The Role of Lamina Cribrosa Tissue Stiffness and Fibrosis as Fundamental Biomechanical Drivers of Pathological Glaucomatous Cupping

Alan A Hopkins, Rory Murphy, Mustapha Irnaten, Deborah M Wallace, Barry Quill, Colm 'Brien
American Journal of Physiology. Cell Physiology 2020 July 15
The primary biomechanical driver of pathological glaucomatous cupping remains unknown. Finite element modelling indicates that stress and strain play key roles. Primarily a review article we utilise known biomechanical data and currently unpublished results from our lab to propose a 3 stage, tissue stiffness-based model to explain glaucomatous cupping occurring at variable levels of translaminar pressure (TLP). In stage 1, a short-term increase in TLP gradient induces a transient increase in LC strain. Beyond a critical level of strain, the tissue stiffness rises steeply provoking cellular responses via integrin mediated mechanotransduction. This early mechanoprotective cellular contraction reduces strain which reduces tissue stiffness by return of the posteriorly deflected LC to baseline. In stage 2 a prolonged period of TLP increase elicits extracellular matrix (ECM) production leading to fibrosis, increasing baseline tissue stiffness and strain, and diminishing the contractile ability/ ability to return to the baseline LC position. This is supported by our 3D collagen contraction assays which show significantly reduced capacity to contract in glaucoma compared to normal LC cells. Secondly, 15% cyclic strain in LC cells over 24 hours elicits a typical increase in ECM profibrotic genes in normal LC cells, but a highly blunted response in glaucoma LC cells. Stage 3 is characterised by persistent fibrosis causing further stiffening and inducing a feed-forward ECM production cycle. Repeated cycles of increased strain and stiffness with profibrotic ECM deposition, prevent optic nerve head (ONH) recoil from the new deflected position. This incremental maladaptive modelling leads to pathological ONH cupping.

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