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Bioactive Dendrimer Drugs As Potential Therapeutic Treatments For Inflammation

Turner, Stephanie
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Date
2014
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2014-12-01
Abstract
Chronic or widespread inflammation has been implicated in the pathophysiology of several human disease states, including adult systemic inflammatory response syndrome (SIRS) and Alzheimer's disease. This chronic inflammation is the result of cytokine production by macrophages and other lymphocytes. One mechanism for the activation of pro-inflammatory cytokines is signaling through toll-like receptor 4 (TLR4) on the surface of the cell. TLR4, with the help of MD-2, specifically binds lipopolysaccharide (LPS), a compound on the outer membrane of gram-negative bacteria. This binding initiates a signal cascade and activates the MAPK pathway, containing intermediates such as JNK and ERK. Results from Western blots of lysates from RAW264.7 cells show a peak in expression of signal cascade intermediates pJNK and pERK following 30 minutes of LPS treatment. Production of downstream TNF-alpha continued to increase at 90 minutes LPS treatment, while IL-1-beta showed no response to LPS up to 90 minutes of treatment. Use two different dendrimers, synthetic chemical compounds designed to bind to MD-2 and therefore prevent binding of LPS and block activation of TLR4-mediated pro-inflammatory cytokine production was found to have no effect on activation of signal cascade intermediates. Similarly, these two compounds did not reduce TNF-alpha or IL-1-beta when compared to LPS or cell alone as hypothesized. Future studies will address the ratio of cells:LPS:compound in order to determine if these results are due to sensitivity of the detection methods used in this experiment or the compound design and its biochemical activity. If positive results can be obtained in vitro, studies can move in vivo to test the ability of this compound to be used as a pharmacological agent to prevent and decrease inflammation.
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Subject
inflammation
sepsis
TLR4
dendrimer
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Biology
Advisor
Chumley, Michael
URI
https://repository.tcu.edu/handle/116099117/10453