title: In vivo TLR9 inhibition attenuates CpG-induced myocardial dysfunction.
abstract: The involvement of toll-like receptor 9 (TLR9), a receptor for bacterial DNA, in septic cardiac depression has not been clarified in vivo. Thus, the aim of the study was to test possible TLR9 inhibitors (H154-thioate, IRS954-thioate, and chloroquine) for their ability to protect the cardiovascular system in a murine model of CpG oligodeoxynucleotide- (ODN-) dependent systemic inflammation. Sepsis was induced by i.p. application of the TLR9 agonist 1668-thioate in C57BL/6 wild type (WT) and TLR9-deficient (TLR9-D) mice. Thirty minutes after stimulation TLR9 antagonists were applied i.v. Survival was monitored up to 18 h after stimulation. Cardiac mRNA expression of inflammatory mediators was analyzed 2 h and 6 h after stimulation with 1668-thioate and hemodynamic parameters were monitored at the later time point. Stimulation with 1668-thioate induced a severe sepsis-like state with significant drop of body temperature and significantly increased mortality in WT animals. Additionally, there was a time-dependent increase of inflammatory mediators in the heart accompanied by development of septic heart failure. These effects were not observed in TLR9-D mice. Inhibition of TLR9 by the suppressive ODN H154-thioate significantly ameliorated cardiac inflammation, preserved cardiac function, and improved survival. This suppressive ODN was the most efficient inhibitor of the tested substances.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Boehm
authors.forename: P
authors.initials: P
authors.lastname: Markowski
authors.forename: M
authors.initials: M
authors.lastname: van der Giet
authors.forename: V
authors.initials: V
authors.lastname: Gielen
authors.forename: A
authors.initials: A
authors.lastname: Kokalova
authors.forename: C
authors.initials: C
authors.lastname: Brill
authors.forename: A
authors.initials: A
authors.lastname: Hoeft
authors.forename: G
authors.initials: G
authors.lastname: Baumgarten
authors.forename: R
authors.initials: R
authors.lastname: Meyer
authors.forename: P
authors.initials: P
authors.lastname: Knuefermann
mesh_terms: D000818:Animals; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000633:toxicity*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D053583:Interleukin-1beta; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D002738:Chloroquine