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Characterization of Pseudomonas lung infection in a pig model of cystic fibrosis
Cystic fibrosis (CF) is a genetic disorder, which ultimately leads to multisystem organ dysfunction and a subsequent decrease in life expectancy. Pseudomonas aeruginosa is the predominant respiratory pathogen in patients with CF, but the means by which the organism is acquired is controversial. Most patients with CF are ultimately infected with P. aeruginosa, and once acquired, the infection is not readily eradicated. The unique tropism of P. aeruginosa for the CF respiratory tract has not been adequately explained; competing and complementary hypotheses abound. However, none of these theories has been widely accepted. Thus, the goal of this project is to establish a new animal model of Pseudomonas aeruginosa colonization using the CF pig. The existing mouse model does not demonstrate chronic colonization, likely because of major anatomical and physiological differences from humans. Having a model such as the CF pig which demonstrates many of the features of the human disease, most notably, mucus plugging of the airways, will allow fundamental studies directed to understanding the conditions leading to Pseudomonas colonization of the CF lung and provide a model for evaluating interventions aimed at preventing or eradicating Pseudomonas, and/or, ameliorating lung injury caused by the inflammatory response to this bacterium. We will first establish the parameters for measuring colonization and bacterial clearance of labeled bacteria in normal piglets. We will then undertake colonization of CF piglets using a variety of bacterial mutants that mimic some of the strains isolated from CF patients. If needed, we will also examine the influence of viral infections and staphylococcal infections in predisposing to the establishment of P. aeruginosa in the lungs. When a state of colonization has been established, we will examine the progression of lung injury, the inflammatory response in the airways, levels of proteases and antiproteases in lung fluids and the phagocytic capabilities of lung neutrophils. These are just some of the infection related issues that can be examined to set the stage for further studies and interventions. The model will also be useful for the preclinical evaluation of a variety of preventative and therapeutic modalities for human CF.