EFFECTS OF PHARMACOLOGICAL MODULATION OF INTRACELLULAR SIGNALING 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 w hich 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 adhes ion of retinal pigment epithelial cells to extracellular matrices. The adherence of human RPE lines to a range of ten substrates was assesse d to determine their preferred substrates for attachment. The effect o f pharmacological inhibitors and stimulators of protein kinase C, cycl ic AMP and calcium/calmodulin intracellular signal transduction system s on attachment to substrates was investigated. RPE cells showed a cle ar substrate preference for fibronectin, and slight preference for col lagen type I. Modulation of the protein kinase C and cAMP pathways had relatively minor effects upon RPE attachment. Increasing intracellula r calcium concentration reduced RPE attachment to 12% of control, whil st reducing intracellular calcium had a less marked, although signific ant effect. Down-regulation of calmodulin reduced attachment to 17% of control. The drug tamoxifen, and the experimental calmodulin antagoni st J8, produced significant inhibition of attachment even when cells h ad 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 sign alling systems. Calmodulin antagonists warrant further investigation a s possible pharmacological inhibitors of PVR.