title: The activity of pathway-selective estrogen receptor ligands in experimental septic shock.
abstract: Estrogen receptors (ER) are widely expressed in multiple genital and nongenital tissues. Upon engagement of these receptors, multiple genes are affected in target tissues via estrogen response elements. Nonsteroidal pathway-selective ER ligands have recently been identified that inhibit NF-kappaB transcriptional activity and are devoid of conventional estrogenic activities on genital tissues. These pathway-selective ligands are potent anti-inflammatory agents in vivo and may prove to be of therapeutic utility in systemic inflammatory states. These pathway-selective ER ligands were tested in the murine listeriosis model, the neutropenic rat model, and the mouse cecal ligation and puncture model. WAY-204688 did not have any significant activity after systemic infection by Listeria monocytogenes. In the neutropenic rat model, WAY-204688 provided a significant survival benefit against an otherwise lethal challenge of Pseudomonas aeruginosa 12.4.4 compared with the control group (88% versus 25% survival; P < 0.05). Preservation of mucosal weight and prevention of histopathologic changes were observed with the administration of WAY-204688. Similar findings were observed in a cecal ligation and puncture model with WAY-204688 and a related compound WAY-169916. These results indicate that oral administration of these pathway-selective ER ligands preserved gastrointestinal barrier function and improve outcome in experimental models of systemic infection and inflammation. These agents may prove to be useful clinically as a novel treatment strategy for severe sepsis.
authors.affiliation: Memorial Hospital of Rhode Island, Brown Medical School, Providence, Rhode Island 02860, USA. Steven_Opal@brown.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
authors.forename: John E
authors.initials: JE
authors.lastname: Palardy
authors.forename: Patricia
authors.initials: P
authors.lastname: Cristofaro
authors.forename: Nicolas
authors.initials: N
authors.lastname: Parejo
authors.forename: Jhung W
authors.initials: JW
authors.lastname: Jhung
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Sue
authors.initials: S
authors.lastname: Chippari
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Caggiano
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Steffan
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Chadwick
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Harnish
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008088:Listeriosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011090:Polyenes / Q000008:administration & dosage*; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
chemical_list: C113323:32-desmethoxyrapamycin; D016328:NF-kappa B; D011090:Polyenes; D011720:Pyrazoles; D011960:Receptors, Estrogen; C499198:WAY-169916