Role of platelet-activating factor in cell death signaling in the cornea: A review

Abstract

Platelet-activating factor (PAF) is a potent bioactive lipid generated in the cornea after injury whose actions are mediated through specific receptors. Studies from our laboratory have shown that PAF interactions with its receptors activate several transmembrane signals involved in apoptosis. Continuous exposure to PAF during prolonged inflammation increases keratocyte apoptosis and inhibition of epithelial adhesion to the basement membrane. As a consequence, there is a marked delay in wound healing, which is not countered by the action of growth factors. While apoptosis of stroma cells is rapid and potent, epithelial cells as well as myofibroblasts, which appear in the stroma during the repair phase, are resistant to apoptosis. However, PAF accelerates apoptosis of corneal epithelial cells exposed to oxidative stress by stimulating phospholipase A2, producing an early release of cytochrome C from mitochondria and activating caspase-3. In myofibroblasts, PAF has a synergistic action with tumor necrosis factor-alpha (TNF-alpha), increasing apoptosis of the cells to 85%. PAF antagonists block the effects of PAF and could have a therapeutic role in maintaining a healthy and transparent cornea.

Fig. 1

Diagram of the structural organization of the cornea

Fig. 2

Transformation of stromal keratocytes after injury in fibroblasts and myofibroblasts and expression of PAF-R in the cells. α-SMA α-smooth muscle actin

Fig. 3

Synthesis of PAF by the remodeling pathway. Corneal injury activates PLA2, which releases AA to form lyso-PAF, a biologically inactive intermediate that, by the action of an acetyltransferase, synthesizes PAF. During corneal injury, the rate of PAF synthesis is higher than the degradation and, as a consequence, PAF accumulates [7]

Fig. 4

Signaling pathway of apoptosis stimulated by PAF in corneal epithelial cells. Apoptosis can be induced by UV irradiation. PAF accelerates the process of releasing cytochrome c and activating the caspase cascade that results in early DNA fragmentation and apoptosis. cPLA2 activation is involved in the process. Although the mechanism is not known, one possibility is that AA can regulate mitochondrial permeability and stimulate the release of cytochrome c. The cPLA2 inhibitor MAFP blocks the effect of PAF on the release of cytochrome c and, as a consequence, increases the time of DNA fragmentation after UV exposure [36]. Apaf-1 apoptotic protease-activating factor-1

Fig. 5

Scheme on the action of PAF in corneal cells. While stromal keratocytes enter into apoptosis in the presence of PAF, there is a synergistic effect in apoptosis of myofibroblasts when TNF-α is combined with PAF. Epithelial cells are resistant to PAF apoptosis, but the lipid mediator accelerates the process after UV irradiation