Persistent Pseudomonas endobronchial infection is a common complication of airway diseases such as cystic fibrosis, resulting in progressive airway destruction despite currently available therapy. While mechanisms by which Pseudomonas persist within the airways have not been well defined, studies suggest that neutrophils may be critically important in host defense against this infection. Recently, members of the ELR+CXC chemokine family have been shown to mediate neutrophil recruitment in pulmonary infections. The hypothesis of this proposal is that the influx of neutrophils into the airways in chronic Pseudomonas endobronchial infection is mediated by ELR+CXC chemokines, and that manipulation of these ligands or their receptor will impact the outcome of infection in airways of mice infected with Pseudomonas. A murine model has been developed to assess the following Specific Aims: I) to examine the time-course and magnitude of expression of the ELR+ CXC chemokines, (KC, Lungkine, MIP-2), and their receptor, CXC chemokine receptor- 2 (CXCR2) in mice with mucoid P. Aeruginosa endobronchial infection; II) to determine the contribution of specific ELR+ CXC chemokines and their receptor CXCR2 in mucoid Pseudomonas endobronchial infection by evaluating the outcome of infection in animals passively immunized with neutralizing antibodies against CXCR2 or selected ligands; and III) to evaluate the effect of airway- specific transgenic expression of relevant ELR+ CXC chemokines in Pseudomonas endobronchial infection, by examining the outcome of infection: a) airway- specific chemokine transgenic animals, and b) animals transiently expressing the chemokine transgene in the airways using adeno-associated viral gene therapy. These studies will provide important insights into mechanisms of the innate antibacterial host response in the airways and potentially identify novel therapeutic strategies to be employed in treatment of this deviating disease.
| Tsai, Wan C; Hershenson, Marc B; Zhou, Ying et al. (2009) Azithromycin increases survival and reduces lung inflammation in cystic fibrosis mice. Inflamm Res 58:491-501 |
| Tsai, Wan C; Rodriguez, Michael L; Young, Katherine S et al. (2004) Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med 170:1331-9 |
