Pulmonary fibrosis is a disordered response to lung injury that involves damage and/or loss of alveolar epithelial cells (AECs), inflammation, fibroblast proliferation, and excessive deposition of extracellular matrix. Fibroblasts are key target cells in fibrotic responses, and much is known about their capacity for activation and matrix secretion. However, there is a growing appreciation that fibrogenesis involves inadequate generation of, or responses to, suppressive signals that ordinarily control fibroblast responses. AECs are an important source of such suppressive signals. This proposal focuses on AEC-derived prostaglandin E2 (PGE2) as a crucial down-regulator of fibrotic responses. Fibrotic stimuli can cause the loss of PGE2 secretion from AECs. The suppressive actions of PGE2 on fibroblasts are mediated by four distinct prostaglandin E2 (EP) receptors. Fibrotic alterations to EP2 and/or EP4 receptor expression and/or signaling could abrogate suppressive PGE 2 actions on fibroblasts. Thus, the hypothesis to be tested in this proposal is that AEC generation of PGE2 and fibroblast responses to PGE2 via EP2/EP4 receptors are critical determinants of AEC-fibroblast interactions governing fibrotic responsiveness, and that both may be impaired by fibrotic insults. This hypothesis will be tested by 1) Examining PGE2 production from AECs isolated from saline- and Neomycin-treated mice. 2) Examining the regulation and signaling of EP2 and EP4 receptors on fibroblasts purified from saline- and Neomycin-treated mice. 3) Examining the ability of AECs to suppress fibroblast proliferation and collagen synthesis during the disease course, and determining the functional significance of PGE2 secretion in mediating these outcomes. 4) Determining the fibrotic response of EP2-/-and EP4-/- mice in vivo. 5) Determining whether AECs, via secretion of PGE2, can inhibit the transformation of fibroblasts into myofibroblasts. These investigations suggest a novel role for AEC-derived PGE2 as an inhibitor of fibrotic reactions in the lung, and suggest that manipulations to increase PGE2 secretion and or enhance suppressive EP2/EP4 signaling in fibroblasts will have therapeutic benefit in the treatment of this devastating disease.
NIH ExPorter
NIH ExPorter