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Synergism Between Glucocorticoids and Prostaglandin E2 Modulate Fibrogenesis Pathways
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A2350 - Synergism Between Glucocorticoids and Prostaglandin E2 Modulate Fibrogenesis Pathways
Author Block: A. B. Mitke1, T. Harris1, M. Schuliga2, F. Jativa3, P. Lee3, J. Jaffar4, G. Westall4, A. Stewart1; 1Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia, 2Hunter Medical Research Institute, Univ of Newcastle, Callaghan, Australia, 3Mechanical Engineering, The University of Melbourne, Melbourne, Australia, 4Alfred Hospital, Melbourne, Australia.
Rationale: Eicosanoid imbalance in the airways is implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF). IPF patients are deficient in the anti-fibrotic and anti-inflammatory prostaglandin E2 (PGE2). In contrast, the levels of profibrogenic and fibroproliferative leukotrienes are elevated in the lung. Currently glucocorticoids, which are highly effective anti-inflammatory agents that inhibit eicosanoid biosynthesis, are not indicated for IPF. Glucocorticoids in combination with other immunomodulators were associated with increased rate of hospitalization and risk of death in IPF. We hypothesize that glucocorticoid and PGE2 analogs/receptor agonist may prove to be an effective and safe anti-fibrotic drug combination.
Methods: Human lung parenchymal fibroblast cell cultures were established using tissues derived from IPF patients and non-diseased controls (non-IPF). The effect of glucocorticoids in combination with PGE2 on collagen type1 and alpha smooth muscle actin (αSMA) synthesis after 48 hours of incubation with transforming growth factor-β1 (TGF-β1) was measured by western blotting. The expression of glucocorticoid inducible genes and extracellular matrix coding genes was measured by qRT-PCR after 16 hours incubation with TGF-β1. Pharmacological inhibitors and short interfering RNAs (siRNAs) were used to characterize novel glucocorticoids-PGE2 anti-fibrotic signaling pathways.
Results: In fibroblasts derived from IPF patients, the combination of budesonide and PGE2 synergistically inhibited collagen type 1 and αSMA synthesis in vitro. We also observed synergistic induction of pyruvate dehydrogenase kinase isozyme 4 (PDK4) expression in IPF fibroblasts. Budesonide and PGE2 have additive effect in inducing glucocorticoid-induced leucine zipper (GILZ) and MAP kinase phosphatase-1 (MKP-1) expression. Incubation of fibroblasts with a combination of dexamethasone and PGE2 showed similar effects to those of budesonide-PGE2.
Conclusion: Fibroblasts derived from IPF patients showed synergistic responsiveness to the combination of glucocorticoids and PGE2 indicating a potential anti-fibrotic effect of this combination of agents.
Author Block: A. B. Mitke1, T. Harris1, M. Schuliga2, F. Jativa3, P. Lee3, J. Jaffar4, G. Westall4, A. Stewart1; 1Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia, 2Hunter Medical Research Institute, Univ of Newcastle, Callaghan, Australia, 3Mechanical Engineering, The University of Melbourne, Melbourne, Australia, 4Alfred Hospital, Melbourne, Australia.
Rationale: Eicosanoid imbalance in the airways is implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF). IPF patients are deficient in the anti-fibrotic and anti-inflammatory prostaglandin E2 (PGE2). In contrast, the levels of profibrogenic and fibroproliferative leukotrienes are elevated in the lung. Currently glucocorticoids, which are highly effective anti-inflammatory agents that inhibit eicosanoid biosynthesis, are not indicated for IPF. Glucocorticoids in combination with other immunomodulators were associated with increased rate of hospitalization and risk of death in IPF. We hypothesize that glucocorticoid and PGE2 analogs/receptor agonist may prove to be an effective and safe anti-fibrotic drug combination.
Methods: Human lung parenchymal fibroblast cell cultures were established using tissues derived from IPF patients and non-diseased controls (non-IPF). The effect of glucocorticoids in combination with PGE2 on collagen type1 and alpha smooth muscle actin (αSMA) synthesis after 48 hours of incubation with transforming growth factor-β1 (TGF-β1) was measured by western blotting. The expression of glucocorticoid inducible genes and extracellular matrix coding genes was measured by qRT-PCR after 16 hours incubation with TGF-β1. Pharmacological inhibitors and short interfering RNAs (siRNAs) were used to characterize novel glucocorticoids-PGE2 anti-fibrotic signaling pathways.
Results: In fibroblasts derived from IPF patients, the combination of budesonide and PGE2 synergistically inhibited collagen type 1 and αSMA synthesis in vitro. We also observed synergistic induction of pyruvate dehydrogenase kinase isozyme 4 (PDK4) expression in IPF fibroblasts. Budesonide and PGE2 have additive effect in inducing glucocorticoid-induced leucine zipper (GILZ) and MAP kinase phosphatase-1 (MKP-1) expression. Incubation of fibroblasts with a combination of dexamethasone and PGE2 showed similar effects to those of budesonide-PGE2.
Conclusion: Fibroblasts derived from IPF patients showed synergistic responsiveness to the combination of glucocorticoids and PGE2 indicating a potential anti-fibrotic effect of this combination of agents.
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