The initiation and maintenance of chronic pulmonary inflammation is due to a dynamic interaction between an inciting agent, inflammatory mediators, leukocytes, and structural cells of the lung. Independent of the etiology granulomatous lung disease usually possess specific pathologic responses, which are characterized by th elicitation and activation of various leukocyte populations to define areas of the lung. The specific objective for this section of the Program Project is to determine the mechanisms whereby the expression and regulation of either a type 1 or type 2 cytokine phenotype. The following hypothesis will be addressed to support this objective: Recruitment and activation of various leukocyte populations to granulomatous lesions supported by specific chemokine receptors. As leukocytes traffick to sites of granulomatous inflammation, they are influenced by cytokines and other mediator systems, which dictate the expression of chemokines and chemokine receptors. The expression of chemokine receptors are important in """"""""sampling"""""""" the environment for chemokine family members which are key for specific leukocyte activation events and continued recruitment. The proposed studies will focus on the following questions: 1) What are the mechanisms involved in the expression of CC type 1 (Th1) or type 2 (Th2) cytokines)? 2) what alterations in the normal development of these lung granulomas are found in CCR1, CCR2, CCR3, or CCR5 knockout mice? 3) What are the chemokine/chemokine receptor- dependent mechanisms by which normal lung fibroblasts or fibroblasts isolated from either type 1 or type 2 granulomas can regulate leukocyte reactivity during granuloma development? and 4) What is the role of cell- to-cell interactions which dictate chemokine and chemokine receptor expression during granuloma development? The expression of chemokines and chemokines and chemokine receptors and mechanisms that regulate their expression will be studied using well characterized models of lung inflammation in normal and knockout mice via bioassays, ELISAs, immuno- histochemistry, Northern blot or RT-PCR, and in situ hybridization analyses. The studies designed in this proposal will show that chemokines and their receptors play novel roles in the initiation and maintenance of pulmonary inflammation and will serve as excellent targets for therapeutic intervention.
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