Amplification of the proinflammatory transcription factor cascade increases with severity of uncontrolled hemorrhage in swine

• Published in: The Journal of surgical research 2003-07, Vol.113 (1), p.74-80
• Main Authors: Brundage, Susan I, Schreiber, Martin A, Holcomb, John B, Zautke, Nathan, Mastrangelo, Mary Ann, Xq, Xu, Macaitis, Joe, Tweardy, David J
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA-Binding Proteins - metabolism; hemorrhage; inflammatory cascade; interleukin-6; Interleukin-6 - metabolism; Medical sciences; NF-kappa B - metabolism; nuclear factor-κB; proinflammatory cytokines; Severity of Illness Index; Shock, Hemorrhagic - immunology; shock, ischemia/reperfusion injury; signal transducer and activator of transcription-3 (Stat3); signal transduction; STAT3 Transcription Factor; Swine; Trans-Activators - metabolism; transcription factors; Transcription Factors - immunology; trauma
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/S0022-4804(03)00129-X

Hypotension causes diffuse liver injury accompanied by increased local production of interleukin-6 (IL-6) in swine models of uncontrolled hemorrhagic shock (HS). IL-6 is transcriptionally up-regulated by nuclear factor (NF)-κB and results in activation of signal transducer and activator of transcription-3 (Stat3) in a murine model of controlled HS. Our objectives were: 1) to determine if increased IL-6 production and NF-κB and Stat3 activation occurs in a swine model of uncontrolled HS, and 2) to assess whether or not levels of IL-6 mRNA and activity of NF-κB and Stat3 correlate with shock severity. Swine were assigned to four groups: 1) control animals ( n = 6): no intervention, 2) sham operation ( n = 6): celiotomy and splenectomy, 3) uncontrolled hemorrhagic shock (UHS) ( n = 6): sham plus grade V vascular liver injury and resuscitation, 4) profound uncontrolled hemorrhagic shock (PUHS) ( n = 8): UHS after dilutional hypothermia. Following euthanasia at 2 h, livers were harvested, total RNA isolated, and IL-6 mRNA levels quantified by Q-RT-PCR (ABI Prism 7700, Applied Biosystems International, Foster City, CA). Protein was extracted for measurement of NF-κB and Stat3 activity by electrophoretic mobility shift assay (EMSA). Compared to shams, IL-6 mRNA levels increased 4.5-fold in UHS and 90-fold in PUHS ( P < 0.001). Compared with shams; NF-κB activity increased 2-fold in both UHS and PUHS ( P < 0.05). Stat3 activity was equivalent (not significant) in UHS when compared with shams but increased 5.3-fold in PUHS. ( P < 0.05). These findings suggest that regional proinflammatory cytokine production results from and perpetuates a proinflammatory transcription factor cascade in a swine model of uncontrolled hemorrhagic shock and indicate that this process is proportional to the severity of shock.