Cell signaling in regulation of the barrier integrity of the corneal endothelium

Abstract

The barrier integrity of the corneal endothelium, which is conferred by its tight and adherens junctions, is critical for the maintenance of deturgescence of the corneal stroma. Although characteristically leaky, the barrier integrity restricts fluid leakage into the stroma such that the rate of leak does not exceed the rate of the endothelial active fluid transport directed toward the aqueous humor. At a molecular level, the barrier integrity is influenced by the actin cytoskeleton and microtubules, which are coupled to tight and adherens junctions via a variety of linker proteins. Since the cytoskeleton is affected by Rho family small GTPases and p38 MAP kinase, among others, many pathophysiological stimuli induce plasticity to the cytoskeleton and thereby elicit dynamic regulation of the barrier integrity. This review presents an overview of the impact of several bioactive factors on the barrier integrity of the corneal endothelium through altered actin cytoskeleton and/or disassembly of microtubules. The main focus is on the effect of TNF-α (tumor necrosis factor-α) which is a pro-inflammatory molecule found in the intraocular milieu during allograft rejection and anterior uveitis. This cytokine elicits acute activation of p38 MAP kinase, induces disassembly of microtubules, disrupts the peri-junctional actomyosin ring, and concomitantly breaks down the barrier integrity. These effects of TNF-α could be inhibited by stabilizing the microtubules, co-treating with a selective p38 MAP kinase inhibitor, and elevating intracellular cAMP via A2B receptors or direct exposure to forskolin. Overall, the corneal edema following a potential breakdown of the endothelial barrier integrity can be rescued pharmacologically by inhibiting specific cell-signaling mechanisms.

Serine Protease Inhibitor A3K Protects Rabbit Corneal Endothelium From Barrier Function Disruption Induced by TNF-α

“…Accordingly, these responses contributed to barrier function disruption. 4 In accordance with the inhibitory effects of SA3K on vascularization, inflammation, fibrosis, and oxidative stress induced responses in the retina and cornea, it also reduced retinal vascular leakage in an oxygen-induced retinopathy model and also prevented hypoxia-induced declines in occludin 30 through blocking Wnt signaling pathway activation. 32,34 In this study, TNF-a induced p-MLC formation, while SA3K inhibited this effect.…”

Construction of a tissue-engineered human corneal endothelium and its transplantation in rabbit models

“…The existence of massive mitochondria and RERs explains a de novo generation of DM in the TE-HCE-transplanted rabbit corneas. All these indicate that the newly reconstructed corneal endothelium has the barrier integrity required for the barrier function of the endothelium, which might explain the successful maintaining of corneal transparency and thickness after TE-HCE transplantation (Davies et al, 1976;Srinivas, 2012). In summary, a high ECD TE-HCE constructed from nontransfected HCE cells and mdAM could maintain corneal transparency and thickness in rabbit models by reconstructing a native-like corneal endothelium with barrier integrity and high ECD, and might have potential applications in replacement therapies as an equivalent of HCE in the future.…”

“…the integrity of tight and adherens junctions, which might be disrupted in low density corneal endothelium (Srinivas, 2012;Singh et al, 2013). Therefore, enough intercellular junctions being established between corneal endothelial cells is another important indicator of endothelial keratoplasty (Schierhölter and Honegger, 1975).…”

Regenerative Cell Therapy for Corneal Endothelium

“…These highly metabolic cells form a barrier in part via tight junctions and demonstrate simple diffusion, facilitated diffusion and active transport mechanisms [3] that together establish a dynamic balance allowing fluid and nutrients to pass into the stroma, and drawing excess fluid and waste products out via active ATP- and bicarbonate-dependent ion pumps [4-6]. As a result, the stromal water content remains at a level that optimizes corneal transparency.…”