Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages

The principal mechanism by which bronchodilator β-adrenoceptor agonists act is to relax airways smooth muscle although they may also be anti-inflammatory. However, the extent of anti-inflammatory activity and the cell types affected by these agonists are uncertain. The purpose of this study was to evaluate whether β-adrenoceptor agonists prevent pro-inflammatory cytokine generation from activated human lung macrophages. Macrophages were isolated and purified from human lung. The cells were pre-treated with both short-acting (isoprenaline, salbutamol, terbutaline) and long-acting (formoterol, salmeterol, indacaterol) β-agonists before activation with lipopolysaccharide (LPS) to induce cytokine (TNFα, IL-6, IL-8 and IL-10) generation. The experiments showed that short-acting β-agonists were poor inhibitors of cytokine generation. Of the long-acting β-agonists studied, formoterol was also a weak inhibitor of cytokine generation whereas only indacaterol and salmeterol showed moderate inhibitory activity. Further experiments using the β2-adrenoceptor antagonist ICI-118,551 suggested that the effects of indacaterol were likely to be mediated by β2-adrenoceptors whereas those of salmeterol were not. These findings were corroborated by functional desensitization studies in which the inhibitory effects of indacaterol appeared to be receptor-mediated whereas those of salmeterol were not. Taken together, the data indicate that the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages are modest

The anti-inflammatory effects of prostaglandin E 2 on human lung macrophages are mediated by the EP 4 receptor

Background and purpose: Prostaglandin E2 (PGE2) has been shown to inhibit cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti-inflammatory effect of PGE2 has not been elucidated definitively. The aim of this study was to identify the EP receptor by which PGE2 inhibits cytokine generation from human lung macrophages. This was determined by using recently-developed EP receptor ligands. Experimental approach: The effects of PGE2 and EP-selective agonists on lipopolysaccharide (LPS) induced tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) generation from macrophages were evaluated. The effects of EP2-selective (PF-04852946, PF-04418948) and EP4-selective (L-161,982, CJ-042794) antagonists on PGE2 responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT-PCR. Key results: PGE2 inhibited LPS-induced and Streptococcus pneumoniae-induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP2 and EP4 receptors. L-902,688 (EP4-selective agonist) was considerably more potent than butaprost (EP2-selective agonist) as an inhibitor of TNFα generation from macrophages. EP2-selective antagonists had marginal effects on the PGE2 inhibition of TNFα generation whereas EP4-selective antagonists caused rightward shifts in the PGE2 concentration-response curves. Conclusions and implications: These studies demonstrate that the EP4 receptor is the principal receptor that mediates the anti-inflammatory effects of PGE2 on human lung macrophages. This suggests that EP4 agonists could be effective anti-inflammatory agents in human lung disease

In-vivo time-dependent articular cartilage contact behavior of the tibiofemoral joint

SummaryObjectiveThe purpose of this study was to investigate the in-vivo time-dependent contact behavior of tibiofemoral cartilage of human subjects during the first 300s after applying a constant full body weight loading and determine whether there are differences in cartilage contact responses between the medial and lateral compartments.DesignSix healthy knees were investigated in this study. Each knee joint was subjected to full body weight loading and the in-vivo positions of the knee were captured by two orthogonal fluoroscopes during the first 300s after applying the load. Three-dimensional models of the knee were created from MR images and used to reproduce the in-vivo knee positions recorded by the fluoroscopes. The time-dependent contact behavior of the cartilage was represented using the peak cartilage contact deformation and the cartilage contact area as functions of time under the constant full body weight.ResultsBoth medial and lateral compartments showed a rapid increase in contact deformation and contact area during the first 20s of loading. After 50s of loading, the peak contact deformation values were 10.5±0.8% (medial) and 12.6±3.4% (lateral), and the contact areas were 223.9±14.8mm2 (medial) and 123.0±22.8mm2 (lateral). Thereafter, the peak cartilage contact deformation and contact area remained relatively constant. The respective changing rates of cartilage contact deformation were 1.4±0.9%/s (medial) and 3.1±2.5%/s (lateral); and of contact areas were 40.6±20.8mm2/s (medial) and 24.0±11.4mm2/s (lateral), at the first second of loading. Beyond 50s, both changing rates approached zero.ConclusionsThe peak cartilage contact deformation increased rapidly within the first 20s of loading and remained relatively constant after ∼50s of loading. The time-dependent response of cartilage contact behavior under constant full body weight loading was significantly different in the medial and lateral tibiofemoral compartments, with greater peak cartilage contact deformation on the lateral side and greater contact area on the medial side. These data can provide insight into normal in-vivo cartilage function and provide guidelines for the improvement of ex-vivo cartilage experiments and the validation of computational models that simulate human knee joint contact

A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia

Background. Therapeutic strategies to modulate the host response to bacterial pneumonia are needed to improve outcomes during community-acquired pneumonia. This study used mice with impaired Fas signalling to examine susceptibility to pneumococcal pneumonia and decoy receptor 3 analogue (DcR3-a) to correct factors associated with increased susceptibility. Methods. Wild-type mice and those with varying degrees of impairment of Fas (lpr) or Fas ligand signalling (gld) were challenged with Streptococcus pneumoniae and microbiological and immunological outcomes measured in the presence or absence of DcR3-a. Results. During established pneumonia, neutrophils became the predominant cell in the airway and gld mice were less able to clear bacteria from the lungs, demonstrating localised impairment of pulmonary neutrophil function in comparison to lpr or wild-type mice. T-cells from gld mice had enhanced activation and reduced apoptosis in comparison to wild-type and lpr mice during established pneumonia. Treatment with DcR3-a reduced T-cell activation and corrected the defect in pulmonary bacterial clearance in gld mice. Conclusions. The results suggest that imbalance in tumour necrosis factor superfamily signalling and excessive T-cell activation can impair bacterial clearance in the lung but that DcR3-a treatment can reduce T-cell activation, restore optimal pulmonary neutrophil function and enhance bacterial clearance during S pneumoniae infection

Electronic Conduction in Annealed Sulfur-Doped a-Si:H Films

In present work, the effect of annealing on dark and photo conductivity as well as the various causes of conduction mechanics in S doped amorphous hydrogenated silicon films (a-Si:H) is discussed. The variation of the dark conductivity as a function of temperature has been carried out on unannealed and annealed (annealed at an optimized temperature of 300 °C) thin film samples and the activation energy of dark conductivity of respective samples was also calculated at different temperatures. The Study concludes that at high temperatures, an activated type mechanism is responsible for conduction in the a-Si:H films

Cross-talk between GABAergic postsynapse and microglia regulate synapse loss after brain ischemia.

Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75 <sup>NTR</sup> ) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO

What is a β cell? - Chapter I in the Human Islet Research Network (HIRN) review series

BACKGROUND: The pancreatic β cell, as the sole source of the vital hormone insulin, has been under intensive study for more than a century. Given the potential of newly created insulin-producing cells as a treatment or even cure of type 1 diabetes (T1D) and possibly in severe cases of type 2 diabetes (T2D), multiple academic and commercial laboratories are working to derive surrogate glucose-responsive, insulin-producing cells. SCOPE OF REVIEW: The recent development of advanced phenotyping technologies, including molecular, epigenomic, histological, or functional, have greatly improved our understanding of the critical properties of human β cells. Using this information, here we summarize the salient features of normal, fully functional adult human β cells, and propose minimal criteria for what should rightfully be termed 'β cells' as opposed to insulin-producing but not fully-functional surrogates that we propose should be referred to as 'β-like' cells or insulin-producing cells. MAJOR CONCLUSIONS: Clear criteria can be established to differentiate fully functional, mature β cells from 'β-like' surrogates. In addition, we outline important knowledge gaps that must be addressed to enable a greater understanding of the β cell

Proton Polarimetry at the Relativistic Heavy Ion Collider

The RHIC polarized proton collider employs polarimeters in each of the Blue and Yellow rings that utilize the analyzing power in p-Carbon elastic scattering in the Coulomb Nuclear Interference region to measure the absolute beam polarization. These are calibrated by the polarized Hydrogen Jet Target that measures the absolute beam polarization in pp elastic scattering in the CNI region. This paper describes the status and performance of these polarimeters in the FY09 run which included both a 250 GeV/c and 100 GeV/c physics data taking periods. We will describe some of the difficulties encountered and the efforts underway to improve the performance in better energy resolution, rate handling capability, and reduced systematic uncertainties

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters