Retinal oxygen: from animals to humans
Section snippets
Importance of the oxygen supply to the retina
Like other parts of the nervous system, the retina requires a continuous supply of oxygen. If the circulation is completely cut off by a sudden increase of intraocular pressure (IOP) to levels above systemic arterial pressure, vision in humans stops in only 4–9 s (Anderson and Saltzman, 1964, Carlisle et al., 1964). The fact that this can be slightly prolonged by inspiration of pure O2 (at 1 amosphere absolute pressure - ATA) to 6–12 s, or to 16–25 s with O2 at 2 ATA (Anderson and Saltzman, 1964
Approaches to retinal oxygen
One can take several approaches to measuring O2 in the retina in vivo (Harris et al., 2003, Hogeboom van Buggenum et al., 1996, Linsenmeier, 2012). These include i) measurements of phosphorescence lifetime of an intravascular (or more recently extravascular) porphyrin-based dye whose lifetime is inversely proportional to the local PO2 (Shahidi et al., 2006, Shahidi et al., 2010), ii) MRI measurements of relative PO2 (Berkowitz, 1996, Berkowitz et al., 2001, Cheng et al., 2006), iii) optical
Fundamentals of O2 supply to the retina
As we have implied in section 2, the retina can be considered to have two domains from the point of view of vasculature and metabolism, the inner and outer retina. The outer avascular retina consists entirely of photoreceptors and Muller cell processes, while the vascularized inner retina, beginning at the outer plexiform layer, consists of the inner nuclear and ganglion cell layers, the two plexiform layers, and the nerve fiber layer. Except in the fovea, where there is no inner retina, the
Hypoxia
Experimental hypoxia is usually produced by lowering the inspired oxygen fraction. Because the retinal and choroidal circulations behave differently in response to systemic hypoxia, PO2 in the outer and inner retina behaves differently as well. The choroidal circulation does not appear to regulate according to the metabolic needs of the outer retina, and its resistance is not thought to change during hypoxia (Bill, 1962), although there has been very little work on this. Choroidal blood flow
Integrating oximetry and microelectrode measurements
With the advances allowed by phosphorescence imaging, PAOM or vis-OCT, more accurate measurements of retinal sO2 have become possible, leading to measurements of IR-MRO2 in animals (Wanek et al., 2011, Wanek et al., 2013, Yi et al., 2015b) and paving the way for measurements in humans. There have been measurements of IR-MRO2 using reflectance oximetry in humans as well (Palkovits et al., 2014a, Palkovits et al., 2014c, Werkmeister et al., 2015). Nevertheless, important challenges remain. One is
Oxygen and diabetes
Attempts to understand the role of O2 in diabetic retinopathy go back several decades and there are many hypotheses about mechanisms (Frank, 2004, Stefansson, 1990, Stitt et al., 2016), but our understanding is still not complete. There are several issues to be considered with respect to O2: 1) whether the retina is hypoxic in diabetes, and if so, when it begins; 2) how to interpret recent work on the protective effects of illumination; and 3) how panretinal photocoagulation and vitrectomy
Oxygen in retinal artery occlusion
Central or branch retinal artery occlusion is a condition for which there is no accepted treatment (Hayreh, 2011), but where O2 could probably play a larger role. It has been demonstrated several times that if the retinal circulation is occluded, which makes the entire thickness of the inner retina anoxic, then inspiration of 100% O2 can bring inner retinal or vitreal PO2 back to nearly normal values in cat and monkey retina (Alder et al., 1990, Braun and Linsenmeier, 1995, Landers, 1978). One
Oxygen and retinal detachment
In retinal detachment the gap between the choroidal circulation and the photoreceptors increases dramatically, and, while there is no tissue that consumes O2 under the detachment, the distance alone is a problem, because it reduces the flux of O2. As a consequence of the lack of O2 and possibly other factors, photoreceptors undergo a number of changes, and also die (Delolme et al., 2012, Fisher et al., 2005, Nork et al., 1995) and there is an activation of Muller cells (Lewis et al., 1999).
Oxygen and AMD
Age-related macular degeneration (AMD) takes two forms, one characterized by drusen and loss of photoreceptors and RPE cells (dry AMD progressing to geographic atrophy), and the other characterized by choroidal neovascularization (wet AMD), and while potentially related, these need to be considered separately here. No PO2 measurements have been made in either type of AMD, which do not naturally occur in animals. Both forms are complicated, with a number of simultaneous changes (Bhutto and
Challenges
The understanding of PO2 and metabolism of the retina has progressed tremendously in the last 30 years, but there is still much more to do. Limitations of our current knowledge have been mentioned throughout and only a few of these will be highlighted here.
Acknowledgements
Many colleagues, students and postdoctoral fellows were critical to the work presented here. In addition, we acknowledge support from NIH R01 EY05034 (RAL), NIH R01 EY021165 (RAL), NIH R01 EY019951 (HFZ), R24 EY022883 (HFZ), and DP3DK108248 (HFZ); NSF grants DBI-1353952 (HFZ) and CBET-1055379 (HFZ); NIH T32 EY007128, and an unrestricted grant to Northwestern University from Research to Prevent Blindness.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Linsenmeier 80%, Zhang 20%.