DPP-4 Inhibitors Attenuate Fibrosis After Glaucoma Filtering Surgery by Suppressing the TGF-β/Smad Signaling Pathway

Yoshida, Masaaki; Kokubun, Taiki; Sato, Kota; Tsuda, S.; Yokoyama, Yû; Himori, Noriko; Nakazawa, Toru

doi:10.1167/iovs.64.10.2

Cited by 3 publications

(1 citation statement)

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“…The timeline over which afferent line pressure increased suggested that fibroblast transdifferentiation into myofibroblasts slowly changed the characteristics of the ECM, progressively increasing its resistance to outflow. As additional ECM proteins were synthesized and remodeled through myofibroblast activity, microscopic flow channels inside the hydrogel likely stenosed and overall tissue patency decreased, similar to the failing filtration bleb (Figure 8) [30,31].…”

Section: Development Of a Three-dimensional Flow Modelmentioning

confidence: 97%

Development and Verification of a Novel Three-Dimensional Aqueous Outflow Model for High-Throughput Drug Screening

Fung,

Armstrong,

Zhang

et al. 2024

Bioengineering

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Distal outflow bleb-forming procedures in ophthalmic surgery expose subconjunctival tissue to inflammatory cytokines present in the aqueous humor, resulting in impaired outflow and, consequently, increased intraocular pressure. Clinically, this manifests as an increased risk of surgical failure often necessitating revision. This study (1) introduces a novel high-throughput screening platform for testing potential anti-fibrotic compounds and (2) assesses the clinical viability of modulating the transforming growth factor beta-SMAD2/3 pathway as a key contributor to post-operative outflow reduction, using the signal transduction inhibitor verteporfin. Human Tenon’s capsule fibroblasts (HTCFs) were cultured within a 3D collagen matrix in a microfluidic system modelling aqueous humor drainage. The perfusate was augmented with transforming growth factor beta 1 (TGFβ1), and afferent pressure to the tissue-mimetic was continuously monitored to detect treatment-related pressure elevations. Co-treatment with verteporfin was employed to evaluate its capacity to counteract TGFβ1 induced pressure changes. Immunofluorescent studies were conducted on the tissue-mimetic to corroborate the pressure data with cellular changes. Introduction of TGFβ1 induced treatment-related afferent pressure increase in the tissue-mimetic. HTCFs treated with TGFβ1 displayed visibly enlarged cytoskeletons and stress fiber formation, consistent with myofibroblast transformation. Importantly, verteporfin effectively mitigated these changes, reducing both afferent pressure increases and cytoskeletal alterations. In summary, this study models the pathological filtration bleb response to TGFβ1, while demonstrating verteporfin’s effectiveness in ameliorating both functional and cellular changes caused by TGFβ1. These demonstrate modulation of the aforementioned pathway as a potential avenue for addressing post-operative changes and reductions in filtration bleb outflow capacity. Furthermore, the establishment of a high-throughput screening platform offers a valuable pre-animal testing tool for investigating potential compounds to facilitate surgical wound healing.

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Section: Development Of a Three-dimensional Flow Modelmentioning

confidence: 97%