Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis
Guorong Li, Chan-Young Lee, A. Thomas Read, Ke Wang, Jung‐Min Ha, Megan Kuhn, Iris Navarro, Jenny Cui, Katherine Young, Rahul Gorijavolu, Todd Sulchek, Casey Kopczynski, Sina Farsiu, John R. Samples, Pratap Challa, C. Ross Ethier, W. Daniel Stamer
Abstract
Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.