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- All Subjects: inflammation
- Creators: Stabenfeldt, Sarah
- Creators: Sweazea, Karen
Description
Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
ContributorsHarrison, Jordan L (Author) / Lifshitz, Jonathan (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Willyerd, Frederick A (Committee member) / Pirrotte, Patrick (Committee member) / Arizona State University (Publisher)
Created2017
Description
There has long been a link tied between obesity and such pathological conditions as nonalcoholic fatty liver disease and type two diabetes. Studies have shown that feeding rats a diet high in fat results in hepatic steatosis and steatohepatitis. Using a novel short term diet of six weeks with male adolescent Sprague-Dawley rats, our laboratory sought to investigate the early effects of high fat intake on the liver. Prior findings in our laboratory found that a high fat diet (HFD) leads to nonalcoholic fatty liver disease as well as other symptoms of metabolic syndrome. This study hypothesized that rats fed a 60% HFD for 6 weeks, unlike a high sucrose or standard chow diet, would have an elevated expression of pro-inflammatory cytokines associated with steatohepatitis. TNF-α, TLR4 and XBP1 were chosen for their link to hepatic inflammation. The results of this study found that contrary to the hypothesis, the high fat diet did not induce significant changes in the expression of any inflammatory marker in comparison to a high sucrose or control chow diet.
ContributorsCalhoun, Matthew (Author) / Sweazea, Karen (Thesis director) / Deviche, Pierre (Reviewer) / Barrett, The Honors College (Contributor)
Created2015-05
Description
One of the most prominent biological challenges for the field of drug delivery is the blood-brain barrier. This physiological system blocks the entry of or actively removes almost all small molecules into the central nervous system (CNS), including many drugs that could be used to treat diseases in the CNS. Previous studies have shown that activation of the adenosine receptor signaling pathway through the use of agonists has been demonstrated to increase BBB permeability. For example, regadenoson is an adenosine A2A receptor agonist that has been shown to disrupt the BBB and allow for increased drug uptake in the CNS. The goal of this study was to verify this property of regadenoson. We hypothesized that co-administration of regadenoson with a non-brain penetrant macromolecule would facilitate its entry into the central nervous system. To test this hypothesis, healthy mice were administered regadenoson or saline concomitantly with a fluorescent dextran solution. The brain tissue was either homogenized to measure quantity of fluorescent molecule, or cryosectioned for imaging with confocal fluorescence microscopy. These experiments did not identify any significant difference in the amount of fluorescence detected in the brain after regadenoson treatment. These results contradict those of previous studies and highlight potential differences in injection methodology, time windows, and properties of brain impermeant molecules.
ContributorsWohlleb, Gregory Michael (Author) / Sirianni, Rachael (Thesis director) / Stabenfeldt, Sarah (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2015-05
Description
Vascular inflammation is a key component for cerebrovascular disease and ischemic injury is suggested to be a significant contributor, resulting in either myocardial ischemia or stroke. A strong inflammatory response is characterized by the release of inflammatory cytokines, thus producing and/or activating pro-inflammatory proteins in the cell. Our previous studies have demonstrated that hypoxia plus glucose deprivation (HGD), an in vitro model of ischemia, increases the proinflammatory mediator, cyclooxygenase-2 levels (COX-2), in vascular tissues. Nuclear factor kappa B (NF-κB) activation is an upstream transcription factor of COX-2 and had been suggested to be involved in “sterile” inflammation in experimental stroke models. Mechanisms underlying the development and progression of inflammation in the cerebrovasculature following ischemic injury in human tissue has not been addressed. Thus, the purpose of this study was to examine the impact of HGD on NF-κB expression and activation in human brain vascular smooth muscle cells (HBVSMC). In addition, we assessed pro-inflammatory mediator levels of downstream NF-κB transcription products, COX-2 and iNOS, and level of its upstream receptor, TLR4. Primary HBVSMC at passage 7 were treated with normoxia (room air) or HGD (1% O2). Following exposure to HGD (3h), cells were isolated, homogenized, and total protein content determined. Lysates, either whole cell or nuclear and cytosolic fractions, were prepped for western blot and analysis. Anti-α-smooth muscle actin was used to verify HBVSMC origin and -actin was used as a loading control. NF-κBp65, phosphorylated NF-κBp65, COX-2, and TLR4 protein levels were all measured post HGD. NF-κBp65 total protein was expressed in HBVSMC and a trend for an increase in levels following HGD was observed. Indirect activation of pNF-kBp65 was assessed via nuclear fractionation studies and was increased following HGD. Lamin AC was used to verify nuclear fractionation. Additional findings suggested that HBVSMC expressed TLR4 however, total protein levels of TLR4 were not altered by HGD. COX-2 and iNOS protein levels were also increased following HGD. In conclusion, these studies indicate that HGD alters proinflammatory enzyme levels, potentially by altering NF-κBp65 activation in human vascular smooth muscle cells. Funding Support: University of Arizona Sarver Heart Center and University of Arizona Valley Research Project Grant VRP P1 (RG).
ContributorsRahman, Sanna (Author) / Sweazea, Karen (Thesis director) / Gonzales, Rayna (Committee member) / Li, Yu-Jing (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Vascular inflammation plays a key role in the development and progression of cardiovascular disease. High fat diet has been associated with cardiovascular risk (1). Therefore, as poor nutrition and poor diet become more widespread, the number of people at risk to cardiovascular disease increases. We hypothesized that using the cancer drug lenalidomide would reverse the inflammation caused by high fat conditions. Human aortic vascular smooth muscle cells were used as an in vitro model to analyze the effect of lenalidomide on high fat diet induced inflammation. Palmitate, a saturated fatty acid was used to induce inflammation. Since lenalidomide has been shown to inhibit cytokine production and attenuate oxidative stress, we investigated whether lenalidomide alters select markers of vascular inflammation in vascular smooth muscle treated with high fat exposure using palmitate. These markers were cyclooxygenase-2 (COX-2) protein levels, TNF-α pro-inflammatory cytokine levels, and superoxide ions. Lenalidomide (5 µM) reversed COX-2 protein expression in cells exposed to high fat conditions (100 µM palmitate). In conclusion, high fat exposure elicits an inflammatory response in cultured primary human vascular smooth muscle, but this response appears to be independent of local cytokine or ROS production. Lenalidomide, although effective at reversing palmitate-induced COX-2, alone augments the pro-inflammatory mediators, COX-2 and TNF-α as well as promotes oxidative stress independent of high fat exposure in human vascular smooth muscle cells.
ContributorsBartel, Robyn Katherine (Author) / Sweazea, Karen (Thesis director) / DeCourt, Boris (Committee member) / Gonzales, Rayna (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Traumatic brain injury (TBI) is a leading cause of death in individuals under the age of 45, resulting in over 50,000 deaths each year. Over 80,000 TBI patients report long-term deficits consisting of motor or cognitive dysfunctions due to TBI pathophysiology. The biochemical secondary injury triggers a harmful inflammatory cascade, gliosis, and astrocyte activation surrounding the injury lesion, and no current treatments exist to alleviate these underlying pathologies. In order to mitigate the negative inflammatory effects of the secondary injury, we created a hydrogel comprised of hyaluronic acid (HA) and laminin, and we hypothesized that the anti-inflammatory properties of HA will decrease astrocyte activation and inflammation after TBI. C57/BL6 mice were subjected to mild-to-moderate CCI. Three days following injury, mice were treated with injection of vehicle or HA-Laminin hydrogel. Mice were sacrificed at three and seven days post injection and analyzed for astrocyte and inflammatory responses. In mice treated with vehicle injections, astrocyte activation was significantly increased at three days post-transplantation in the injured cortex and injury lesion. However, mice treated with the HA-Laminin hydrogel experienced significantly reduced acute astrocyte activation at the injury site three days post transplantation. Interestingly, there were no significant differences in astrocyte activation at seven days post treatment in either group. Although the microglial and macrophage response remains to be investigated, our data suggest that the HA-Laminin hydrogel demonstrates potential for TBI therapeutics targeting inflammation, including acute modulation of the astrocyte, microglia, and macrophage response to TBI.
ContributorsGoddery, Emma Nicole (Author) / Stabenfeldt, Sarah (Thesis director) / Addington, Caroline (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Neurological disorders are difficult to treat with current drug delivery methods due to their inefficiency and the lack of knowledge of the mechanisms behind drug delivery across the blood brain barrier (BBB). Nanoparticles (NPs) are a promising drug delivery method due to their biocompatibility and ability to be modified by cell penetrating peptides, such as transactivating transciptor (TAT) peptide, which has been shown to increase efficiency of delivery. There are multiple proposed mechanisms of TAT-mediated delivery that also have size restrictions on the molecules that can undergo each BBB crossing mechanism. The effect of nanoparticle size on TAT-mediated delivery in vivo is an important aspect to research in order to better understand the delivery mechanisms and to create more efficient NPs. NPs called FluoSpheres are used because they come in defined diameters unlike polymeric NPs that have a broad distribution of diameters. Both modified and unmodified 100nm and 200nm NPs were able to bypass the BBB and were seen in the brain, spinal cord, liver, and spleen using confocal microscopy and a biodistribution study. Statistically significant differences in delivery rate of the different sized NPs or between TAT-modified and unmodified NPs were not found. Therefore in future work a larger range of diameter size will be evaluated. Also the unmodified NPs will be conjugated with scrambled peptide to ensure that both unmodified and TAT-modified NPs are prepared in identical fashion to better understand the role of size on TAT targeting. Although all the NPs were able to bypass the BBB, future work will hopefully provide a better representation of how NP size effects the rate of TAT-mediated delivery to the CNS.
ContributorsCeton, Ricki Ronea (Author) / Stabenfeldt, Sarah (Thesis director) / Sirianni, Rachael (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05