Lung epithelium as a sentinel and effector system in pneumonia – molecular mechanisms of pathogen recognition and signal transduction

Pneumonia, a common disease caused by a great diversity of infectious agents is responsible for enormous morbidity and mortality worldwide. The bronchial and lung epithelium comprises a large surface between host and environment and is attacked as a primary target during lung infection. Besides acting as a mechanical barrier, recent evidence suggests that the lung epithelium functions as an important sentinel system against pathogens. Equipped with transmembranous and cytosolic pathogen-sensing pattern recognition receptors the epithelium detects invading pathogens. A complex signalling results in epithelial cell activation, which essentially participates in initiation and orchestration of the subsequent innate and adaptive immune response. In this review we summarize recent progress in research focussing on molecular mechanisms of pathogen detection, host cell signal transduction, and subsequent activation of lung epithelial cells by pathogens and their virulence factors and point to open questions. The analysis of lung epithelial function in the host response in pneumonia may pave the way to the development of innovative highly needed therapeutics in pneumonia in addition to antibiotics

Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the rat

Yondelis (ET-743) is a promising antitumor drug with hepatotoxic properties in animals and humans. Here the hypothesis was tested that dexamethasone can ameliorate manifestations of yondelis-induced hepatotoxicity in the female Wistar rat, which is the animal species with the highest sensitivity toward the adverse hepatic effect of yondelis. Hepatotoxicity was adjudged by measurement of plasma levels of alkaline phosphatase, aspartate aminotransferase, and bilirubin, and by liver histopathology. Yondelis (40 micro g/kg i.v.) alone caused a dramatic elevation of plasma alkaline phosphatase, aspartate aminotransferase, and bilirubin levels, and degeneration and patchy focal necrosis of bile duct epithelial cells. Pretreatment of rats with dexamethasone (5-20 mg/kg, p.o.) 24 h before yondelis ameliorated or abrogated the biochemical and histopathological manifestations of yondelis-induced liver changes. In contrast, when dexamethasone was administered simultaneously with yondelis, its toxicity was not reduced. Pretreatment with dexamethasone (10 mg/kg) also reversed the gene expression changes induced by yondelis in rat liver. However, dexamethasone pretreatment did not interfere with the antitumor efficacy of yondelis in rats bearing the 13762 mammary carcinoma or in four murine models. Dexamethasone (10 mg/kg) administered 24 h before yondelis decreased hepatic levels of yondelis dramatically compared with those obtained after administration of yondelis alone, whereas yondelis plasma levels after the drug combination were not markedly different from those in rats on yondelis alone. The results suggest that pretreatment with high-dose dexamethasone effectively protects rats against yondelis-mediated hepatic damage by decreasing hepatic exposure to yondelis, perhaps linked to induction of metabolism by cytochrome P450 enzymes. Pretreatment with high-dose dexamethasone should be investigated in patients who receive yondelis to ameliorate its unwanted effect on the liver

Caenorhabditis elegans BAF-1 and its kinase VRK-1 participate directly in post-mitotic nuclear envelope assembly

Barrier-to-autointegration factor (BAF) is an essential, highly conserved, metazoan protein. BAF interacts with LEM (LAP2, emerin, MAN1) domain-carrying proteins of the inner nuclear membrane. We analyzed the in vivo function of BAF in Caenorhabditis elegans embryos using both RNA interference and a temperature-sensitive baf-1 gene mutation and found that BAF is directly involved in nuclear envelope (NE) formation. NE defects were observed independent of and before the chromatin organization phenotype previously reported in BAF-depleted worms and flies. We identified vaccinia-related kinase (VRK) as a regulator of BAF phosphorylation and localization. VRK localizes both to the NE and chromatin in a cell-cycle-dependent manner. Depletion of VRK results in several mitotic defects, including impaired NE formation and BAF delocalization. We propose that phosphorylation of BAF by VRK plays an essential regulatory role in the association of BAF with chromatin and nuclear membrane proteins during NE formation

Endothelium-Dependent Relaxation and Angiotensin II Sensitivity in Experimental Preeclampsia

<p>Objective: We investigated endothelial dysfunction and the role of angiotensin (Ang)-II type I (AT1-R) and type II (AT2-R) receptor in the changes in the Ang-II sensitivity in experimental preeclampsia in the rat.</p><p>Methods: Aortic rings were isolated from low dose lipopolysaccharide (LPS) infused pregnant rats (experimental preeclampsia; n=9), saline-infused pregnant rats (n=8), and saline (n=8) and LPS (n=8) infused non-pregnant rats. Endothelium-dependent acetylcholine--mediated relaxation was studied in phenylephrine-preconstricted aortic rings in the presence of vehicle, N-G-nitro-L-arginine methyl ester and/or indomethacin. To evaluate the role for AT1-R and AT2-R in Ang-II sensitivity, full concentration response curves were obtained for Ang-II in the presence of losartan or PD123319. mRNA expression of the AT1-R and AT2-R, eNOS and iNOS, COX1 and COX2 in aorta were evaluated using real-time RT-PCR.</p><p>Results: The role of vasodilator prostaglandins in the aorta was increased and the role of endothelium-derived hyperpolarizing factor and response of the AT1-R and AT2-R to Ang-II was decreased in pregnant saline infused rats as compared with non-pregnant rats. These changes were not observed during preeclampsia.</p><p>Conclusion: Pregnancy induced adaptations in endothelial function, which were not observed in the rat model for preeclampsia. This role of lack of pregnancy induced endothelial adaptation in the pathophysiology of experimental preeclampsia needs further investigation.</p>