Topical losartan inhibits corneal scarring fibrosis and collagen type IV deposition after Descemet's membrane-endothelial excision in rabbits

Sampaio, Lycia Pedral; Hilgert, Guilherme Simões Luz; Shiju, Thomas Michael; Murillo, Sofia; Santhiago, Marcony R.; Wilson, Steven E.

doi:10.1016/j.exer.2022.108940

Cited by 37 publications

(30 citation statements)

References 40 publications

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“…AB769; Millipore, Temecula, CA, USA) was raised against purified human and bovine collagen type IV that had been affinity purified with human and bovine collagen type IV crosslinked to agarose and cross-absorbed by the manufacturer with human and bovine collagens type I, II, III, V, and VI to eliminate cross-reactivity. This collagen type IV antibody was shown previously to bind rabbit collagen IV in IHC 7 , 22 and recognizes the α-1/α-2 chains but not the α-3 to α-6 chains. Winston Kao, PhD, gifted the keratocan antibody raised against peptide H2N-LRLDGNEIKPPIPIDLVAC-OH.…”

Section: Methodsmentioning

confidence: 97%

“… 4 – 6 Losartan is an angiotensin-converting enzyme II receptor antagonist that has been shown in numerous studies to inhibit TGF-β signaling. 7 – 13 The specific mechanism(s) through which losartan inhibits TGF-β signaling have not been fully characterized. One study found that losartan interfered with the SMAD signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“…Another study demonstrated that topical, but not oral, losartan decreased TGF-β–mediated myofibroblast development and stromal fibrosis after removal of the central Descemet's membrane and corneal endothelial complex (descemetorhexis) in rabbits. 7 …”

Section: Introductionmentioning

confidence: 99%

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Topical Losartan and Corticosteroid Additively Inhibit Corneal Stromal Myofibroblast Generation and Scarring Fibrosis After Alkali Burn Injury

Sampaio

Hilgert

Shiju

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose To evaluate the efficacy of losartan and prednisolone acetate in inhibiting corneal scarring fibrosis after alkali burn injury in rabbits. Methods Sixteen New Zealand White rabbits were included. Alkali injuries were produced using 1N sodium hydroxide on a 5-mm diameter Whatman #1 filter paper for 1 minute. Four corneas in each group were treated six times per day for 1 month with 50 µL of (1) 0.8 mg/mL losartan in balanced salt solution (BSS), (2) 1% prednisolone acetate, (3) combined 0.8 mg/mL losartan and 1% prednisolone acetate, or (4) BSS. Area of opacity and total opacity were analyzed in standardized slit-lamp photos with ImageJ. Corneas in both groups were cryofixed in Optimal cutting temperature (OCT) compound at 1 month after surgery, and immunohistochemistry was performed for alpha-smooth muscle actin (α-SMA) and keratocan or transforming growth factor β1 and collagen type IV with ImageJ quantitation. Results Combined topical losartan and prednisolone acetate significantly decreased slit-lamp opacity area and intensity, as well as decreased stromal myofibroblast α-SMA area and intensity of staining per section and confined myofibroblasts to only the posterior stroma with repopulation of the anterior and mid-stroma with keratocan-positive keratocytes after 1 month of treatment. Corneal fibroblasts produced collagen type IV not associated with basement membranes, and this production was decreased by topical losartan. Conclusions Combined topical losartan and prednisolone acetate decreased myofibroblast-associated fibrosis after corneal alkali burns that produced full-thickness injury, including corneal endothelial damage. Increased dosages and duration of treatment may further decrease scarring fibrosis. Translational Relevance Topical losartan and prednisolone acetate decrease myofibroblast-mediated scarring fibrosis after corneal injury.

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Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Topical Losartan and Corticosteroid Additively Inhibit Corneal Stromal Myofibroblast Generation and Scarring Fibrosis After Alkali Burn Injury

Sampaio

Hilgert

Shiju

et al. 2022

Trans. Vis. Sci. Tech.

Self Cite

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“…Anti-vascular endothelial growth factor (VEGF) treatments with bevacizumab and ranibizumab have been shown to prevent corneal vascularization [ 51 ] and enhance transplant graft survival [ 52 ]. Pharmaceutical options, such as topical MMC [ 53 ] and losartan [ 54 ], have been shown to aid in vivo corneal wound-healing response during surgeries prone to causing fibrosis, respectively. However, sufficient long-term clinical trials are lacking.…”

Section: What Is the Clinical Relevance Of Corneal Scarring/fibrosis?mentioning

confidence: 99%

“…In the cornea, bidirectional communication between the corneal epithelium and stroma plays a critical role in corneal wound repair. The aberrant activation of multiple processes that includes cell death, migration, proliferation; myofibroblast differentiation; and ECM remodeling can lead to corneal fibrosis that is accompanied with inflammation and neovascularization [ 8 , 12 , 31 , 33 , 36 , 54 ]. It is increasingly understood that cell-to-cell communication by paracrine mechanism(s), precisely by EVs have shown to influence physiological and pathological responses in relation to corneal wound healing.…”

Section: What Roles Do Extracellular Vesicles Play In Corneal Fibrosi...mentioning

confidence: 99%

Extracellular Vesicles in Corneal Fibrosis/Scarring

Yeung

Boychev

Farhat

et al. 2022

IJMS

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Communication between cells and the microenvironment is a complex, yet crucial, element in the development and progression of varied physiological and pathological processes. Accumulating evidence in different disease models highlights roles of extracellular vesicles (EVs), either in modulating cell signaling paracrine mechanism(s) or harnessing their therapeutic moiety. Of interest, the human cornea functions as a refractive and transparent barrier that protects the intraocular elements from the external environment. Corneal trauma at the ocular surface may lead to diminished corneal clarity and detrimental effects on visual acuity. The aberrant activation of corneal stromal cells, which leads to myofibroblast differentiation and a disorganized extracellular matrix is a central biological process that may result in corneal fibrosis/scarring. In recent years, understanding the pathological and therapeutic EV mechanism(s) of action in the context of corneal biology has been a topic of increasing interest. In this review, we describe the clinical relevance of corneal fibrosis/scarring and how corneal stromal cells contribute to wound repair and their generation of the stromal haze. Furthermore, we will delve into EV characterization, their subtypes, and the pathological and therapeutic roles they play in corneal scarring/fibrosis.

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Classic lattice corneal dystrophy: a brief review and summary of treatment modalities

Milovanova,

Gomon,

Rocha

2023

Graefes Arch Clin Exp Ophthalmol

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Topical losartan inhibits corneal scarring fibrosis and collagen type IV deposition after Descemet's membrane-endothelial excision in rabbits

Cited by 37 publications

References 40 publications

Topical Losartan and Corticosteroid Additively Inhibit Corneal Stromal Myofibroblast Generation and Scarring Fibrosis After Alkali Burn Injury

Topical Losartan and Corticosteroid Additively Inhibit Corneal Stromal Myofibroblast Generation and Scarring Fibrosis After Alkali Burn Injury

Extracellular Vesicles in Corneal Fibrosis/Scarring

Classic lattice corneal dystrophy: a brief review and summary of treatment modalities

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