Inhibition of Scarring Fibrosis and Neovascularization After Corneal Injury
Abstract
The cornea is the clear front wall of the eye that transmits and focuses vision on the retina. Corneal injuries caused by trauma (such as explosions, projectiles, or rifle butts), chemical burns, or infections (with bacteria, viruses, fungus or acanthamoeba) are an important cause of vision loss or blindness in military personnel or non-military individuals. Usually, this vision loss or blindness is caused by scarring in the cornea that makes it cloudy. This cloudiness results from the development of cells called myofibroblasts that are not normally found in the cornea. These cells produce scarring when they accumulate in the central part of the cornea, called the stroma, and produce disordered collagens and other materials that decrease the transparency in the cornea. Pioneering studies in our laboratory have shown that damage to the connective tissue the surface epithelial cells sit on at the front surface of the cornea (epithelial basement membrane) or the connective tissue the endothelial cells sit on at the back surface of the cornea (Descemet s basement membrane) causes special immune cells to migrate into the cornea from the blood vessels at the edge of the cornea. These cells, called fibrocytes, and also cells produced locally called corneal fibroblasts, change into myofibroblasts, if the injuries to either one or both of the basement membranes in the cornea are severe, because soluble proteins called transforming growth factor betas (TGF betas) can then gain long-term entry into the center of the cornea from the tears, injured corneal skin (epithelium), or the fluid behind the cornea in the anterior chamber called the aqueous humor. Our studies have shown the myofibroblasts will stay in the cornea for many months or years unless the damaged basement membrane (or both damaged basement membranes) is repaired or replaced. Studies supported by our prior Department of Defense Vision Research Program grant showed conclusively that topical, but not oral, losartan inhibits the development of myofibroblasts and collagen production by myofibroblasts after posterior injury to the corneal endothelium and Descemet s membrane (Descemetorhexis), since losartan interferes with the TGF beta signals to the cells that give rise to myofibroblasts and also to the myofibroblasts themselves. Losartan, a drug approved by the Food and Drug Administration, is taken by millions of people to control high blood pressure, but it also has a documented effect of inhibiting TGF beta signaling. There is no drug currently available that significantly inhibits the development of myofibroblasts and their production of disordered collagens. Corticosteroids applied to the cornea decrease inflammation but have little effect on myofibroblast development or disordered collagen production by these cells after corneal injury. In preparation for trials in humans with corneal injuries, in the present grant we will determine whether losartan also decreases corneal scarring after anterior corneal injuries such as corneal blast injuries, alkali burns, and corneal lacerations that are common in soldiers, sailors, and airmen. It will also ascertain the optimal frequency of administration in rabbit models simulating corneal blast injury (using an excimer laser to produce an irregular corneal surface that interferes with regeneration of the epithelial basement membrane) and in corneal lacerations that extend from the edge to the center of the cornea. We anticipate losartan will have this effect in these other models because they are much more anterior in the cornea and the topical losartan can better penetrate into the anterior cornea. We will also determine whether the losartan is effective when given a month after the original corneal alkali burn because many patients injured in battle have a delay in receiving ophthalmology care. The normal cornea does not have blood vessels in its center since it must be transparent to carry out its normal fu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210745
Entities
People
- Steven E. Wilson
Organizations
- Cleveland Clinic
- United States Army