Patients with AIDS continue to die predominantly as a result of respiratory infections. Bacterial empyema with pyogenic organisms is a common complication of pneumonia in patients with AIDS. Though multiple organisms can cause pleural infections in patients with AIDS, one of the commonest organisms to cause empyema is Staphylococcus aureus. It is the hypothesis of this proposal that recruited neutrophils represent important phagocytic cells involved in effective pleural antibacterial host defense in bacterial empyema. We have developed a model of bacterial empyema in CD4 knockout mice that mimics bacterial empyema in patients with AIDS. Pleural mesothelial cells play a critical role in neutrophil recruitment by the production of neutrophil activating and chemotactic chemokines MIP-2, and KC in our murine model of staphylococcal empyema CD4 depletion alters pleural neutrophil recruitment and bacterial clearance by inhibition the in vivo compartmentalized production of the chemokines. Macrophage inflammatory protein-2 (MIP-2) and KC (murine gro-alpha). The inhibitory effect of CD4 depletion is in part due to the relative imbalance between Th1 type Interferon Gamma (IFN-gamma) and Th2 type cytokines, Interleukin-10 (IL-10). We will evaluate our hypothesis both in vivo and in vitro. Using an in vivo model of staphylococcal empyema in CD4, knockout mice, we will evaluate the regulation of MIP-2 and KC by 1TH and 2TH cytokines. In vitro, mesothelial cell responses to S. Aureus by release of neutrophil chemokines and their regulation will be studied. Understanding the mechanism of regulation of neutrophil recruitment to the pleural space may help us discern the pathophysiology of the fulminant bacterial empyema seen in patients with AIDS and may help develop therapeutic modalities that augment host defense responses.
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