Macrophages play an essential role in inflammation and fibrosis through the release of a variety of mediators including reactive oxygen and nitrogen species, proteases, and cytokines. The mechanisms regulating macrophage activation in chronic inflammatory states are poorly understood. A hallmark of chronic inflammation and fibrosis is the increased production and turnover of the extracellular matrix (ECM). Hyaluronan (HA) is a glycosaminoglycan ECM component produced at sites of inflammation. Pulmonary inflammation and fibrosis are associated with the accumulation of HA fragments in the lung interstitium. We have previously shown that HA fragments, but not the native precursor, induce the expression of a number of inflammatory genes including several members of the cytokine family. The purpose of this proposal is to investigate the molecular mechanisms regulating HA-induced chemokine expression in alveolar macrophages. We intend to do so in the following manner: 1) to define the cis-acting elements that convey responsiveness to HA fragments in the promotors of the chemokine genes RANTES and IP-10 (crg-2); 2) to define the mechanism for the inhibition of HA-fragment-induced expression of macrophage Inflammatory Peptide-1alpha by IL-10 and gamma-interferon in mouse primary bone marrow cells; 30 to determine the effects of gamma-interferon and il-10 on HA fragment-induced expression of chemokines in alveolar macrophages isolated from bleomycin-treated mice.
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