published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Biological Sciences / Master / Master of Philosophy

The purpose of this study was to separate acute and chronic effects of moderate exercise on the immune system by analyzing three sets of experimental and control groups; (1) 72 hours, (2) 1 week, (3) 2 weeks post exercise. Mice swam 5 days per week for 3 weeks accumulating a total of 125, 225, and 225 minutes of exercise in weeks 1, 2, and 3, respectively. Moderate swimming exercise did not result in a significant increase in SDH levels (p > 0.05). There was no change in tissue cell responses as measured by mitogen responsiveness, nor in splenic and thymic cell counts in response to the training regimen at any time point (p ≥ 0.05). Total, CD4, CD8, and T cell counts in the lymph nodes were significantly suppressed at 72 hours and 2 weeks post exercise (p ≤ 0.05). It appears that chronic exercise resulted in an increased trafficking of lymphatic cells, which could be interpreted as a sign of heightened immune reactivity.

The alteration of insulin-like growth factor I (IGF-I) and its binding proteins (IGFBP) and their effects on proliferation and differentiation of murine bone marrow-derived macrophage (BMM) precursors were investigated. Bone marrow cells exposed to 20% L929-fibroblast conditioned medium (LCM) were cultured in serum-free medium for 24 h. Western ligand blotting (WLB) analysis detected four bands in all samples. 41-kDa and 30-kDa bands were detected after 12 h and remained constant during BMM differentiation. The 28-kDa and 25-kDa proteins were almost undetectable until day 2, but accumulated significantly from day 3 to day 7. Immunoblotting analysis verified these two bands as IGFBP-4. Northern blotting analyses detected both IGFBP-4 and IGFBP-3 mRNA in the cells. The 41-kDa protein was postulated to be IGFBP-3 in a glycosylated form. The identity of the 30-kDa band is not known. Northern blotting analysis showed that IGF-I mRNA level increased in a time-dependent manner until day 3, and decreased thereafter during BMM differentiation. The effect of IGF-I and its analogs on cell proliferation was studied by ($ sp3$H) thymidine incorporation. IGF-I and its analogs enhanced cell proliferation of freshly isolated bone marrow cells. Both IGF-I and long R$ sp3$ IGF-I, but not des(1-3)IGF-I, continued to exert a stimulating effect on day 1, although to a lesser extent. The effect of IGF-I and its analogs on BMM differentiation was studied by checking morphology, non-specific esterase-1 (NSE-1) activity, and mannose receptor expression. No significant differences in morphology and NSE-1 activity were observed among the treatment groups. There was no difference of mannose receptor expression on day 4 between the IGF-I group and the control cells, whereas long R${ sp3}$ and des(1-3)IGF-I increased the receptor number by 260% and 228% respectively, with less increased K$ rm sb{d}$ values. (Abstract shortened by UMI.)

Sepsis is a systemic inflammatory response that causes, increased heart rate, respirations, fever, and inadequate blood flow to organs. One of the most prevalent causes of sepsis is Staphylococcus aureus (S. aureus). With increasing numbers of strains of bacteria becoming antibiotic resistant, new methods for the treatment and clearance of sepsis are needed. Studies have shown that the lipid lowering drug simvastatin is protective for incidence of sepsis, having immunomodulatory effects and anti-inflammatory properties, specifically. Thus, it may be an alternative way to prevent sepsis due to S. aureus infections. Studies in our laboratory have shown that simvastatin pretreatment increases survival of mice infected with S. aureus and alters the adaptive immune response such that levels of IgG2c are reduced to the level of uninfected controls. Our studies have demonstrated that while simvastatin does not enhance bacterial clearance, or affect serum C5a levels, it does decrease serum levels of TNF. / Department of Biology

The kinetics of production and role of tumor necrosis factor-alpha (TNF-$ alpha$) and nitric oxide (NO) during the early phase of blood-stage infection with Plasmodium chabaudi AS were investigated using two inbred strains of mice which differ in the level of resistance to this parasite. Analysis of the in vivo expression of TNF-$ alpha$ and inducible nitric oxide synthase (iNOS) revealed that, early during infection, resistant C57BL/6 mice, which clear the infection by 4 weeks, have higher levels of TNF-$ alpha$ and iNOS mRNA in the spleen and TNF-$ alpha$ mRNA in the liver than susceptible A/J mice which succumb to the disease 10 days after initiation of infection. Moreover, resistant mice expressed high levels of IFN-$ gamma$ (a Th1 marker) and low levels of IL-4 (a Th2 marker) mRNA in the spleen, whereas susceptible A/J mice had low levels of IFN-$ gamma$ but high levels of IL-4 mRNA in the spleen early during infection. Increased levels of NO$ sb3 sp-$ were detected in serum of resistant C57BL/6 mice only at the time of peak parasitemia. Furthermore, treatment of resistant C57BL/6 mice with anti-IFN-$ gamma$ and anti-TNF-$ alpha$ monoclonal antibody demonstrated that TNF-$ alpha$, either alone or in synergy with IFN-$ gamma$, plays a major role in the up-regulation of NO production during P. chabaudi AS malaria. Moreover, treatment with the iNOS inhibitor aminoguanidine, eliminated resistance of these mice to infection with P. chabaudi AS without affecting parasitemia, suggesting that NO may not be involved in parasite killing in vivo. Taken together, these results demonstrate that a Th1-associated increase in TNF-$ alpha$ early during infection, as occurs in resistant mice, leads to the up-regulation of NO production which is crucial for survival of the host. On the other hand, our results also suggest that a Th2 response, as occurs in susceptible mice, does not result in protective levels of TNF-$ alpha$ and NO. However, susceptible A/J mice were found to

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