In the lower respiratory tract, alveolar macrophages (AMs) phagocytose inorganic particles and microorganisms, thus playing an important role in host defense. AMs have a complex array of intracellular machinery to respond and direct inflammatory and fibrotic processes. Through releasing peptide growth factors such as platelet-derived growth factor and insulin-like growth factor-I, they stimulate fibroblast proliferation and contribute to fibrosis. Through releasing interleukin-8 (IL-8), they attract neutrophils and lymphocytes by chemotaxis to participate in immune-effector functions. The macrophage processes antigen and presents it to naive T lymphocytes, activating them in immune or cytotoxic responses. AMs are a major source of cytokines IL-b, TNF-a, and IL-6, all of which participate in granulomatous lung inflammation. AMs can phagocytose apoptotic neutrophils and lymphocytes participating in programmed cell death.

We also analyze BAL cells, bronchial brush, and microdissected samples from lung resections to search for tumor suppressor gene mutations and gene expression changes that will help us identify workers exposed to asbestos and cigarette smoke making them at high risk for lung cancer.

In tuberculosis studies, we investigate IL-8, TNF-a, IL-1b, and IL-6 roles in the granulomatous response. Regarding the transcriptional regulation of these genes, we identified NF-IL6 enhancer site(s) that respond to Mycobacterium tuberculosis or cytokines stimulated by the mycobacterium. Interferon-g activates AM to enhance M. tuberculosis killing and IL-12 promotes the TH1 cytokine response; we evaluate how these cytokines alter the immune response in vivo by BAL. Also, we study the interaction of NF-IL6 with the natural resistance in the AM (Nramp) gene to dissect the genetic control of AM activation.