xigris/200-sepsis-management-challenges.jsp
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In the United States, more than 500,000 patients a year develop sepsis with mortality reported between 30 and 70%. These treatments have been calculated to cost more than 15 billion dollars per year. HMGB1 is a late cytokine mediator in sepsis, and has been linked to cytokine production. Knockout receptor peritoneal macrophages were used to observe varying effects of HMGB1. Knockout TLR2, TLR4, T4R, T2R and RAGE macrophages were treated with LPS, HMGB1 and PGN to observe HMGB1’s cytokine activation. Results suggest that knockout TLR4 receptors significantly reduce cytokine production in a sepsis model. TLR2 knockout macrophages responded with lesser amount of cytokines, however there were still signs of cytokine encroachment. RAGE knockout receptor cells showed best results in the dual knockout receptor trials. Collected data can help shape a clinical model in antagonizing receptors to prevent HMGB1 binding. http://www.xigris.com/200-sepsis-management-challenges.jsp http://blogs.cgdev.org/globalhealth/ under_5_deaths.gif Invasive Infection Immune Cells and Cytokines HMGB1 Release Receptor Binding Toll- Like Receptor RAGE Dual Knockout Receptor TNF Release Dual knockout receptor cells will have similar TNF levels as compared to each other and single knockout receptor cells, when exposed to all HMGB1 and LPS concentrations. The dual knockouts will have the lowest TNF levels in both the HMGB1 and TNF Trials. To determine the effectiveness of the dual knockout receptors T2R and TR4, in lowering TNF levels as compared to single knockout receptors. Capture Sample Detection Second Substrate ELISA Pro-Inflammatory Protection- Critical Illness Normal –Lethal Response Appears in 16-24 hrs Plateaus 24-32 hrs Late Action-Therapeutic Target in Inflammation High Mobility Group Box-1 http://www.uic.edu/classes/bios/bios100/lecturesf04am/ inflammation01a.jpg Purpose Hypothesis 1 Hypothesis 2 Cytokines and Proteins linked to Sepsis-HMGB1 Normal/ Septic Conditions. TLR4, TLR2, RAGE. Single Knockout Receptors Yang (2005) Yang, 2005
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In the United States, more than 500,000 patients a year develop sepsis with mortality reported between 30 and 70%. These treatments have been calculated to cost more than 15 billion dollars per year. HMGB1 is a late cytokine mediator in sepsis, and has been linked to cytokine production. Knockout receptor peritoneal macrophages were used to observe varying effects of HMGB1. Knockout TLR2, TLR4, T4R, T2R and RAGE macrophages were treated with LPS, HMGB1 and PGN to observe HMGB1’s cytokine activation. Results suggest that knockout TLR4 receptors significantly reduce cytokine production in a sepsis model. TLR2 knockout macrophages responded with lesser amount of cytokines, however there were still signs of cytokine encroachment. RAGE knockout receptor cells showed best results in the dual knockout receptor trials. Collected data can help shape a clinical model in antagonizing receptors to prevent HMGB1 binding.
http://www.xigris.com/200-sepsis-management-challenges.jsphttp://blogs.cgdev.org/globalhealth/under_5_deaths.gif
Invasive Infection
Immune Cells and Cytokines
HMGB1 ReleaseReceptor Binding
Toll- Like Receptor
RAGE
Dual Knockout Receptor
TNF Release
Dual knockout receptor cells will have similar TNF levels as compared to each other and single knockout receptor cells, when exposed to all HMGB1 and LPS concentrations.
The dual knockouts will have the lowest TNF levels in both the HMGB1 and TNF Trials.
To determine the effectiveness of the dual knockout receptors T2R and TR4, in lowering TNF levels as compared to single knockout receptors.
Capture Sample Detection Secondary Substrate
ELISA
Pro-InflammatoryProtection- Critical IllnessNormal –Lethal ResponseAppears in 16-24 hrsPlateaus 24-32 hrs Late Action-Therapeutic Target in Inflammation
High Mobility Group Box-1
http://www.uic.edu/classes/bios/bios100/lecturesf04am/inflammation01a.jpg
Purpose
Hypothesis 1 Hypothesis 2
Cytokines and Proteins linked to Sepsis-HMGB1
Normal/ Septic Conditions. TLR4, TLR2, RAGE. Single Knockout Receptors
Yang (2005)
Yang, 2005
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