New Zealand Black/New Zealand White (NZB/NZW) mice, a murine lupu

New Zealand Black/New Zealand White (NZB/NZW) mice, a murine lupus model, had higher Fli-1

mRNA expression in splenic lymphocytes than normal control mice [6]. Two- to threefold overexpression of Fli-1 protein in transgenic mice resulted in the development of a lupus-like disease [7]. The phenotype of the Fli-1 transgenic mice included autoantibody production, renal deposition of immune complexes, glomerulonephritis, hypergammaglobulinaemia, an increased number of autoreactive T and B lymphocytes, and increased mortality [7]. Targeted disruption of the Fli-1 Lenvatinib solubility dmso gene resulted in haemorrhage into the neural tube and embryonic death due in part to thrombocytopenia and inadequate vascular formation [8,9]. Heterozygous (Fli-1+/−) mice develop normally. The expression level of Fli-1 protein, including immune cells, in Fli-1+/− mice is half that found in Fli-1+/+ wild-type (WT) mice [8]. Murphy Roths Large (MRL)/MpJ-Faslpr (MRL/lpr) mice have many clinical manifestations found in human SLE [10]. Autoantibodies produced by these mice are similar in spectrum to those seen in human lupus including anti-double-stranded this website DNA (anti-dsDNA) antibodies and anti-Sm antibodies [10]. MRL/lpr mice

develop proliferative glomerulonephritis at an early age (4–5 months) and renal failure is a primary cause of death in these mice [10]. The lpr (lymphoproliferation) phenotype is due to a defect in the fas gene, a key mediator of apoptosis [11,12]. We found that MRL/lpr mice had higher splenic Fli-1 protein expression than normal control BALB/c mice as early as 10 weeks of age [13]. We generated Fli-1+/− MRL/lpr mice with 50% reduced expression of Fli-1 protein and found that Fli-1+/− MRL/lpr mice had significantly lower serum autoantibodies and proteinuria than littermate WT MRL/lpr Carnitine dehydrogenase mice [13]. Fli-1+/− MRL/lpr mice had significantly reduced pathological renal disease and markedly prolonged survival compared to WT MRL/lpr mice. Bone marrow (BM) transplantation

is used to investigate the contribution of haematopoietic versus non-haematopoietic cell lineages in autoimmune disease development [14,15]. In this study, our aim was to investigate whether BM-derived cells play a role in the profound improvement of renal disease and survival in Fli-1+/− MRL/lpr mice. We hypothesized that, due to the more profound impact of Fli-1 deficiency on renal disease and survival than on autoantibody production, both haematopoietic cell lineages and non-haematopoietic lineages would have a greater impact on disease expression. We performed BM transplantation from Fli-1+/− MRL/lpr mice to WT MRL/lpr mice, as well as the reverse transplant, and evaluated disease development in these mice.

Efficacy of AGP in both endotoxemia and CLP support the potential

Efficacy of AGP in both endotoxemia and CLP support the potential utility of this novel, natural colloidal resuscitation fluid. The ability of AGP to maintain liver perfusion and decrease leukocyte adherence to the liver microvasculature could arise from numerous previously suggested AUY-922 manufacturer potential mechanisms, ranging from altering the ratio

of pro-inflammatory to anti-inflammatory cytokines and signals in hepatic inflammation, to restoring glycocalyx/barrier functions of the liver microcirculation, to directly binding and sequestering LPS. Of these possibilities, we selected the last one for further investigation, given that it was amenable to testing using methodologies already employed in this study. When AGP was combined with LPS and then injected intraperitoneally, it attenuated the pro-inflammatory effects of LPS on the hepatic microcirculation, at least with respect to leukocyte adhesion to PSV and sinusoidal perfusion. AGP has been shown to bind to LPS in two in vitro studies [25, 16]. If AGP bound LPS in the peritoneal space, it may have prevented the endotoxin from reaching the circulation and exerting systemic

effects, given the slow uptake of AGP from the peritoneal space into the circulation detected in our clearance experiments with radiolabeled AGP. Alternatively, LPS and AGP may not have interacted in the peritoneal space, but instead both reached selleck chemicals the circulation, where AGP exerted the anti-inflammatory effects we previously observed. To discriminate more fully between these

possibilities, we amended our experimental endotoxemia protocol to permit administration of both AGP and LPS intravenously, by reducing the LPS dose to 0.08 mg/kg, avoiding the mortality likely to ensue from an intravascular 5 mg/kg LPS dose. While administration of AGP just prior to LPS injection into the vasculature resulted in a non-significant trend toward decreased inflammation, pre-incubation of AGP with LPS significantly improved liver perfusion and reduced leukocyte adherence in both the post-sinusoidal venules and the sinusoids. Although in hindsight the latter experiment was likely underpowered, taken together our results support the concept that AGP is an LPS-binding ADAMTS5 protein and demonstrate this binding can have consequences in vivo. The anti-inflammatory effects of AGP manifested in the hepatic microcirculation are consistent with previous reports that infusion of pharmacological quantities of AGP purified from healthy cattle or humans limited mortality in disease models of uncontrolled inflammation [15, 20, 26]. However, they differ from two reports suggesting that AGP mediates a failure of leukocyte migration to the site of infection, both in normal and diabetic mice subjected to the CLP procedure. Mestriner et al. found that human AGP administered at the remarkably low dose of 4 μg/rat (approximately 0.

© 2013 Wiley Periodicals, Inc Microsurgery

34:240–244, 2

© 2013 Wiley Periodicals, Inc. Microsurgery

34:240–244, 2014. “
“Although the devices for large-caliber vessel (>2-mm diameter) anastomosis are available, there are no devices for performing anastomosis of small-caliber vessels. We designed a hooked device composed of a bioabsorbable polymer for sutureless anastomosis of small-caliber vessels. The efficacy of this device was evaluated by in vitro degradation and arterial-fixation strength tests as well as in vivo transplantation experiments with common carotid arteries of growing SD rats. A nonabsorbable device without hooks served as the control in the fixation strength and animal experiments. The tensile strength of the bioabsorbable device decreased Protease Inhibitor Library in vitro to 27 and 9% of the initial value after 8- and 24-week incubation, respectively. The fixation strength was greater and the anastomotic time was shorter with this device than with the control. The transplantation experiments showed complete endothelial bridging in both devices at 2 weeks after surgery (n = 6). The control device created a considerable protrusion into the arterial lumen at 8 postoperative weeks, whereas the experimental device did not (n = 6). Arterial diameter measurements detected a significant difference between the inner diameters at the respective anastomotic sites (n = 6, P < 0.05) and demonstrated that the control device hindered the vessel

growth while the experimental NVP-BGJ398 datasheet device did not. Therefore, the bioabsorbable hooked device was an effective tool for anastomosis of small-caliber arteries (ca. 1-mm diameter). © 2010 Wiley-Liss, Inc. Microsurgery 30:494–501, 2010. “
“Free tissue transplantations are lengthy procedures that result in prolong tissue ischemia. Restoral of blood flow is essential for free flap recovery; however, upon reperfusion tissue that is viable may continue to be nonperfused. To further elucidate this pathophysiology skeletal muscle microcirculation was investigated during reperfusion following 4-hour single arteriole occlusion.

A blunt micropipette probe was use to compress a single arteriole in the unanesthetized hamster (N = 20) dorsal skinfold chamber. Arteriole (n = 20), capillary (n = 97), and postcapillary venule (n = 16) diameters and blood flow were analyzed at 0, 30, 60, 120, Vildagliptin 240 min and 24 hours of reperfusion after 4 hour occlusion. Results: Feeding arcade arterioles exhibited a brief (<10 min) vasoconstriction [0.31 ± 0.26 (mean ± SE) of baseline] upon reperfusion followed by a maximum vasodilation at 120 min (1.3 ± 0.10: P < 0.05). Vasodilation was observed in transverse arterioles (A3) (1.8 ± 0.20: P < 0.05). Correspondingly, all arteriole and venule flow was increased by 120 min (P < 0.05) of reperfusion. There was a transient decrease in the number of flowing capillaries at 0 and 30 min reperfusion (0.73 ± 0.09 and 0.84 ± 0.06: P < 0.05, respectively).

The RD1 and RD9 genomic regions are present in all virulent and c

The RD1 and RD9 genomic regions are present in all virulent and clinical strains of M. tuberculosis but deleted in all M. bovis BCG vaccine strains [29]. The importance of proteins encoded

by RD1, both for diagnosis and vaccine development, is highly suggestive because three genes of this region have been conclusively shown to be expressed in M. tuberculosis and are major antigens recognized by antibodies (ORF14) and T cells (EsxA and EsxB) of patients with TB and/or healthy but exposed individuals [30, 31]. In particular, EsxA and EsxB proteins are recognized by T cells with protective phenotype, i.e. memory and effector IFN-γ secreting T cells in mice and human T cells producing large quantities of IFN-γ [32–35]. To prepare DNA vaccine constructs using the plasmids, DNA fragments corresponding to PE35, PPE68, EsxA, EsxB and EsxV genes were PCR amplified by using gene-specific primers, and Palbociclib manufacturer the amplified DNA were first cloned into pGEM-T Easy vector, before subcloning into

pUMVC6 and pUMVC7. This was performed to facilitate the cloning of appropriate DNA into the eukaryotic expression vectors, as has been performed previously for prokaryotic expression vectors [14, 15]. A total of 10 recombinant DNA plasmids (five for each vector) were constructed. All the aforementioned recombinant DNA plasmids were studied for expression and immunogenicity of the cloned fragments by immunizing mice. The results show that both the vectors induced antigen-specific cellular proliferation to PE35, EsxA, EsxB, and EsxV proteins. However, recombinant pUMCV6 induced relatively better responses Kinase Inhibitor Library solubility dmso than recombinant pUMCV7.

The improved responses with recombinant pUMCV6 suggest that hIL2 secretory protein acted as a better Sodium butyrate adjuvant and enhanced cellular immune responses, assessed by antigen-induced proliferation of splenocytes, to the fused mycobacterial proteins more effectively than the tPA signal peptide. The relevance of antigen-specific cellular proliferation induced by DNA vaccine constructs with protection against M. tuberculosis challenge has been demonstrated in the mouse model of TB [36]. Although the results of this study, showing induction of antigen-specific immune responses to the antigens encoded by genes present in DNA vaccine constructs, are interesting, the work should be extended to demonstrate their protective efficacy in challenge experiments with M. tuberculosis using various animal models of TB, e.g. mice, guinea pigs, rabbits and monkeys. If found effective in animals, such vaccines may be useful in both prophylactic and therapeutic applications in humans. Furthermore, DNA-based vaccines expressing M. tuberculosis-specific antigens may even be useful in BCG-vaccinated subjects as preventive vaccines, because revaccination with BCG has not shown beneficial effects [4, 37, 38] and may even be combined with BCG to improve its protective efficacy [39].

7), IL-6 (0 9), IL-4 (4 5), IL-1ra (8 3), MIP-1α (2 9), and MCP-1

7), IL-6 (0.9), IL-4 (4.5), IL-1ra (8.3), MIP-1α (2.9), and MCP-1 (1.9). Leukocytes subsets were characterized find more in ChL and PL using the BD Multitest IMK kit following the manufacturer’s protocol (BD Biosciences, CA, USA; Cat. No. 340504): total leukocytes/CD45+(clone 2D1-HLe-1), NK cells/CD16+ (clone B73.1), CD56+ (clone NCAM 16.2), B cells/CD19+ (clone SJ25C1), and monocytes/macrophages/CD14+ (clone HCD14), and subsets of T cells/CD3+ (clone SK7), CD8+ (clone SK1), and CD4+ (clone SK3). Leukocyte subsets were analyzed within the CD45+ gate using a FACSCalibur flow cytometer, and data analysis was performed by BD Cell Quest software (BD Biosciences, CA, USA). Gelatinase activity in culture media

was determined by SDS–PAGE containing 1% gelatin under non-denaturing conditions as described previously.[21] Culture supernatants (0.5 μg of total protein) were loaded into each well. Enzymatic activity standards for MMP-2 and MMP-9 were included using conditioned media on the U-937 promyelocyte cell line.[24] Specific quantification of active and total MMP-9 in culture supernatants of choriodecidual and peripheral leukocytes was carried out using the Biotrak MMP-9 Activity Assay System (General Electric Healthcare, Buckinghamshire, UK) following the protocol suggested by the manufacturer. To measure the total MMP-9 content, bound enzyme was activated with

p-aminophenylmercuric acetate. The MI-503 concentration of total and active MMP-9 in the samples is reported as nanograms (ng) of MMP-9 per μg of protein. Protein was measured by Bradford’s method.[25] For each variable, descriptive

statistics (mean, standard deviation, standard error, median, and range) were obtained, and the data distribution was tested for normality using the Kolmogorov–Smirnoff and Shapiro–Wilk tests. Student’s t-test was Progesterone performed to compare leukocytes subsets between ChL and PL. A P value ≤0.05 was considered to be statistically significant. Two-way analysis of variance using repeated measurement model was used to compare cytokines/chemokines concentrations in the culture media from ChL and PL. Differences with P ≤ 0.05 were considered statistically significant. All statistical analyses were carried out using spss, version 20 software (IBM Corporation, Armonk, NY, USA). The two-step method, using a density gradient followed by selection by plastic adherence, yielded in 1,33,000 ± 3,500 choriodecidual leukocytes per cm[2] of fetal membranes (n = 18). According to the flow cytometry data, this method also allowed enriching and purifying (≥80%) choriodecidual leukocytes. Flow cytometry analysis revealed that T lymphocytes and natural killer cells were the major subsets in the ChL and PL preparations (Table 1). Choriodecidual leukocytes showed a distinct secretion pattern of cytokines and chemokines when compared with intervillous placental blood leukocytes (Fig. 1).

If only studies that did not measure early sexual debut as a cont

If only studies that did not measure early sexual debut as a continuous variable are considered, then four of seven remain

significant. There was no support for the third pathway. Table 6 clearly shows that the only two studies that controlled for women’s age difference with their first sexual partner, whether the partner was drunk or on drugs during their first Smoothened Agonist concentration sexual intercourse or the partner’s estimated HIV infection risk continued to show a significant association between women’s onset of sexual debut and their HIV infection risk. No influence was established on the association between early onset of sexual debut and women’s HIV infection risk by differing socio-economic BGB324 research buy and demographic factors in all three studies that solely controlled for these factors (see Table 6). In addition, no study included information on the biological risk pathways, such as physiological immaturity or genital trauma, nor on determinants of early first sex relating to gender inequality, such as whether the first sex was forced, child sexual abuse or social norms supporting transactional sex apart from low levels of education and socio-economic status of women. To our knowledge, this is the first systematic review that investigates the association between age of sexual

debut and women’s risk of HIV infection. This is surprising given

the high rates of infection among adolescent girls in many sub-Saharan African countries, PI-1840 and its potential link with age at sexual debut. The review shows mixed results. Among high-quality studies, there is consistent evidence of an association between early sex and HIV risk, which remained after several potential confounders were adjusted for. The evidence is more mixed when all published evidence is considered, although several methodological limitations mean that some of these findings need to be interpreted with caution. We had expected that the review would provide clearer insights into the likely pathways in which risk may be increased. As the evidence for each pathway was mixed, each pathway will be discussed separately. We did not find evidence to support the claim that early sexual debut is associated with increased HIV infection risk through the increased duration of sexual activity and the therefore increased exposure time. However, we acknowledge that this issue has only been explored in research from Zimbabwe and may therefore not be generalisable to other settings. Several studies explored whether the association between early onset of sexual debut and HIV risk did remain once they had controlled for women’s later HIV risk behaviours, such as number of sexual partners, no condom use and STI infection.

After obtaining written informed consent, 5 ml of venous blood fr

After obtaining written informed consent, 5 ml of venous blood from patients and their parents was collected into heparin-containing syringes and used for immunological assays and sequencing.

The study protocol was approved selleck inhibitor by the Ethics Committee of the Children’s Hospital of Fudan University. Routine evaluation of immunological function included analysis of lymphocyte subsets and the detection of immunoglobulins G, A, M and E. As previously reported [11], lymphocyte subsets were analysed using a FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA). Immunoglobulins G, A and M were detected by nephelometry. Immunoglobulin E was detected by UniCAP (Pharmacia, Uppsala, Sweden). Genomic DNA was isolated from peripheral blood mononuclear cells using the RelaxGene Blood DNA System (Tiangen Biotech, Beijing, China) according to the manufacturer’s instructions. Genomic DNA was amplified by PCR using synthetic oligonucleotide primers designed to amplify the SH2D1A and XIAP genes. The primer sequences

are shown in Supplemental Table. After an initial denaturation step of 5 min at 95 °C, 35 cycles of amplification were performed as Navitoclax purchase follows: 95 °C for 30 s, 60 °C for 30 s and 72 °C for 40 s. Final extension was performed at 72 °C for 7 min. PCR products were purified with Performa DTR Gel Filtration Cartridges and directly sequenced by ABI Prism BigDye terminators. Both strands were sequenced. After patients were confirmed with SH2D1A or XIAP gene mutation, the patients’ clinical events and laboratory features were assessed by retrieval of data from medical records. During the study period, 21 male patients with FIM (n = 2), EBV-associated HLH (n = 13) or active EBV infection lasting more than 6 months (n = 6) were enrolled and completed SH2D1A and XIAP sequencing. Five patients with EBV-associated HLH

were found to have SH2D1A or XIAP mutations. Therefore, we summarize the clinical and genetic features of these five patients below. Patient 1 was 4 years old at diagnosis. He initially received treatment in our hospital for fever. He tested positive for EBV-DNA and EBV-VCA IgM and exhibited low serum immunoglobulin G levels. He was administered acyclovir and IVIG, and his symptoms improved. One month selleckchem later, he showed neutropenia, anaemia and thrombocytopenia. After the SH2D1A gene mutation was found, he received HSCT and is well. Patient 2 is the youngest among the five patients, with his age of onset being only 1 month. He had fever, thrombocytopenia and liver dysfunction (ALT 95 IU/l, AST 83 IU/l). Atypical lymphocyte counts were elevated, accounting for 36% of peripheral blood leucocytes, while bone marrow was normal. His mother had negative EBV-VCA IgM and EBV-VCA IgG. Although he tested negative for EBV-DNA and EBV-VCA IgM, he was diagnosed with EBV infection. He was treated with acyclovir, IVIG and other symptomatic treatments.


NOD/LTj see more mice were bred in our own facility under specified pathogen-free conditions. Breedings were done from the age of 8 weeks and older. The appearance of the vaginal plug was noted as E0.5. Pregnant mice were sacrificed and embryos dissected at embryonic age of E15.5. BM cells were isolated from the femora from mice of 8 weeks. All mice were female and were supplied with water and standard chow ad libitum. Experimental procedures were approved by the Erasmus University Animal Ethical Committee.

Embryonic (E15.5) pancreas (pooled) and liver were isolated and micro-dissected from the stomach and digested with Collagenase Type 1 (1 mg/mL), hyaluronidase (2 mg/mL) (both Sigma Aldrich, St. Louis, MO, USA)

and DNAse I (0.3 mg/mL) (Roche Diagnostics, Almere, The Netherlands) for 10 min at 37°C. Embryonic pancreas and liver cells were flushed through a 70 μm filter and washed. Pancreases of 5-week-old mice were isolated after a cardiac perfusion and cut into small pieces and digested with Collagenase Type 1, hyaluronidase and DNAse I for 40 min at 37°C. Cells were flushed through a 70 μm filter and washed. Blood of 4 week old mice was collected selleck chemical in EDTA tubes using a heartpunction. Erythrocytes were lysed with NHCL2 buffer and washed. Single-cell suspensions of BM were prepared as described previously 39. All cells were resuspended in PBS containing 0.1% BSA and were ready for flow cytometry staining. Single-cell suspensions from pancreas (E15.5 and 5 wk) were labeled with mAbs. Ceramide glucosyltransferase Antibodies used were ER-MP58-biotin (own culture), Ly6C-FITC (Abcam, Cambridge, UK), Ly6G-Pacific Blue (Biolegend, Uithoorn, The Netherlands), CD11b-allophycocyanin-Cy7,

CD86-PE (both Becton Dickinson, San Diego, CA, USA), CD11c-allophycocyanin, CD11c-PE, CD11c-PE-Cy7, CD86-Pacific Orange, F4/80-PE-Cy5 (all eBiosciences, San Diego, CA, USA), MHC class II-PE (C57BL/6, clone M5/114, Becton Dickinson) and MHC class II-biotin (NOD clone 10.2.16, own culture). Afterwards cells were washed and incubated with streptavidin-allophycocyanin (Becton Dickinson). To detect proliferation, the cells were fixed in 2% paraformaldehyde, and permeabilized using 0.5% saponin. Subsequently, cells were incubated with Ki-67-FITC (Becton Dickinson) diluted in 0.5% saponin, washed and resuspended in 0.1% BSA. Cells suspensions were analyzed using a FACS Canto HTSII (Becton Dickinson) flow cytometer and FACS Diva and Flowjo software. Antigen processing was determined by measurement of the fluorescence upon proteolytic degradation of the self-quenched conjugate DQ-Ovalbumin 40. Briefly, cells were resuspended in PBS with 2% FCS and 100 μg/mL DQ-Ovalbumin (Molecular Probes, Breda, The Netherlands) and incubated for 30 min at 37°C.

The relative contribution to transmission by

The relative contribution to transmission by ABT-199 solubility dmso cell-associated or cell-free virus is still not defined for the different routes

of transmission. Although the main target cells for HIV-1 replication are the CD4+ T lymphocytes, which are rapidly depleted both in the periphery and in the mucosal tissues, dendritic cells, Langerhans’ cells, and macrophages are players in each of these processes. The predominant cells involved may differ according to the tract of the gut and the route of transmission. The microenvironment of the intestinal mucosa, including mucus, antibodies, or chemo-cytokines, can as well influence infection and replication of the virus: their role is still under investigation. The understanding of these processes may help in developing efficient prevention strategies. “
“The O-polysaccharide chain of the lipopolysaccharide (O-antigen) on the bacterial cell surface is one of the most structurally variable cell components and serves as a basis for serotyping of Gram-negative bacteria, including human opportunistic

pathogens of the genus Providencia. ROCK inhibitor In this work, the O-antigen of Providencia alcalifaciens O40 was obtained by mild acid degradation of the isolated lipopolysaccharide and studied by chemical methods and high-resolution NMR spectroscopy. The following structure of the O-polysaccharide was established: 4)-β-d-Quip3NFo-(13)-α-d-Galp-(13)-β-d-GlcpA-(13)-β-d-GalpNAc-(1,

where GlcA stands for glucuronic acid and Qui3NFo for 3,6-dideoxy-3-formamidoglucose. The Inositol monophosphatase 1 O40-antigen was found to be structurally and serologically related to the O-antigens of P. alcalifaciens O5 and Providencia stuartii O18. The O40-antigen gene cluster between cpxA and yibK was sequenced, and the gene functions were predicted in silico. In agreement with the O-polysaccharide structure established, the genes for the synthesis of dTDP-d-Qui3NFo, UDP-d-Gal, UDP-d-GlcA, and UDP-d-GalNAc as well as those encoding three glycosyltransferases, flippase (Wzx), and O-antigen polymerase (Wzy) were recognized. In addition, homologues of wza, wzb, and wzc genes, which are required for the surface expression of capsular polysaccharides, were found within the gene cluster, suggesting that the O-polysaccharide studied is a part of the capsule-related form of the lipopolysaccharide called KLPS. Gram-negative bacteria of the genus Providencia are opportunistic pathogens that are isolated from a wide variety of environment and organisms, ranging from fruit flies and sea turtles to humans (Galac & Lazzaro, 2011). Currently, the genus consists of eight species (O’Hara et al., 2000; Somvanshi et al., 2006; Juneja & Lazzaro, 2009), among which P. stuartii, P. rettgeri, P. rustigianii, and P. alcalifaciens are the most common Providencia species that cause human infection. P.

Results of the apoptosis percentage are referred to this basal va

Results of the apoptosis percentage are referred to this basal value. In our study, neither FPR2/ALX agonists nor CysLT1 antagonists exerted any effect on the inhibition of neutrophil survival induced by IL-8 (100 nM) at the concentrations tested (0·1 nM–1 μM) (Fig. 4). Caspase inhibitor I was used as a control of apoptosis inhibition, resulting in a complete blockade of caspase 3/7 activity. Similar results were observed using annexin V staining as a marker Doxorubicin of apoptotic cells and propidium iodide as a control of the number

of necrotic cells (Figs 5 and 5). 15-epi-LXA4 (100 nM) could not reverse the percentage of neutrophil apoptosis arrest induced by IL-8 stimulation (21% and 23% of apoptotic cells in IL-8 alone and IL-8 plus 15-epi-LXA4, respectively). As expected, the CXCR2 antagonist SCH527123 reversed IL-8-induced apoptosis

arrest and returned the apoptotic cell index to the basal conditions (Fig. 6). Of interest, compound 43 (100 nM) by itself increased neutrophil survival in the absence of IL-8, confirming the recent published data regarding the inflammatory actions associated with this small molecule FPR2/ALX agonist [28, 32]. All the other reference compounds tested showed no effect on neutrophil survival by themselves (Fig. 6). Overall, these results indicate that 15-epi-LXA4 is inactive in reversing the survival signal induced by proinflammatory find more chemokines such as IL-8 in human neutrophils, and compound 43 by itself induces proinflammatory signals in neutrophils. LXs and 15-epi-LXs are arachidonic acid-derived metabolites suggested to play an important

role as novel anti-inflammatory and pro-resolution agents. LX stable analogues display potent bioactivity in vivo in several murine model systems of acute inflammation [25] and block airway hyper-responsiveness and allergic inflammation in ovalbumin and cockroach allergen-induced airway inflammation models [26]. In addition, transgenic over-expressing mice of human FPR2/ALX receptor show shorter resolution times and doses required in response to lipoxin stable Bacterial neuraminidase analogues [16], and are protected from acid-induced acute lung injury [33] and allergen-induced pulmonary inflammation [34]. FPR2 knock-down cell lines no longer signal in response to LXA4 and deficiency of FPR2 in mice decreases the ability of lipoxin A4 and annexin peptide to reduce inflammation in vivo [14, 15]. Nevertheless, all the in-vivo data supporting the role of FPR2/ALX mediating the anti-inflammatory actions of LXs has been generated in mice and differences in FPR2/ALX signalling between species cannot be discarded. Moreover, no FPR2/ALX knock-out or transgenic mice studies have been addressed to study in particular the relevance of the LX–FPR2/ALX axis in neutrophil migration in vivo. In humans, differences in FPR2/ALX expression have been observed in acute and chronic inflammatory responses.