LIPID PATHWAYS AND LUNG INJURY

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The project does not focus on a single disease but on the mechanisms common to several forms of lung disease. The diseases have in common a mediation by leukocytes, alterations in the activities of lipid mediator pathways (releasing eicosanoids, lysophospholipids, PAF), and lung injury. The global implications of these pathways are emphasized among the projects by the different leukocyte cell types being studied. The function of this core will be to provide human cells from normal donors and from donors with inflammatory lung diseases as appropriate for each Project. Much of the function of the core will involve obtaining samples from normal donors for detailed study in vitro. Normal samples to be obtained will include blood cells (neutrophils, eosinophils, monocytes) and lung cells (isolated by bronchoalveolar lavage (BAL) or endobronchial biopsy or from lung tissue). Samples from patients with asthma and ARDS will also be acquired. ARDS is generally accepted as being primarily mediated by uncontrolled acute inflammation; neutrophil and probably macrophage pathways are hypothesized to play a central role in the pathogenesis of ARDS. In contrast, although neutrophils and macrophages may contribute to asthma, most evidence points to mast cells and eosinophils as being major components of the immediate and late asthmatic responses, respectively. Each project examines specific aspects of these cells and their modulation during the disease(s) which stimulate that specific cell type. In all projects, the format will be to study in detail the pathways in normal cells and in cells modulated in vitro. Neutrophils and macrophages will be studied after priming with endotoxin or TNF, eosinophils after priming with IL-5, and mast cells after binding of IgE. Once the experimental conditions are defined, the investigators will study cells from patients with the disease process which prompted development of the in vitro model in the first place. For example, neutrophils and macrophages from patients with ARDS will be compared with neutrophils and macrophages treated with TNF or IL-1, but eosinophils obtained from blood and BAL during asthma, in particular during the late phase asthmatic response, will be compared with eosinophils primed with IL-5. The main hypothesis is that these specific cells and these cell-specific agonists will activate a common series of lipid pathways within the cells, which in turn contribute to the lung injury. The purpose of this clinical core will be the collection of patient samples and provision of samples to the members of the program project. These samples will include blood, and bronchoalveolar cells and alveolar lining fluid, the latter two obtained by bronchoalveolar lavage (BAL). While the Core will also maintain clinical data on all patients, the focus of this Program is the elucidation of the cellular and biochemical pathways of inflammatory lung injury. Methods: Asthmatic subjects undergo allergen skin testing, inhaled allergen challenge and then endobronchial challenge with collection of bronchoalveolar lavage fluid. The inhaled allergen challenge permits assessment of the presence of a late asthmatic response (LAR) which is likely a reflection of inflammation and its sequellae in contrast to the non-inflammatory early reaction. Normal volunteers and subjects with SIRS and ARDS will also undergo bronchoscopy with BAL.