Leukotrienes in inflammatory arthritis

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

The complex cellular and molecular interactions that function pathogenically in human synovial[unreadable] inflammatory diseases such as rheumatoid arthritis remain only partially understood. We have recently[unreadable] demonstrated a previously unappreciated critical role for the leukotriene lipid mediators of inflammation in[unreadable] the K/BxN serum transfer model of inflammatory arthritis. Furthermore, we find that the critical leukotriene[unreadable] species for arthritis induction is LTB4 and that neutrophils are an important source of this arthritogenic[unreadable] LTB4. These findings identify an important effector function for the neutrophil lineage in this model of[unreadable] inflammatory arthritis. In this proposal, we will investigate the response of the synovial mesenchyme and[unreadable] synovial fibroblasts in particular to LTB4. In specific, the aims of this proposal will define the breadth of[unreadable] inflammatory effector functions elicited in synovial fibroblasts by LTB4 in mouse and man (Aims 1,3).[unreadable] Furthermore, we will define the role of specific LTB4 receptors in engendering these effector responses.[unreadable] We will gain further mechanistic insight into regulation of LTB4 receptor function by examining the role of barrestins[unreadable] and G-protein receptor kinases (GRKs) in modulating LTB4-induced effector functions in synovial[unreadable] fibroblasts (Aim 2). Finally, we will extend our in vitro analyses by examining the role of LTB4 and specific[unreadable] LTB4 receptors in regulating the synovial mesenchyme response in vivo (Aim 4). Thus, this proposal will[unreadable] utilize both in vitro cellular and molecular techniques and in vivo genetic approaches to define[unreadable] mechanisms by which LTB4 participates in synovial tissue inflammation. These analyses will shed light on[unreadable] pathogenic mechanisms relevant to human inflammatory arthritis such as rheumatoid arthritis. It is likely[unreadable] that further understanding of synovial LTB4 participation in inflammatory arthritis will shed light on[unreadable] pathogenic mechanisms directly relevant to human inflammatory arthritis (e.g., rheumatoid arthritis) and[unreadable] open new avenues of treatment for these diseases. Furthermore, these studies will expand our[unreadable] understanding of eicosanoid biology in inflammatory responses.