Ward, Christie2009-09-282009-09-282009-07https://hdl.handle.net/11299/53837University of Minnesota Ph.D. dissertation. July 2009. Major: Veterinary Medicine. Advisors: Trevor R. Ames and Samuel K. Maheswaran. 1 computer file (PDF); xii, 205 pages, appendices A-B.Bovine pneumonic mannheimiosis (BPM), an acute fibrinonecrotic pleuropneumonia caused by Mannheimia (Pasteurella) haemolytica, remains a leading source of economic losses to North American beef and dairy industries. Current evidence indicates that pulmonary inflammatory responses, rather than the bacterium itself, are primarly responsible for the severe lung injury associated with disease. We therefore hypothesized that inflammatory cytokines participate in the pathogenesis of BPM, and that modulation of their expression may serve to prevent or reduce inflammatory lung injury. The specific objective of Phase 1 of the project was to characterize patterns of TNFα, IL–1β, and IL–8 expression within the lungs of experimentally infected calves. All 3 cytokines were upregulated, and results demonstrated a spatial and temporal association between inflammatory cytokine expression and lung pathology, indirectly supporting the hypothesis that these mediators contribute to lung injury in BPM. The objective of Phase 2 was to identify drugs capable of suppressing TNFα, IL–1β, and IL–8 gene and protein expression in bovine alveolar macrophages exposed to M. haemolytica lipopolysaccharide and leukotoxin in vitro. Compounds tested included dexamethasone, tetrahydropapaveroline, pentoxifylline, rolipram, SB203580, and thalidomide. Dose-dependent inhibition of cytokine secretion occurred in response to pretreatment with dexamethasone, tetrahydropapaveroline, pentoxifylline, rolipram, and SB203580. Dose-dependent inhibition of cytokine mRNA expression occurred in response to pretreatment with dexamethasone, tetrahydropapaveroline, and pentoxifylline. Dexamethasone was the most effective inhibitor by far. The objective of Phase 3 was to assess the ability of dexamethasone to ameliorate disease development in an in vivo experimental model of BPM. Clinical disease scores for DEX-treated calves were significantly lower than those for controls, and the percent lung volume exhibiting gross pneumonic lesions was significantly lower in DEX-treated calves (6.0% ± 1.1%) as compared to controls (68.9% ± 13.3%). Histopathological lesions were also less severe and extensive in DEX-treated calves. Taken together, these findings support the hypothesis that pharmacological modulation of pulmonary inflammation may represent a novel approach to the prevention and treatment of BPM. Successful implementation of this strategy will require additional research to identify drug agents that target the expression of cytokines and other inflammatory mediators without compromising host immune responses.en-USCattleInterleukin-1 betaInterleukin-8Mannheimia HaemolyticaPneumoniaTumor Necrosis Factor-alphaVeterinary MedicineThesis or Dissertation