sw033291 and Disease-Models--Animal

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.

Topics: Animals; Anti-Inflammatory Agents; Bleomycin; Body Weight; Dinoprostone; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Extracellular Matrix; Female; Gene Expression; Humans; Hydroxyprostaglandin Dehydrogenases; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Macrophages; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Pyridines; Respiratory Function Tests; Survival Analysis; Thiophenes

Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.

Topics: Adrenergic beta-Antagonists; Adrenergic Fibers; Animals; Bone and Bones; Bone Density; Bone Regeneration; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Feedback, Physiological; Female; Humans; Hydroxyprostaglandin Dehydrogenases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Osteoporosis; Propranolol; Pyridines; Receptors, Prostaglandin E, EP4 Subtype; Sensory Receptor Cells; Thiophenes