42 EWAP DECEMBER 2023 CORNEA Minas T. Coroneo, MD Professor, UNSW Sydney 2 St. Pauls Street, Randwick NSW 2031, Australia m.coroneo@unsw.edu.au ASIA-PACIFIC PERSPECTIVES Given the critical importance of transparency of the normally avascular cornea, interventions to reduce scarring have surprisingly lagged behind this in internal and aesthetic medicine. Dr. Wilson’s commendable repurposing of the antihypertensive drug losartan, an angiotensin II (ATII) receptor blocker, is a welcome and timely innovation. One of three recent innovations in managing corneal transparency, recycling kEDTA from blood collection tubes for treating band keratopathy 1 and the development by Dr. Dean Ouano of mitomycin intravascular chemoembolization (MICE) for corneal neovascularization and lipid keratopathy, 2 we are at the beginning of a new era of medical treatment of corneal opacity, with potential combination of these treatment modalities. This path has the potential to safely salvage a proportion of opaque corneas with positive consequences for patients and in relation to demands on eye banks and health budgets. Corneal refractive surgery experience over decades has demonstrated that the cornea can usually heal with minimal scarring, a healing response to maintain tissue barriers and integrity. However, when the normally tightly coordinated regenerative response becomes pathologic, 3 the complexity of this process has generally defied universally successful interventions. An early indication that losartan inhibits scarring was in experimental models of renal fibrosis in the 1990s 4 and the effect was thought to be mediated via ATII pathways. An understanding of the role of losartan reducing TGF and other factors followed. Recent studies using topical losartan in the management of mammoplasty and abdominoplasty scars (in a well-controlled clinical trial) demonstrates both how seemingly positive results can be questioned 5 - 7 and how ophthalmology may be at an advantage with high quality imaging and reproducible outcome measures. Clearly, longer-term, well controlled studies with well-defined outcome measures are required. News of this development spread rapidly via the Cornea Society’s international Keranet group as issues relating to dosage, patient selection and treatment duration were sorted out. 8 Our clinical experience, still small, mirrors that of Dr Wilson with some notable exceptions: cases where excessive corneal tissue has been removed. In that scar tissue consists mainly of fibrillar collagen produced by myofibroblasts, their activators, including growth factors, such as TGF and PDGF; inflammation and a mechanical stress response, 8 all likely play a role in the cornea. Another potential factor is the role of stem cells, 9 including corneal stromal cells, particularly in cases where corneal tissue removal may have been excessive. While this appears to be a great step forward, and Paul Ehrlich’s first “magic bullet” led to advances, given the complexity of the scarring process, I suspect other measures will also be required and in fact, additive, beneficial effects of topical steroids have already been shown. 10 From an anterior segment perspective, improved management of conjunctival scarring is a critical area and of related interest is that in a rabbit model, losartan has been shown to attenuate scar formation of trabeculectomy-associated filtering blebs. 11 References 1. Lee ME, et al. “Off-the-Shelf” K2-EDTA for Calcific Band Keratopathy. Cornea. 2018 Jul;37(7):916-918. doi: 10.1097/ICO.0000000000001558. 2. Mimouni M, Ouano D. Initial outcomes of mitomycin intravascular chemoembolization (MICE) for corneal neovascularization. Int Ophthalmol. 2022 Aug;42(8):2407 -2416. doi: 10.1007/s10792 - 022 - 02240 - 6. 3. Karppinen SM, et al. Toward understanding scarless skin wound healing and pathological scarring. F1000Res. 2019 Jun 5;8:F1000 Faculty Rev-787. doi: 10.12688/ f1000research.18293.1. 4. Burdmann EA, et al. Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril. Am J Physiol. 1995 Oct;269(4 Pt 2):F491-9. doi: 10.1152/ajprenal.1995.269.4.F491. 5. Khodaei B, et al. Efficacy of Topical Losartan in Management of Mammoplasty and Abdominoplasty Scars: A Randomized, Double-Blind Clinical Trial. Aesthetic Plast Surg. 2022 Oct;46(5):2580 - 2587. doi: 10.1007/s00266 - 022 - 02935 - 2. 6. Tian F, et al. Comments on ‘’Efficacy of Topical Losartan in Management of Mammoplasty and Abdominoplasty Scars: A Randomized, Double-Blind Clinical Trial’’. Aesthetic Plast Surg. 2023 Jun;47(Suppl 1):114 -115. doi: 10.1007/s00266 - 022 - 03046 - 8. 7. Khodaei B, et al. Invited Response on: Comment: “Efficacy of Topical Losartan in Management of Mammoplasty and Abdominoplasty Scars: A Randomized, Double-Blind Clinical Trial”. Aesthetic Plast Surg. 2023 Jun;47(Suppl 1):133 -134. doi: 10.1007/s00266 - 022 - 03085 -1. 8. Erratum in: Topical Losartan and Corticosteroid Additively Inhibit Corneal Stromal Myofibroblast Generation and Scarring Fibrosis After Alkali Burn Injury. Transl Vis Sci Technol. 2022 Oct 3;11(10):30. doi: 10.1167/tvst.11.10.30. Erratum for: Transl Vis Sci Technol. 2022 Jul 8;11(7):9. 9. Hertsenberg AJ, Funderburgh JL. Stem Cells in the Cornea. Prog Mol Biol Transl Sci. 2015;134:25-41. doi: 10.1016/bs.pmbts.2015.04.002. 10. Shi H, et al. Losartan Attenuates Scar Formation in Filtering Bleb After Trabeculectomy. Invest Ophthalmol Vis Sci. 2017 Mar 1;58(3):1478-1486. doi: 10.1167/ iovs.16-21163. 11. Sampaio LP, et al. Topical Losartan and Corticosteroid Additively Inhibit Corneal Stromal Myofibroblast Generation and Scarring Fibrosis After Alkali Burn Injury. Transl Vis Sci Technol. 2022 Jul 8;11(7):9. doi: 10.1167/tvst.11.7.9. Erratum in: Transl Vis Sci Technol. 2022 Oct 3;11(10):30. Editors’ note: Dr. Coroneo disclosed no relevant financial interests.
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