HMGB1 Accelerates Alveolar Epithelial Repair via an IL-1β- and αvβ6 Integrin-dependent Activation of TGF-β1

High mobility group box 1 (HMGB1) protein is a danger-signaling molecule, known to activate an inflammatory response via TLR4 and RAGE. HMGB1 can be either actively secreted or passively released from damaged alveolar epithelial cells. Previous studies have shown that IL-1β, a critical mediator acute lung injury in humans that is activated by HMGB1, enhances alveolar epithelial repair, although the mechanisms are not fully understood. Herein, we tested the hypothesis that HMGB1 released by wounded alveolar epithelial cells would increase primary rat and human alveolar type II cell monolayer wound repair via an IL-1β-dependent activation of TGF-β1. HMGB1 induced in primary cultures of rat alveolar epithelial cells results in the release of IL-1β that caused the activation of TGF-β1 via a p38 MAPK-, RhoA- and αvβ6 integrin-dependent mechanism. Furthermore, active TGF-β1 accelerated the wound closure of primary rat epithelial cell monolayers via a PI3 kinase α-dependent mechanism. In conclusion, this study demonstrates that HMGB1 released by wounded epithelial cell monolayers, accelerates wound closure in the distal lung epithelium via the IL-1β-mediated αvβ6-dependent activation of TGF-β1, and thus could play an important role in the resolution of acute lung injury by promoting repair of the injured alveolar epithelium

Consert Radar Tomography in transmission, a new technique for glaciers characterisation: Perspectives and preliminary results for the Glacier de l'Argentière

abstract EGU06-A-08114The radar tomography in transmission is an imagery technique developed to investigate the internal structure of cometary nucleus. The Consert instrument of the Rosetta probe (ESA) launched in 2004 will image the Churyumov-Gerasimenko Comet in 2014 and allows us to identify the mean dielectric permittivity, the main structures and the heterogeneity scales of the nucleus (1). This technique seems promising for earth applications in arid or frozen regions, especially to detect liquid water cells in temperate glaciers for risks management. In order to evaluate its potential, the first measurement campaign on the Glacier de l'Argentière (French Alps) was done last September using Consert prototypes (2). The transmitter was located under the glacier at the bedrock level using the water caption tunnels. The radio wave propagates throughout a few hundreds meters of glacier and were acquired by the receiver located on the glacier surface. In this talk, we explain the radar tomography concept: instrument, measurements and data inversion. Than we present the measurement campaign, the data and the first results

IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism

Patients with acute lung injury (ALI) who retain maximal alveolar fluid clearance (AFC) have better clinical outcomes. Experimental and small clinical studies have shown that β(2)-adrenergic receptor (β(2)AR) agonists enhance AFC via a cAMP-dependent mechanism. However, two multicenter phase 3 clinical trials failed to show that β(2)AR agonists provide a survival advantage in patients with ALI. We hypothesized that IL-8, an important mediator of ALI, directly antagonizes the alveolar epithelial response to β(2)AR agonists. Short-circuit current and whole-cell patch-clamping experiments revealed that IL-8 or its rat analog CINC-1 decreases by 50% β(2)AR agonist-stimulated vectorial Cl(−) and net fluid transport across rat and human alveolar epithelial type II cells via a reduction in the cystic fibrosis transmembrane conductance regulator activity and biosynthesis. This reduction was mediated by heterologous β(2)AR desensitization and down-regulation (50%) via the G-protein-coupled receptor kinase 2 (GRK2)/PI3K signaling pathway. Inhibition of CINC-1 restored β(2)AR agonist-stimulated AFC in an experimental model of ALI in rats. Finally, consistent with the experimental results, high pulmonary edema fluid levels of IL-8 (>4000 pg/ml) were associated with impaired AFC in patients with ALI. These results demonstrate a novel role for IL-8 in inhibiting β(2)AR agonist-stimulated alveolar epithelial fluid transport via GRK2/PI3K-dependent mechanisms.—Roux, J., McNicholas, C. M., Carles, M., Goolaerts, A., Houseman, B. T., Dickinson, D. A., Iles, K. E., Ware, L. B., Matthay, M. A., Pittet, J.-F. IL-8 inhibits cAMP-stimulated alveolar epithelial fluid transport via a GRK2/PI3K-dependent mechanism

Effect of irradiation on the survival and susceptibility of female Anopheles arabiensis to natural isolates of Plasmodium falciparum

International audienceBackground: The sterile insect technique (SIT) is a vector control strategy relying on the mass release of sterile males into wild vector populations. Current sex separation techniques are not fully efficient and could lead to the release of a small proportion of females. It is therefore important to evaluate the effect of irradiation on the ability of released females to transmit pathogens. This study aimed to assess the effect of irradiation on the survival and competence of Anopheles arabiensis females for Plasmodium falciparum in laboratory conditions.Methods: Pupae were irradiated at 95 Gy of gamma-rays, and emerging females were challenged with one of 14 natural isolates of P. falciparum. Seven days post-blood meal (dpbm), irradiated and unirradiated-control females were dissected to assess the presence of oocysts, using 8 parasite isolates. On 14 dpbm, sporozoite dissemination in the head/thorax was also examined, using 10 parasites isolates including 4 in common with the 7 dpbm dissection (oocyst data). The survivorship of irradiated and unirradiated-control mosquitoes was monitored.Results: Overall, irradiation reduced the proportion of mosquitoes infected with the oocyst stages by 17% but this effect was highly inconsistent among parasite isolates. Secondly, there was no significant effect of irradiation on the number of developing oocysts. Thirdly, there was no significant difference in both the sporozoite infection rate and load between the irradiated and unirradiated-control mosquitoes. Fourthly, irradiation had varying effects on female survival with either a negative effect or no effect.Conclusions: The effect of irradiation on mosquito competence strongly varied among parasite isolates. Because of such isolate variability and, the fact that different parasite isolates were used to collect oocyst and sporozoite data, the irradiation-mediated reduction of oocyst prevalence was not confirmed for the sporozoite stages. Our data indicate that irradiated female An. arabiensis could contribute to malaria transmission, and highlight the need for perfect sex-ing tools, which would prevent the release of females as part of SIT programmes