Exposure to irritant crystals such as crystalline silica (CS) induces inflammation of lungs leading to chronic, irreversible disease-silicosis. Silicosis is incurable due to impaired particle clearance resulting in chronic lung inflammation and may eventually lead to many inflammatory diseases such as arthritis and lung cancer. CS exposure leads to recruitment of inflammatory cells to lungs, of which neutrophils are key mediators of the pathophysiology of silicosis. Our results in mouse models showed that CS-induced pulmonary inflammation is attenuated in leukotriene B4 receptor1 (BLT1-/-) deficient. Extensive in vivo studies in CS exposed mice and ex vivo studies in isolated bone marrow derived mast cells and macrophages suggested an intricate interplay of mediators such as LTB4, IL-1? and neutrophil active chemokines regulate silicosis. Moreover, our results suggest that CS-induced LTB4 production by mast cells sets the pace of sterile neutrophilic inflammation in the lung. Such inflammation is further perpetuated by IL-1? and CXC and CC neutrophil chemokines. The hypothesis of this proposal is that ?CS-induced lipidosome and inflammasome pathways function in consort with chemokines to coordinate sustained chronic sterile inflammation in silicosis?. In the proposed research plan in two specific aims we will perform studies to 1) delineate the molecular links between phagosome, lipidosome and inflammasome pathways in regulating the CS-induced production of neutrophil chemoattractants (LTB4, IL-1? and CXCL1). Signaling intermediates unique to each of these pathways will be identified as they can serve as potential drug targets to block neutrophil recruitment into silicotic lungs.
In aim2 we will identify the cellular mechanisms that integrate the lipid/cytokine/chemokine (LTB4, IL-1? and CXCL1) responses into chronic inflammation in vivo. Select inhibitors of the leukotriene pathway will be tested for their efficacy in controlling CS-induced neutrophilic inflammation in preclinical mouse models. This knowledge will facilitate development of immunotherapeutic strategies to fight silicosis.
Chronic exposure of crystalline silica (CS) often encountered in occupational settings such as construction, mining, glass and concrete production is a worldwide problem with tens of millions of people at risk. Such exposure is well known to induce lung inflammation and eventually causes an incurable, irreversible disease of lung-silicosis. Silicosis has now been shown to promote many inflammatory diseases including arthritis and lung cancer. The research proposed in this project will identify the molecular and cellular basis for CS-mediated lung inflammation in mouse models. These studies will lead to new approaches to treat silicosis.
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