Effects of pharmacological modulation of intracellular signalling systems on retinal pigment epithelial cell attachment to extracellular matrix proteins.

Complication of retinal detachment by proliferative vitreoretinopathy (PVR) is common. In the contraction of intraocular collagen matrices which occurs in PVR cell proliferation, migration and adhesion seem to be more important than any inherent cellular contractility. The aim of this study was to investigate the pharmacological inhibition of adhesion of retinal pigment epithelial cells to extracellular matrices. The adherence of human RPE lines to a range of ten substrates was assessed to determine their preferred substrates for attachment. The effect of pharmacological inhibitors and stimulators of protein kinase C, cyclic AMP and calcium/calmodulin intracellular signal transduction systems on attachment to substrates was investigated. RPE cells showed a clear substrate preference for fibronectin, and slight preference for collagen type I. Modulation of the protein kinase C and cAMP pathways had relatively minor effects upon RPE attachment. Increasing intracellular calcium concentration reduced RPE attachment to 12% of control, whilst reducing intracellular calcium had a less marked, although significant effect. Down-regulation of calmodulin reduced attachment to 17% of control. The drug tamoxifen, and the experimental calmodulin antagonist J8, produced significant inhibition of attachment even when cells had been allowed to adhere for 24 h prior to exposure to these agents. The adhesion of RPE to extracellular matrices may be markedly affected by drugs which modulate the intracellular calcium and calmodulin signalling systems. Calmodulin antagonists warrant further investigation as possible pharmacological inhibitors of PVR.