生物力學對眼前房的病生理影響：從臨床到實驗室

Abstract

我們的研究旨在探討生物力學對前房病理生理的影響。首先，我們發現osteogenesis imperfecta患者在Corvis biomechanical index (CBI) 和tomographic and biomechanical index (TBI)較正常人更高，而Corvis biomechanical factor (CBiF)則較低。這些結果表明，角膜膠原缺陷對角膜的穩定性有很大影響。因為前房的力學穩定性降低可能導致擁擠的前房內虹膜和小樑網的接觸增加，我們進一步研究前房的力學穩定性是否與房角閉塞的發生有關。我們發現原發性閉角型青光眼患者的CBiF較正常人低。多變量邏輯回歸分析顯示CBiF較低與原發性閉角型青光眼的發生機率增加有關。與僅使用前房體積(ACV)相比，ACV和CBiF的結合在檢測原發性閉角型青光眼方面具有更好的診斷性能。

根據這些臨床研究的結果，我們認識到有必要進一步研究前房生物力學對眼內壓的調節作用。小樑網透過控制房水排出在眼內壓調節中起著關鍵作用，然而，小樑網細胞對機械力的反應機制尚未完全理解。我們發現拉伸會引發感應機械力的轉錄因子YAP/TAZ和MRTF-A的核轉位，暗示基因表達的改變。此外，拉伸顯著增強了p38和MK2的磷酸化，表明p38-MK2信號通路被激活。值得注意的是，使用SB203580抑制p38可以抑制拉伸引起的一氧化氮生成。綜上所述，這些發現表明p38信號通路作為感應器，將拉伸的機械信號傳遞到小樑網細胞中，以調節一氧化氮的生成。

這項研究為我們對眼內壓調節中拉伸誘導的分子機制提供了新的見解。進一步研究p38誘導的下游反應和轉錄活性可能揭示創新的青光眼治療方法的分子標靶。

We aimed to investigate the impact of biomechanics on the pathophysiology of the anterior chamber. Firstly, we revealed that OI patients exhibited higher Corvis biomechanical index (CBI) and tomographic and biomechanical index (TBI), and lower Corvis Biomechanical Factor (CBiF) compared to healthy controls. These findings suggest that corneal collagen defect greatly affects the stability of the cornea. Consequently, we investigated whether the stability of anterior chamber could be associated with the occurrence of angle closure, as the impaired biomechanical stability of the anterior chamber may lead to iridotrabecular contact in crowded anterior chamber. We demonstrated that primary angle closure glaucoma (PACG) patients had lower CBiF compared to normal controls. Multivariable logistic regression analysis revealed that a lower CBiF was associated with higher odds of PACG. The combination of anterior chamber volume (ACV) and CBiF exhibited superior diagnostic performance in detecting PACG compared to ACV alone.

Based on the above clinical study findings, we recognized the need for additional research into the biomechanics of anterior chamber in regulating intraocular pressure. The trabecular meshwork plays a critical role in intraocular pressure regulation through aqueous humor drainage, yet the mechanisms underlying trabecular meshwork cell response to mechanical forces remain incompletely understood. We revealed that stretch stress activated nuclear translocation of mechanosensitive transcription cofactors YAP/TAZ and MRTF-A, indicating functional nuclear remodeling. Moreover, uniaxial cyclic stretch significantly enhanced p38 and MK2 phosphorylation, suggesting activation of the p38-MK2 signaling pathway. Notably, pharmacological inhibition of p38 using SB203580 mitigated stretch-induced nitric oxide production. Collectively, these findings indicate that the p38 pathway acts as a mechanosensor, transducing mechanical cues from stretch stress to modulate nitric oxide generation in TM cells.

This study provides novel insights into the role of p38 signaling in intraocular pressure regulation. Further research on downstream signaling events and transcriptional networks elicited by stretch induced p38 activation will likely unveil additional molecular targets for innovative glaucoma treatments.