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Colm J O'Brien, Rory Murphy, Mustapha Irnaten, Alan Hopkins; The role of lamina cribrosa tissue stiffness as a fundamental biomechanical driver of pathological glaucomatous cupping. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6187.
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© ARVO (1962-2015); The Authors (2016-present)
The primary biomechanical driver of pathological glaucomatous cupping remains unknown, finite element modelling suggests stress and strain play an important role. We utilised previously published biomechanical data and currently unpublished results from experimental three-dimensional (3D) contraction assays to assess whether normal and glaucoma lamina cribrosa (LC) cells respond differently in support of our stiffness driven paradigm.
We propose three stages which account for glaucomatous change occurring at variable levels of translaminar pressure (TLP). TLP induces a strain on the LC and beyond a critical level of strain the stiffness rises steeply provoking cellular responses. Integrin mediated mechanotransduction allows for early/acute and chronic/profibrotic response to elevated stiffness. These responses involve early mechanoprotective cellular contraction. We conducted 3D collagen gel contraction studies to assess for differences in normal or glaucomatous LC cells.
In our paradigm the first stage relates to short-term elevation of TLP. The second two stages show progression to a chronic positive feedback loop of increasing stiffness and persistent profibrotic gene activation. The short-term response involves cellular contraction to mechanically reduce the strain which in turn reduces tissue stiffness. The collagen gel contraction assay showed that both normal and glaucoma LC cells contracted the collagen gel but in normal LC cells this was significantly (P<0.05) greater (3.37 ± 0.38 mm) compared to Glaucoma LC cells (2.73 ± 0.26 mm) after 48h incubation. In rationalising the chronic profibrotic response to increased TLP, we reviewed the ONH biomechanical determinants with a focus on the LC biological structure and explored the role of integrin mechanotransduction.
Our three stages are: 1) In response to TLP induced elevated stiffness there is an ECM and contractile response which reduces strain and therefore stiffness. 2)Over time prolonged ECM response leads to fibrosis and increased tissue stiffness with an associated reduction in protective contractility supported by our data. 3) Continuing fibrosis with increased stiffening induces a feed-forward cycle of further ECM production, supported by a post-mortem study which showed worsening fields with increased stiffness (Zeimer and Ogura, 1989,Arch. Ophthalmol. 107, 1232–1234)
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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