Preconditioning with endoplasmic reticulum stress ameliorates endothelial cell inflammation

Endoplasmic Reticulum (ER) stress, caused by disturbance in ER homeostasis, has been implicated in several pathological conditions such as ischemic injury, neurodegenerative disorders, metabolic diseases and more recently in inflammatory conditions. Our present study aims at understanding the role of ER stress in endothelial cell (EC) inflammation, a critical event in the pathogenesis of acute lung injury (ALI). We found that preconditioning human pulmonary artery endothelial cells (HPAEC) to ER stress either by depleting ER chaperone and signaling regulator BiP using siRNA, or specifically cleaving (inactivating) BiP using subtilase cytotoxin (SubAB), alleviates EC inflammation. The two approaches adopted to abrogate BiP function induced ATF4 protein expression and the phosphorylation of eIF2α, both markers of ER stress, which in turn resulted in blunting the activation of NF-κB, and restoring endothelial barrier integrity. Pretreatment of HPAEC with BiP siRNA inhibited thrombin-induced IκBα degradation and its resulting downstream signaling pathway involving NF-κB nuclear translocation, DNA binding, phosphorylation at serine536, transcriptional activation and subsequent expression of adhesion molecules. However, TNFα-mediated NF-κB signaling was unaffected upon BiP knockdown. In an alternative approach, SubAB-mediated inactivation of NF-κB was independent of IκBα degradation. Mechanistic analysis revealed that pretreatment of EC with SubAB interfered with the binding of the liberated NF-κB to the DNA, thereby resulting in reduced expression of adhesion molecules, cytokines and chemokines. In addition, both knockdown and inactivation of BiP stimulated actin cytoskeletal reorganization resulting in restoration of endothelial permeability. Together our studies indicate that BiP plays a central role in EC inflammation and injury via its action on NF-κB activation and regulation of vascular permeability.Antony Leonard, Adrienne W. Paton, Monaliza El-Quadi, James C. Paton, Fabeha Faza

Deterministic Seismic Hazard Assessment for North Morocco

The purpose of this work is to evaluate the regional seismic hazard for Morocco, following the deterministic approach proposed by Costa et al [1], based on the computation of complete P-SV and SH synthetic seismograms. The input for the computations is represented by source and structural models. Seismic sources are parameterized using the knowledge about past seismicity and the tectonic regime. The regional structural model we adopted is the one proposed by Cherkaoui [2], modified in its shallower part to account for the effects of the uppermost sedimentary layers. Maps of peak acceleration, velocity, and displace- ments are used for the general representation of the hazard. Accelerations are in good agreement with the values determined by Jimenez et al [3] with the standard probabilistic approach