Mechanism of IL-6-mediated cardiac dysfunction following trauma-hemorrhage.
Cardiac function is depressed and circulating IL-6 levels increase following trauma-hemorrhage (T-H). Although sustained elevated IL-6 after T-H correlate with poor outcome, the mechanism by which IL-6 produces cardiac dysfunction remains unknown. We hypothesized that IL-6-mediated cardiac depression is due to upregulation of NF-small ka, CyrillicB, ICAM, CINC and neutrophil infiltration. Six groups of male adult rats (275-300 g) were used: sham/T-H + vehicle, sham/T-H + IgG, sham/T-H + anti-IL-6mAb. Following midline laparotomy, 60% of the circulating blood was withdrawn and after 90 min, crystalloid fluid resuscitation was provided. Either normal goat IgG or anti-rat IL-6mAb (16.7 microg/kg BW) was administered intraperitoneally at 30 min after the onset of resuscitation. Two hours after resuscitation, cardiac function was measured, blood samples collected, cardiomyocytes isolated and intracellular IL-6 levels measured by flow cytometry. Cardiac IL-6, IL-6R, gp130, NF-small ka, CyrillicB, Ismall ka, CyrillicB-alpha, and ICAM-1 protein levels were measured in freshly isolated hearts by immunoblotting. Moreover, cardiac MPO activity and CINC-1 and -3 were measured. Cardiac function was depressed and cardiac IL-6, NF-small ka, CyrillicB, ICAM-1, MPO activity, and CINC-1 and -3 were markedly increased after T-H. Administration of anti-IL-6mAb following T-H: 1) improved cardiac output (P<0.05); 2) downregulated cardiac IL-6 levels (P<0.05); 3) attenuated cardiac NF-small ka, CyrillicB, ICAM-1, CINC-1, -3, and MPO activity (P<0.05). Administration of IgG, however, did not significantly influence these parameters. Thus, IL-6-mediated upregulation of cardiac NF-small ka, CyrillicB, ICAM-1, CINC-1, -3, and MPO activity likely contributes to altered cardiac function following T-H and neutralization of IL-6 therefore appears to be an effective and novel adjunct for improving organ/cell function under those conditions.
Yang
Shaolong
S
Center for Surgical Research and Department of Surgery, The University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall, Room G094, Birmingham, AL 35294-0019, USA.
Hu
Shunhua
S
Hsieh
Ya-Ching
YC
Choudhry
Mashkoor A
MA
Rue
Loring W
LW
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood* / Q000276:immunology; D008297:Male; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000097:blood* / Q000276:immunology / Q000473:pathology; D014947:Wounds and Injuries / Q000097:blood* / Q000276:immunology / Q000473:pathology
D000906:Antibodies; D015850:Interleukin-6