Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

A positive blood alcohol concentration is detected in nearly half of burn patients admitted to the emergency room. The combined insult of being intoxicated at the time of burn injury results in more clinical complications, in comparison to non-intoxicated burn patients. Severe burn, with or without inhalation injury, is a common predisposing factor for the development of acute respiratory distress syndrome (ARDS). Exacerbated pulmonary inflammation and a net result of insufficient gas exchange underlie the large percentage of burn fatalities due to pulmonary complications. Previous studies in our laboratory indicate a drastic elevation in pulmonary inflammation in a mouse model of intoxication and burn injury, characterized by heightened levels of alveolar wall thickening, neutrophil accumulation, neutrophil chemokines KC and macrophage inflammatory protein 2 (MIP-2), and pro-inflammatory IL-6.

Alveolar macrophages (AMs) are the lungs first line of defense against inhaled particles or pathogens and elegantly coordinate the on-set and resolution of inflammation. Importantly, AM efferocytosis of apoptotic cells stimulates anti-inflammatory mediator release and promotes the resolution of inflammatory responses, while a disruption in this function can result in drastically increased levels of inflammation.

A common feature of both ARDS and burn injury is an increase in apoptosis in lung tissue. Since the removal of apoptotic cells by AMs is important for the termination of inflammation, a dysregulation in the activation state or survival of AMs can result in prolonged pulmonary inflammation. Thus, the role of AMs in pulmonary inflammation after intoxication and injury is extremely important. With this knowledge, we hypothesize that intoxication at the time of burn injury leads to an increase in AM apoptosis, resulting in exacerbated pulmonary inflammation and impaired lung function. To test this hypothesis, three aims are proposed: 1) to determine if pulmonary inflammation after intoxication and burn injury affects physiological parameters of lung function, 2) identify the role of alveolar macrophages in post-burn pulmonary inflammation, and 3) to determine if exogenous mesenchymal stem cell treatment will attenuate pulmonary inflammation after intoxication and burn injury.

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

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