The New Therapeutic Concept of Using a Rho Kinase Inhibitor for the Treatment of Corneal Endothelial Dysfunction

Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Cornea (Impact Factor: 2.04). 10/2011; 30 Suppl 1(Suppl 1):S54-9. DOI: 10.1097/ICO.0b013e3182281ee1
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Corneal endothelial cells (CECs) show poor regenerative ability in humans, and noncompensatory damage of CECs causes irreversible corneal haziness in cases of bullous keratopathy. Although corneal transplantations provide considerable clinical benefits, allograft rejection, primary graft failure, and the shortage of donor corneas are problems that still need to be overcome. The establishment of new treatment therapies is the key to solving these problems, and we have attempted to establish a new clinical intervention for corneal endothelial dysfunction. We previously demonstrated that the inhibition of Rho/Rho kinase (ROCK) signaling by Y-27632, a specific ROCK inhibitor, promoted cell adhesion, inhibited apoptosis, and enhanced cell proliferation in cultured primate CECs. These results raise the possibility that the ROCK inhibitor might serve as a new tool for establishing an effective culture method for newly emerging cultivated CEC transplantation therapies. Moreover, because Y-27632 enhances cell proliferation in vitro, we hypothesized that the use of a ROCK inhibitor could be a new pharmacological intervention for the treatment of corneal endothelial dysfunction. We demonstrated that the topical instillation of a ROCK inhibitor promotes corneal endothelium wound healing in an animal model. This indicates that use of a ROCK inhibitor is a less invasive and novel therapy that should prove promising for the treatment of corneal endothelial dysfunction.

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Available from: Naoki Okumura, Jul 07, 2015
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    • "When HCE cells are damaged due to various causes (e.g., viral infection, intraocular surgery, or Fuchs dystrophy), corneal endothelial dysfunction occurs. Currently, such damage can be repaired only with corneal transplantation [3-5], although a specific Rho/Rho kinase inhibitor has potential for the treatment of corneal endothelial dysfunction [6]. Unfortunately, a very limited number of healthy donor corneas are available for corneal transplantation worldwide [7]. "
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    ABSTRACT: Activation of cytoskeleton regulator Rho-kinase during inflammatory stimulations plays a major role in cellular dysfunction and apoptosis. Because endothelial dysfunction may be influenced by increased circulating membrane microparticles (MPs), we hypothesized that inhibition of Rho-kinase can prevent interferon-α (IFN-α)-induced endothelial cell (EC) apoptosis and that protective effects of Rho-kinase inhibition are facilitated by prevention of F-actin rearrangement. In this study, Lewis rats were subjected to an intraperitoneal injection of IFN-α or IFN-α + Y-27632. FCM was performed to analyze circulating endothelial MPs (EMPs) from the blood samples of these animals by detecting the expression of CD144, CD62E, CD31, CD51, and CD54 on EMPs. IFN-α-induced pulmonary injury was assessed by measurement of lung wet-to-dry weight ratios and measurement of alveolar wall thickness. Human pulmonary microvascular ECs (HPMECs) were cultured with IFN-α or EMPs to elucidate the probable mechanisms of the release of EMPs. Injection of IFN-α resulted in much higher levels of CD144 EMPs, CD62E EMPs, CD31 EMPs, CD51 EMPs, and CD54 EMPs. Pulmonary injury was also observed after injection of IFN-α. Furthermore, IFN-α induced F-actin rearrangement and apoptosis of HPMECs in vitro, and the Toll-like receptor 4/MyD88 and nuclear factor-κB pathways and EMPs per se played important roles in this process. The results demonstrate that increased Rho-kinase activity causes the release of EMPs and cellular apoptosis. Moreover, HPMEC apoptosis that resulted from EMP stimulation indicates that EMPs can be considered as a potential target to regulate the rearrangement of cytoskeleton during endothelial cell apoptosis.
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