Molecular Mechanisms of Lung Inflammation

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DESCRIPTION (provided by applicant): The sepsis syndrome is often a systemic consequence of localized infections in the lungs. The mechanisms that initiate and modulate inflammatory responses in the lungs of humans with sepsis need to be better defined in order to design specific therapies that can be used to protect the lungs and systemic organs. Bacteria and their products in the lungs and systemic circulation initiate the sepsis syndrome, in part through specific recognition molecules on the surface of leukocytes and other cells in tissue and the circulation. The major goal of our ongoing studies is to understand how innate immune mechanisms initiated via specific pattern recognition receptors on the cell surface initiate and perpetuate acute lung injury and sepsis syndrome. Our Specific Aims are: 1) to define the pathways that mediate host responses to bacterial products in the lungs of normal humans and patients with ARDS; 2) to define the cells in the lungs that express the major pattern recognition receptors for gram negative and gram positive bacterial products, and the changes in expression that occur in acute bacterial pneumonia; 3) to determine the role of pattern recognition receptors on leukocytes and non-myeloid cells (CD14, TLR2, TLR4 and the signaling protein MyD88) in the clearance of gram positive and gram negative bacteria from the lungs, using mice with targeted gene deletions; 4) to determine whether blockade of CD14, TLR4, TLR2 and/or MD2 protects rabbits from the deleterious systemic effects of localized lung infections. The results of these continuing studies will provide important new information about the mechanisms that control the response to bacterial products in the lungs, and the consequences of inhibiting specific pattern recognition pathways in the lungs and the systemic circulation.