Chemokine regulation of immune cell recruitment

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Despite improved antiretroviral therapy, Pneumocystis carinii pneumonia (PcP) remains the most common AIDS-defining illness, and is a significant cause of AIDS-related morbidity and mortality. Recent studies have reported mortality rates as high as 50% for AIDS patients with severe PcP, and one study named PcP as the leading cause of death among HIV-infected patients. Importantly, the clinical severity of PcP correlates more closely with the level of inflammation than with organism burden, and using mouse models of AIDS-related PcP we have directly demonstrated that immune-mediated lung injury plays a central role in the pathophysiology of PcP. However, the mechanisms by which pathologic immune cells are recruited to the lung remain largely unknown. PC interacts closely with the alveolar epithelium (AECs), and this interaction results in the secretion of chemotactic factors called chemokines that could function to recruit damaging immune cells to the lung during PC infection. We hypothesize that AECs are critically involved in the pathway leading to immune-mediated lung injury during PcP, and that interrupting this pathway will alleviate lung injury and improve patient outcome. The Specific Aims of this proposal are designed to: 1) define the mechanism of Pc-stimulated chemokine production by AECs; 2) determine whether chemokine production by AECs modulates immune cell recruitment to the lung; 3) determine how chemokine receptor expression on responding immune cells affects their recruitment to the lung; and 4) determine whether therapeutic modulation of chemokine function alleviates PcP-related lung injury. We will use a combination of primary cell culture and chimeric knockout mouse models to definitively answer these questions. The long-term goals of this project are to understand the consequences of the Pc-AEC interaction for immune cell recruitment to the lung, and how this interaction may be exploited to alleviate inflammatory injury during PcP. PcP remains an important concern of the health care community. While the incidence of PcP has decreased due to antibiotic prophylaxis, it remains the most common AIDS-defining illness as well as a significant cause of disease and death in other immunocompromised patients such as those with cancer or who receive medications that suppress the immune system. Antibiotic treatment of PcP does not always result in immediate clinical improvement because the host's ongoing immune response is a major cause of PcP-related lung injury. Thereforethe proposed studies are designed to increase our understanding of the mechanisms leading to PcP-related lung injury with the hope of identifying specific therapeutic targets.