Retinal oxygen: from animals to humans

https://doi.org/10.1016/j.preteyeres.2017.01.003Get rights and content

Abstract

This article discusses retinal oxygenation and retinal metabolism by focusing on measurements made with two of the principal methods used to study O2 in the retina: measurements of PO2 with oxygen-sensitive microelectrodes in vivo in animals with a retinal circulation similar to that of humans, and oximetry, which can be used non-invasively in both animals and humans to measure O2 concentration in retinal vessels. Microelectrodes uniquely have high spatial resolution, allowing the mapping of PO2 in detail, and when combined with mathematical models of diffusion and consumption, they provide information about retinal metabolism. Mathematical models, grounded in experiments, can also be used to simulate situations that are not amenable to experimental study. New methods of oximetry, particularly photoacoustic ophthalmoscopy and visible light optical coherence tomography, provide depth-resolved methods that can separate signals from blood vessels and surrounding tissues, and can be combined with blood flow measures to determine metabolic rate. We discuss the effects on retinal oxygenation of illumination, hypoxia and hyperoxia, and describe retinal oxygenation in diabetes, retinal detachment, arterial occlusion, and macular degeneration. We explain how the metabolic measurements obtained from microelectrodes and imaging are different, and how they need to be brought together in the future. Finally, we argue for revisiting the clinical use of hyperoxia in ophthalmology, particularly in retinal arterial occlusions and retinal detachment, based on animal research and diffusion theory.

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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