New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC > 512 µg/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens.
antigen, carcinoembryonic antigen, and epithelial membrane The cell of origin of intrahepatic bile ducts during fetal antigen. [13][14][15][16][17][18][19][20][21][22][23] These studies have further supported the hepadevelopment remains a subject of controversy, although tocytogenic theory. there has been recent evidence that they form from heCytokeratins are the intermediate filaments of the cypatocytes. However, the origin of neoductules and ducts toskeleton characteristic of epithelial cells. [24][25][26][27] At least 20 in the setting of liver disease has not been extensively CKs have been distinguished on the basis of different molecuinvestigated in humans. Using anticytokeratins characlar weights and isoelectric points on two-dimensional gels. 24-26 teristic of hepatocytes and bile ducts, we repeated ear-The human embryonic liver is composed of liver cell precurlier studies of fetal development to compare ductule forsors (hepatoblasts) in its earliest developmental stages. mation in normal developing and newborn livers withThese hepatoblasts express cytokeratins 8, 18, and 19. 19 At the ductules formed during extrahepatic biliary atresia. We utilized an antibody to proliferating cell nuclear an-approximately the eighth week of gestation, the hepatoblasts tigen (PCNA) staining to determine which cells were in that are adjacent to the mesenchyme surrounding the largest active DNA synthesis (S phase) during fetal development hilar portal veins become more immunoreactive for cytokeraand liver disease progression. The results indicated that tins 8, 18, and 19. These cells, which surround the portal hepatocytes undergo a phenotypic switch (metaplasia) vein branches, become smaller and later flatten to form the to form ductular cells during fetal development. There ductal plate. 1 They become more immunoreactive to the CK was no ductular cell replication in the fetal livers. In antibodies, while the hepatoblasts away from the mesencontrast, both bile ductular metaplasia and proliferation chyme start to lose their antigenicity for cytokeratin 19, and were observed in biliary atresia. Therefore, both a lim-by 10 weeks of gestation, the future parenchymal cells are iting plate phenotypic switch to ductules and replication antigenic for only cytokeratins 8 and 18, as seen in adult of ductular cells play a role in the increase in the duct-liver parenchymal cells. ules seen in the progression to biliary cirrhosis. Bile duc-The ductal plate later becomes a double cell layer, and a tular proliferation in biliary atresia, however, was less slitlike opening begins to form between the cell layers to form than that seen in hepatocytes, whereas the number of lumens. The formation of these ductal plates starts at the bile ductules increased and the relative proportion of hilum where the largest portal vein branches are located, hepatocytes diminished as the accompanying periductu-and then progresses to the smaller portal tracts away from lar fibrosis progressed to cirrhosis. (HEPATOLOGY 1996; the hilum. At 20 weeks of gestati...
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