It is important to remember that the retina undergoes a period of intense maturation from birth until approximately P30, when it reaches both structural and functional maturity.
20 Consequently, this process must occur throughout both the hyperoxic (P0–P14) and the relative hypoxic phases (P15 and on) in the OIR model. Previous studies of ours also suggested a normal age-related decline in amplitude of scotopic and photopic ERG parameters between P30 and P60.
19 –24,48 Interestingly, only the a-wave showed a similar age-dependent amplitude attenuation after exposure to hyperoxia, whereas the rod
V max, rod-cone b-wave, and photopic b-wave did not.
20 Similarly, findings obtained by Penn et al.
49 also revealed a decline in the scotopic b-wave amplitude (by ∼40%) between control animals aged 5 and 9 weeks (P35–P63), but no similar attenuation was evident in the hyperoxic cohort, even at later time points (P112). In contrast, the a-waves obtained from the normoxic and hyperoxic groups within that age range were similarly attenuated. Collectively, these findings suggest that whereas normal developing animals are subjected to a progressive decline in retinal function, in addition to the normal thinning of the retinal layers between eye opening (∼P15) through adulthood,
50 exposure to hyperoxia alters this process. This normal retinal thinning, which likely contributes to the observed functional attenuation with age, probably occurs through apoptotic mechanisms or as part of the normal aging process. Our previous findings,
20 therefore, suggest that because hyperoxia is of little consequence on the a-wave, photoreceptors are relatively well preserved and the normal cellular refinement of the outer retina that occurs with time (between P30 and P60) is not hampered under hyperoxic conditions. It is also of interest that, although delayed by 5 days, the maximum a-wave amplitude reached in hyperoxic rats is not significantly different from that reached in normal rats (attained at P19 in the normoxic cohort compared with P24 in the hyperoxic cohort). On the other hand, given the extreme damage generated by hyperoxia to the inner retina, which resulted in cellular dropout, reorganization of the inner retinal layers, and a severely depressed ERG b-wave, further deterioration of the retina with age was precluded. As early as P6, our results suggested a significantly lower number of apoptotic cells in the hyperoxic cohort compared with control (13.75 ± 3.40 vs. 42.25 ± 4.92;
P < 0.05), suggesting that at this early stage of hyperoxic exposure, cells that would normally have died as a result of the normal maturation process likely survived to replace those that were affected by an excessively rich oxygen environment. This might also explain the decreased severity of the retinopathy we observed after early exposure (P0–P6) with respect to retinal function and structure.
19,22,23 After exposure until P14, this “rescue” phenomenon could no longer be observed whereby apoptotic cell death was significantly higher in hyperoxic cohorts (
Figs. 10,
11). It has been shown that the rat retina exhibits an increased metabolic rate in the second to third week of life that is accompanied by a significant maturation phase.
51,52 Given that this enhanced metabolism has been associated with an increase in electron leaks in the mitochondria, thus leading to the facilitation of free radical generation, one could hypothesize that the number of available cells initially able to replace those that succumb to the hyperoxic environment would no longer be available as a replacement because of the combined effect of hyperoxia and maturation. Consequently, this could lead to both the permanent structural consequences we are currently reporting along with the functional consequences that we have previously described.
19 –24 Although the steps involved in this cascade of events remain to be fully understood, recent studies of ours have already begun to address the progressive evolution of the ultrastructural manifestations after the cessation of hyperoxia (at P15, P16, P17, P19, and P24) in SD
20 and LE rats (Dorfman A, et al.
IOVS. 2010;51:ARVO E-Abstract 5590). Our ongoing studies are aimed at better understanding the relationship between normal cellular refinement throughout the retinal maturation process and progressive cell loss and reorganization throughout the initial hyperoxic stress and the return to normoxia.