Ciprostene Calcium

The controlled accumulation of fibroblasts to sites of inflammation is crucial to effective tissue repair after injury. Either inadequate or excessive accumulation of fibroblasts could result in abnormal tissue function. Prostacyclin (PGI2) is a potent mediator in the coagulation and inflammatory processes. The aim of this study was to investigate the effect of PGI2on chemotaxis of human fetal lung fibroblasts (HFL-1). Using the blind well chamber technique, we found that the PGI2analog carbaprostacyclin (10−6M) inhibited HFL-1 chemotaxis to human plasma fibronectin (20 μg/ml) 58.0 ± 13.2% ( P < 0.05) and to platelet-derived growth factor (PDGF)-BB (10 ng/ml) 48.7 ± 4.6% ( P < 0.05). Checkerboard analysis demonstrated that carbaprostacyclin inhibits both directed and undirected migration. The inhibitory effect of the carbaprostacyclin was concentration dependent and blocked by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, suggesting that a cAMP-PKA pathway may be involved in the process. Two other PGI2analogs, ciprostene and dehydro-15-cyclohexyl carbaprostacyclin (both 10−6M), significantly inhibited fibroblast migration to fibronectin. In summary, PGI2appears to inhibit fibroblast chemotaxis to fibronectin and PDGF-BB. Such an effect may contribute to the regulation of fibroblasts in wound healing and could contribute to the pathogenesis of diseases characterized by abnormal tissue repair remodeling.

Thromboxane A2 stimulation of smooth muscle cells contributes to the development of vascular lesions after percutaneous transluminal coronary angioplasty. In view of this, we examined the signaling pathways stimulated by a thromboxane receptor agonist, U-46619, in cultures of rat aortic smooth muscle cells. Treatment of rat aortic smooth muscle cells with U-46619 induced cellular hypertrophy ([14C]leucine incorporation) without stimulating mitogenesis ([3H]thymidine incorporation). Analysis of signaling pathways elicited by U-46619 revealed enhanced tyrosine phosphorylation and increased enzymatic activity of mitogen-activated protein (MAP) kinase (Erk2). U-46619 also activated signaling proteins upstream of p21-ras, inducing tyrosine phosphorylation on Shc and complex formation between Shc and growth factor receptor binding protein-2 (GRB2). Exposure of cells to a stable prostacyclin analogue, ciprostene calcium, attenuated U-46619-induced cellular hypertrophy and MAP kinase activity. Ciprostene treatment elevated cellular cAMP and inhibited U-46619-induced tyrosine phosphorylation on Shc and Shc/GRB2 complex formation. These results demonstrate that stimulation of thromboxane A2 and prostacyclin receptors have opposing effects on smooth muscle cell hypertrophy and the signaling pathways associated with this process. We conclude that inhibition of Shc/GRB2 complex formation and MAP kinase activity by ciprostene may contribute to its ability to limit restenosis injury.