Treatment of retinas with the conventional CW laser at a clinically relevant energy level caused the rapid appearance of significant lesions that were associated with ablated RPE, induction of both instant and delayed photoreceptor death, and widespread edema. It was also evident that even though RPE cells in the irradiated regions were killed, there was no associated destruction of the underlying Bruch's membrane. This is significant because it theoretically allows for the replacement of dead RPE by either migration or proliferation of cells from outside of the lesion site. In fact, this was borne out by the present data: By 7 days after laser treatment, new RPE cells were typically found overlying Bruch's membrane within lesion sites. This is in agreement with work by von Leithner and colleagues, who have shown that induction of focal laser-induced lesions in the RPE layer cause a global proliferative drive in these cells, which lasts for several days, in order to repair the damage.
42 Roider and colleagues have reported similar observations in rabbits after laser photocoagulation, namely that reestablishment of the RPE monolayer was essentially in place by 3 days after laser treatment and that this event was coincident with a reduction in local edema.
28 As stated previously, it is not clear where the beneficial influence for retinal laser photocoagulation actually lies, but certainly the stimulation of RPE cells located away from the lesion site in the present study represents a significant tissue response. The RPE are likely being driven to alter their physiological functions by factors released as a result of laser injury. Such factors, for example platelet-derived growth factor (PDGF),
43 VEGF,
44 or pigment epithelium-derived factor (PEDF),
45,46 can be released by surviving RPE cells that have been either directly or indirectly physically or chemically stressed. These factors could also, obviously, have effects on other local non-RPE cell types too, and these latter influences would also likely contribute to the overall retinal response to laser photocoagulation. Other mechanisms for the therapeutic potential of laser photocoagulation have been mooted; these include the alteration of immune cell signaling and activity, vascular thrombosis, and improvements in transport across Bruch's membrane.
27,47–53 Indeed, it has been suggested that the establishment of a new RPE layer at the laser lesion site, with a dilution of the intracellular debris that is known to accumulate with aging,
54 will restore the efficiency of the blood–retinal barrier, and that this is what provides the therapeutic benefit of laser photocoagulation.
55 The RPE layer repair seen in the present study would add some support to this theory. Finally, an interesting study from Machalinska and colleagues has also shown that bone marrow–derived stem cells are mobilized to the retina in response to RPE damage and that these could provide factors that contribute to the local repair processes.
56