Editors Selection IGR 21-1

Basic Science: Trabecular Meshwork Response to High IOP

Paul Kaufman

Comment by Paul Kaufman on:

84633 Elevated pressure influences relative distribution of segmental regions of the trabecular meshwork, Vranka JA; Staverosky JA; Raghunathan V et al., Experimental Eye Research, 2020; 190: 107888

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The article by Vranka et al. is the latest in a long line of work emanating from the group led by Ted Acott at the Oregon University of Health & Science. Their go-to experimental model, the perfused human organ-cultured anterior segment (HOCAS) allows measurement of conventional outflow pathway resistance and its ability to change according to the pressure challenge presented to it, manifested by the normalized flow rate over time. Adding fluorescently-labeled amine modified 200nm red and green Fluospheres to the perfusate allows quantifiable visualization and regionalization of outflow around the entire circumference. Thus, high flow (HF), intermediate flow (MF) and low flow (LF) regions can be identified, quantified and localized.

At 8.8 mmHg in ten normal eyes, HF, MF and LF regions respectively comprised ~15%, 35% and 45% of the circumference, with little change from day one to day eight of perfusion. At 17.6 mmHg in six normal eyes, on day one, HF, MF and LF regions respectively comprised 20%, 20% and 60 % of the circumference, while on day eight the distribution was ~10%, 45% and 45%. Thus, at the higher pressure challenge, there was a larger 'redistribution' of flow over time. The data were analyzed for statistical significance by one-way ANOVA with Tukey test for multiple comparisons and using a paired t-test (mean of the difference in the right versus the left eye, N = 8) for the pairs of eyes that were both flowed at a continuous 1x perfusion pressure, as well as for those pairs of eyes in which one was flowed continuously at 1x pressure and the other eye from the same donor was flowed continuously at 2x pressure.

The 'take-away' message from the authors is that the conventional outflow pathway not only provides the resistance required to generate an intraocular pressure needed to maintain the shape of the globe for optical clarity, but also regionally redistributes resistance around its circumference in an attempt to maintain homeostasis when confronted with a pressure challenge. This expands the concept of the conventional outflow pathway as a 'sentient being' with regulatory functions at a molecular/cellular level (think actomyosin contractility mediated via the rho pathway, with NO as a signaling molecule, giving us ocular hypotensive drugs like rho kinase inhibitors and nitric oxide donators) and at a more macro level.

Caveats: Despite the relatively small sample sizes / number of eyes studied, the differences found under the different conditions were statistically significant. That said however, one must still be cautious about generalizing into a major regulatory mechanism from such a small number of eyes, with some twists and turns around the data and their interpretation. Other complicating factors may be the old age (range 65-90 years, mean 77.6 + 3.0 yrs) and the length of time from death to stationary culture (up to 48hrs); these parameters may affect the regulatory responses being studied despite 'the anterior segments being initially placed into serum-free stationary organ culture for 5-7 days to facilitate postmortem recovery'.

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