title: Functional significance of inflammatory mediators in a murine model of resuscitated hemorrhagic shock.
abstract: The mechanisms that underlie the development of myocardial dysfunction after resuscitated hemorrhagic shock (HS) are not known. Recent studies suggest that systemic activation of inflammatory mediators may contribute to cellular dysfunction and/or cell death in various organs, including the heart. However, the precise role that inflammatory mediators play in the heart in the setting of resuscitated HS is not known. Accordingly, the purpose of the present study was to use a well-defined murine model of resuscitated HS to characterize the functional significance of inflammatory mediators in the heart in vivo. Mice were subjected to sham operation or resuscitated HS. Left ventricular (LV) function was assessed by two-dimensional echocardiography 6 h after resuscitation. Myocardial TNF, IL-1beta, and IL-6 proteins were measured 1 and 6 h after resuscitation. To determine the role of TNF in HS-induced LV dysfunction, mice were treated with a soluble TNF receptor antagonist (etanercept) before HS or at the time of resuscitation. LV fractional shortening was significantly depressed (P < 0.05) in resuscitated HS mice (28 +/- 1.5%) compared with sham controls (35.8 +/- 1.0%). TNF and IL-1beta levels were significantly increased (P < 0.05) in resuscitated HS mice. Pretreatment with etanercept abrogated resuscitated HS-induced LV dysfunction, whereas treatment at the time of resuscitation significantly attenuated, but did not abrogate, LV dysfunction. Together, these data suggest that TNF plays a critical upstream role in resuscitated HS-induced LV dysfunction; however, once the deleterious consequences of reperfusion injury are initiated, TNF contributes to, but is not necessary for, the development of LV dysfunction.
authors.affiliation: Winters Center for Heart Failure Research, Houston, Texas 77030, USA.
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Vallejo
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nemoto
authors.forename: Masakuni
authors.initials: M
authors.lastname: Ishiyama
authors.forename: Bi
authors.initials: B
authors.lastname: Yu
authors.forename: Pascal
authors.initials: P
authors.lastname: Knuefermann
authors.forename: Abinav
authors.initials: A
authors.lastname: Diwan
authors.forename: J Scott
authors.initials: JS
authors.lastname: Baker
authors.forename: Gilberto
authors.initials: G
authors.lastname: Defreitas
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018124:Receptors, Tumor Necrosis Factor; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology
chemical_list: D007074:Immunoglobulin G; D007155:Immunologic Factors; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept