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.
University 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.
Pulmonary expression of inflammatory cytokines in experimental Bovine pneumonic mannheimiosis..
Retrieved from the University of Minnesota Digital Conservancy,
Content distributed via the University of Minnesota's Digital Conservancy may be subject to additional license and use restrictions applied by the depositor.