Fibroblasts are the principal effector cells that mediate tissue remodeling in idiopathic pulmonary fibrosis (IPF) via their capacities for enhanced survival, proliferation, collagen deposition, and myofibroblast differentiation. Although research in the pathogenesis of pulmonary fibrosis has been dominated by studies investigating fibroblast activation signals, evidence indicates that this disorder is also characterized by a relative deficiency in counter-regulatory anti-fibrotic signals. Two such anti-fibrotic signals are the prostanoid prostaglandin E2 (PGE2) and plasminogen activator (PA) activity. Each of these has been shown to be deficient in patients with IPF, and deficiency of each has been established to be pathogenically important in animal models of pulmonary fibrosis. PGE2 is a lipid mediator derived from cyclooxygenase metabolism of the fatty acid arachidonic acid that acts via cell surface G protein-coupled E prostanoid receptors. The PA system is a proteolytic cascade that includes the protease urokinase-type PA (uPA) and its associated inhibitor (plasminogen activator inhibitor-1). Although PGE2 inhibits the activation of all relevant pro-fibrotic cellular phenotypes in lung fibroblasts via intracellular cyclic AMP (cAMP) signaling, the downstream mechanisms by which it does so are incompletely understood. The PA system is recognized to orchestrate fibrinolysis and to modulate cellular adhesion and cellular signaling, but little is known about its direct effects on fibroblasts or their relevant phenotypes. Finally, there is no information about cross-talk between PGE2 and the PA system in lung cells of any kind, including fibroblasts. This project seeks to understand the mechanisms by which both mediators modulate fibroblast function, to characterize the cross-talk between them, and to determine how fibrotic lung injury influences the responses of fibroblasts to each of them. The general hypothesis is that the PGE2 and PA systems up-regulate each other and interact to influence pulmonary fibroblast phenotypes in a manner which favors lung repair over fibrosis. This hypothesis will be tested in fibroblast cell lines and in primary cells isolated from normal and fibrotic murine and human lungs.
Aim 1 will examine the roles of cAMP effectors protein kinase A and guanylate exchange protein activated by cAMP as well as the phosphatase PTEN in mediating PGE2 effects on fibroblast phenotypes.
Aim 2 will determine the mechanisms by which PGE2 and PA activity influence the expression of each other, while the role of each in mediating the actions of the other will be explored in Aim 3.
Aim 4 will compare the effects of PGE2 and PA activity on phenotypes of fibroblasts derived from normal vs. injured mouse lungs and from histologically normal vs. IPF human lungs. The proposed studies will provide novel insights into the regulation of fibroblast activation by these two mediators, and will inform future efforts to target these molecules therapeutically.
The development of a serious condition known as lung scarring (pulmonary fibrosis) is opposed by two substances produced by the body, prostaglandin E2 and urokinase plasminogen activator. This proposal will examine how these two substances act and interact to suppress scarring responses of the key lung cell type known as the fibroblast. These studies will enhance our understanding of how scarring responses are regulated, and may provide insight as to whether these substances could be administered to patients to treat this devastating condition.
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