrenaline, noradrenaline, hydrocortisone, or dexamethasone to lipopolysaccharide-activated peritoneal macrophages dose-dependently suppressed the expression and release of IL-17s. The production of IL-17s required activation of c-Jun-N-terminal kinase, which was antagonized by both catecholamines and glucocorticoids. These data provide novel insights into the molecular mechanisms of immune modulation by catecholamines and glucocorticoids during acute inflammation.