Relation of exaggerated cytokine responses of CF airway epithelial cells to PAO1 adherence

In many model systems, cystic fibrosis (CF) phenotype airway epithelial cells in culture respond to P. aeruginosa with greater interleukin (IL)-8 and IL-6 secretion than matched controls. In order to test whether this excess inflammatory response results from the reported increased adherence of P. aeruginosa to the CF cells, we compared the inflammatory response of matched pairs of CF and non CF airway epithelial cell lines to the binding of GFP-PAO1, a strain of pseudomonas labeled with green fluorescent protein. There was no clear relation between GFP-PAO1 binding and cytokine production in response to PAO1. Treatment with exogenous aGM1 resulted in greater GFP-PAO1 binding to the normal phenotype compared to CF phenotype cells, but cytokine production remained greater from the CF cell lines. When cells were treated with neuraminidase, PAO1 adherence was equalized between CF and nonCF phenotype cell lines, but IL-8 production in response to inflammatory stimuli was still greater in CF phenotype cells. The polarized cell lines 16HBEo-Sense (normal phenotype) and Antisense (CF phenotype) cells were used to test the effect of disrupting tight junctions, which allows access of PAO1 to basolateral binding sites in both cell lines. IL-8 production increased from CF, but not normal, cells. These data indicate that increased bacterial binding to CF phenotype cells cannot by itself account for excess cytokine production in CF airway epithelial cells, encourage investigation of alternative hypotheses, and signal caution for therapeutic strategies proposed for CF that include disruption of tight junctions in the face of pseudomonas infection

Staphylococcus aureus enterotoxins induce IL-8 secretion by human nasal epithelial cells

BACKGROUND: Staphylococcus aureus produces a set of proteins which act both as superantigens and toxins. Although their mode of action as superantigens is well understood, little is known about their effects on airway epithelial cells. METHODS: To investigate this problem, primary nasal epithelial cells derived from normal and asthmatic subjects were stimulated with staphylococcal enterotoxin A and B (SEA and SEB) and secreted (supernatants) and cell-associated (cell lysates) IL-8, TNF-α, RANTES and eotaxin were determined by specific ELISAs. RESULTS: Non-toxic concentrations of SEA and SEB (0.01 μg/ml and 1.0 μg/ml) induced IL-8 secretion after 24 h of culture. Pre-treatment of the cells with IFN-γ (50 IU/ml) resulted in a further increase of IL-8 secretion. In cells from healthy donors pretreated with IFN-γ, SEA at 1.0 μg/ml induced release of 1009 pg/ml IL-8 (733.0–1216 pg/ml, median (range)) while in cells from asthmatic donors the same treatment induced significantly higher IL-8 secretion – 1550 pg/ml (1168.0–2000.0 pg/ml p = 0.04). Normal cells pre-treated with IFN-γ and then cultured with SEB at 1.0 μg/ml released 904.6 pg/ml IL-8 (666.5–1169.0 pg/ml). Cells from asthmatics treated in the same way produced significantly higher amounts of IL-8 – 1665.0 pg/ml (1168.0–2000.0 pg/ml, p = 0.01). Blocking antibodies to MHC class II molecules added to cultures stimulated with SEA and SEB, reduced IL-8 secretion by about 40% in IFN-γ unstimulated cultures and 75% in IFN-γ stimulated cultures. No secretion of TNF-α, RANTES and eotaxin was noted. CONCLUSION: Staphylococcal enterotoxins may have a role in the pathogenesis of asthma

Mechanisms of the noxious inflammatory cycle in cystic fibrosis

Multiple evidences indicate that inflammation is an event occurring prior to infection in patients with cystic fibrosis. The self-perpetuating inflammatory cycle may play a pathogenic part in this disease. The role of the NF-κB pathway in enhanced production of inflammatory mediators is well documented. The pathophysiologic mechanisms through which the intrinsic inflammatory response develops remain unclear. The unfolded mutated protein cystic fibrosis transmembrane conductance regulator (CFTRΔF508), accounting for this pathology, is retained in the endoplasmic reticulum (ER), induces a stress, and modifies calcium homeostasis. Furthermore, CFTR is implicated in the transport of glutathione, the major antioxidant element in cells. CFTR mutations can alter redox homeostasis and induce an oxidative stress. The disturbance of the redox balance may evoke NF-κB activation and, in addition, promote apoptosis. In this review, we examine the hypotheses of the integrated pathogenic processes leading to the intrinsic inflammatory response in cystic fibrosis

InAlN/GaN HEMT technology for robust HF receivers: An overview of the HF and LF noise performances

International audienceFrom the first developments of Nitride technologies using AlGaN/GaN heterostructures for designing high power, high frequency HEMT devices, we now assist to the emergence of new declination with InAlN/GaN heterostructures. Considering the expected better interface quality of this last technology as a consequence of the better lattice match, and better electrical properties, these HEMT devices attract much interest for high frequency applications (transmitter for power, receiver for low noise and robustness versus jamming). Different InAlN/GaN technological developments have been studied considering their frequency and noise parameters for low noise amplifiers in Ka-band. The paper addresses two issues related to noise in InAlN/GaN HEMT devices; one concerns the study of the HF noise performance for different technological processes and for the optimized technology, whereas the second focuses on the gate and drain current LFN spectra of competing technological versions featuring good HF dynamic and noise performance. Keywords—Low Frequency Noise, High Frequency Noise, X and K band, InAlN/GaN HEM

Low-frequency noise in reverse-biased Schottky barriers on InAlN/AlN/GaN heterostructures

International audienceWe present low-frequency gate noise characteristics of InAlN/AlN/GaN heterostructures grown by low-pressure metal-organic vapor phase epitaxy. The electric field in the InAlN barrier is determined from C-V measurements and is used for gate leakage current modeling. The latter is dominated by Poole-Frenkel emission at low reverse bias and Fowler-Nordheim tunneling at high electric field. Several useful physical parameters are extracted from a gate leakage model including polarizations-induced field. The gate noise fluctuations are dominated by trapping-detrapping processes including discrete traps and two continuums of traps with distributed time constants. Burst noise with several levels and time constant values is also observed in these structures. Low-frequency noise measurements confirm the presence of field-assisted emission from trap states. The 1/f noise model of McWorther is used to explain the 1/f-like noise behavior in a restricted frequency range

Excess noise in microwave GaInP/GaAs heterojunction bipolar transistors

Low-Frequency (L.F.) noise experiments are performed on n-p-n GaInP/GaAs heterojunction bipolar transistors. The results show that this device exhibit very attractive performance since we have obtained a value of current noise generator in the range of 10-23 A2/Hz at 10 kHz with a noise corner frequency in the 20 kHz range. Investigations on geometry and bias influence have revealed the presence of surface recombination effects. Finally noise measurements performed on transmission line models show that the input noise voltage generator is due to g-r noise in the base access resistance with a 0.48 eV activation energy and to 1/f noise in the emitter access resistance of the device

Relationship between IkappaBalpha deficiency, NFkappaB activity and interleukin-8 production in CF human airway epithelial cells.

Several recent reports have suggested that airway inflammation may precede infection and relate to an endogenous dysregulation of pro-inflammatory cytokines in cystic fibrosis (CF) airways. Evidence suggests that activation of the nuclear factor kappa B (NFkappaB), which regulates the inflammatory gene transcription, depends on the degradation of the inhibitory factor IkappaBalpha. We show that, in in situ human DeltaF508 CF bronchial tissues, inhibitor factor IkappaBalpha is not present in gland cells, although endogenous levels of chemokine IL-8 are high. These data are confirmed by studying cultured CF human bronchial gland cells, in which a lack of cytosolic IkappaBalpha and high levels of activated NFkappaB, concomitant with IL-8 overproduction (a 13-fold increase) are found when compared to non-CF bronchial gland cells. Interestingly, treatment of CF gland cells with the isoflavone genistein, a well known CFTR mutant Cl(-) channel stimulator, results in a significant decrease ( P < 0.001) in IL-8 production down to levels released by non-CF gland cells. The addition of genistein also reverses the effects of lipopolysaccharide (LPS) Pseudomonas-aeruginosa-induced nuclear translocation of NFkappaB by increasing IkappaBalpha protein level (65%) in CF gland cells. Our data indicate that the induction of IkappaBalpha protein in CF airway glandular epithelial cells may be a novel mechanism by which IL-8-mediated lung inflammatory events are markedly reduced in CF patients, at least at the airway glandular level

Ka-band low noise amplifiers based on InAlN/GaN technologies

International audienceLow noise amplifiers in receivers are usually addressed by III-V (narrow bandgap) technologies: but when the receivers are subject to EM exposure or jamming, the need for protection devices before the active low noise amplifier (LNA) degrades the overall noise figure, and decreases the effective radio link budget. This vulnerability of the LNA can be overcome thanks to robust designs or robust technologies. Nitride technologies are investigated for power modules in transmitters and stand as promising solutions to avoid the use of limiters for robust low noise circuits in receivers. This work focuses on HF noise in InAlN/GaN HEMT devices and circuits for Ka-band SATCOM applications. Different versions of LNA have been designed at 30 GHz, in hybrid and MMIC technologies. For these designs, 1-stage and 3-stages LNAs have been realized; 1-stage amplifiers are designed to assess and study the stress tolerance under RF signal, whereas 3-stages LNAs are designed as demonstrators of operational module for receiver's blocks (Gain>20dB featuring the lowest noise figure achievable)

DC, RF and low frequency noise characterization of C and In/C doped GalnP/GaAs HBT's

This paper presents a comparative study, based on DC, RF and low frequency noise (LFN) measurements, between Carbon-doped, and Indium/Carbon doped GalnP/GaAs HBT's featuring different emitter widths. Both technologies exhibit an evident emitter size ef­fect, while C-doped devices have larger DC and RF gains and a lower input voltage noise level. The bet­ter performance has been justified in terms of a higher quality of the extrinsic base surface. This explanation was supported by the LFN measurements carried out on self-aligned devices, which revealed an electron dif­fusion current from the emitter toward the base, proba­bly due to the pinning of the Fermi level at the surface. The HBT's have been compared also in terms of relia­bility by means of electrical stress performed at room temperature. The effect, of the stress Was a DC cur­rent gain increase associated with a reduction of the base current and of the input voltage noise lorentzian component. The In/C doped devices exhibited the largest variations, and were more sensitive to the cur­rent stress