Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biochemistry Program

Abstract

The risk of complications and death after a moderate sized burn injury is significantly higher in persons over the age of 65, while almost non-existant in young, healthy individuals. The studies outlined below use a murine model to determine the mechanisms behind the development of pulmonary complications that frequently occur in aged individuals following burn injury. We hypothesized that, since aged mice maintain an elevated proinflammatory state prior to injury, they are at an even greater risk of pulmonary inflammation than young mice given a comparable sized wound. We found that neutrophils continue to accumulate in the lungs of aged mice at 24 hours after burn injury, but do not migrate into the alveoli. We also showed that neutrophil migration towards KC--a dominant neutrophil chemokine--in a transwell chemotaxis assay is robust in neutrophils from young mice, but blunted in those from aged mice. These differences are likely due to intracellular signaling defects, as levels of the receptor for KC, CXCR2, is not different on neutrophils between age groups. In addition, we found that burn injury causes a significant decrease in CXCR2 on the surface of neutrophils, indicating that these cells are more susceptible to receptor desensitization. When anti-CXCR2 antibody is injected immediately post-burn, the aberrant pulmonary inflammation is completely abolished in aged mice compared to those receiving a control antibody, suggesting that targeting this pathway in the acute stages of burn help dampen the inflammatory response of the aged mice. In a separate set of experiments, we demonstrated that expression of the cell adhesion molecule, ICAM-1, on pulmonary vasculature and non-specific neutrophil adhesion is increased in aged mice following burn injury. In sum, we concluded that neutrophils accumulate in the lungs of aged mice as a result of sequestration in the pulmonary vasculature due to defective CXCR2-mediated migration and increased adhesion. These studies are critical to understanding why aged patients are at such a higher risk for pulmonary complications after burn injury and reveal targets for new and better therapeutic regimens that could potentially help older patients reach full recovery.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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