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Hemorrhage activates myocardial NFkappaB and increases TNF-alpha in the heart
D R Meldrum1, R Shenkar, B C Sheridan
1Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Insights
Hemorrhagic shock significantly increases heart tumor necrosis factor-alpha (TNFalpha) by activating nuclear factor kappa B (NFkappaB). This finding highlights potential clinical implications for trauma and organ failure.
Area of Science:
- Cardiovascular Biology
- Inflammation and Immunology
Background:
- The heart produces tumor necrosis factor-alpha (TNFalpha), a cytokine implicated in myocardial dysfunction, apoptosis, and hypertrophy.
- Previous research indicates elevated myocardial TNFalpha following endotoxemia, but its role in non-septic shock remains unclear.
Purpose of the Study:
- To investigate whether hemorrhagic shock, independent of sepsis, activates myocardial nuclear factor kappa B (NFkappaB) and increases TNFalpha levels in the heart.
- To elucidate the signaling pathways involved in myocardial TNFalpha production during hemorrhagic shock.
Main Methods:
- Rats were subjected to hemorrhage and subsequent resuscitation.
- Hearts were harvested post-resuscitation for analysis of NFkappaB activation using electrophoretic mobility shift assay.
- Myocardial TNFalpha levels were quantified.
Main Results:
- Hemorrhage and resuscitation led to significant activation of myocardial NFkappaB.
- A dramatic increase in myocardial TNFalpha levels was observed following hemorrhagic shock.
- This study provides the first evidence that hemorrhagic shock activates NFkappaB and upregulates TNFalpha in the heart.
Conclusions:
- Hemorrhagic shock activates the NFkappaB signaling pathway in the myocardium, resulting in increased TNFalpha production.
- Elevated myocardial TNFalpha during hemorrhagic shock may contribute to cardiac dysfunction and organ failure.
- These findings have potential clinical relevance for managing trauma patients and preventing multiple organ failure.
Abstract:
The heart is a tumor necrosis factor (TNFalpha) producing organ. Locally (v systemically)-produced TNFalpha likely contributes to myocardial dysfunction via direct suppression of myocardial contractile function, the induction of myocardial apoptosis, and the genesis of cardiac hypertrophy. Although recent studies have demonstrated increased myocardial TNFalpha following endotoxemia, it remains unknown whether shock, in the absence of sepsis, activates myocardial nuclear factor kappa B (NFkappaB, a TNFalpha transcription factor) and/or increases TNFalpha in the heart. To study this, rats were hemorrhaged and resuscitated, after which hearts were harvested and analysed for evidence of NFkappaB activation (electrophoretic mobility shift assay) and assayed for TNFalpha levels. Hemorrhage and resuscitation activated NFkappaB and resulted in a dramatic increase in myocardial TNFalpha. This study constitutes the initial demonstration that hemorrhagic shock activates the signaling mechanisms which culminate in increased myocardial TNFalpha. Indeed, this may have important clinical implications, since hemorrhage is a frequent complication of both iatrogenic and accidental trauma, as well as a potent instigator of multiple organ failure.