Corneal Opacity: Cell Biological Determinants of the Transition From Transparency to Transient Haze to Scarring Fibrosis, and Resolution, After Injury

Abstract

Purpose To highlight the cellular, matrix, and hydration changes associated with opacity that occurs in the corneal stroma after injury. Methods Review of the literature. Results The regulated transition of keratocytes to corneal fibroblasts and myofibroblasts, and of bone marrow-derived fibrocytes to myofibroblasts, is in large part modulated by transforming growth factor beta (TGFβ) entry into the stroma after injury to the epithelial basement membrane (EBM) and/or Descemet's membrane. The composition, stoichiometry, and organization of the stromal extracellular matrix components and water is altered by corneal fibroblast and myofibroblast production of large amounts of collagen type I and other extracellular matrix components—resulting in varying levels of stromal opacity, depending on the intensity of the healing response. Regeneration of EBM and/or Descemet's membrane, and stromal cell production of non-EBM collagen type IV, reestablishes control of TGFβ entry and activity, and triggers TGFβ-dependent myofibroblast apoptosis. Eventually, corneal fibroblasts also disappear, and repopulating keratocytes reorganize the disordered extracellular matrix to reestablish transparency. Conclusions Injuries to the cornea produce varying amounts of corneal opacity depending on the magnitude of cellular and molecular responses to injury. The EBM and Descemet's membrane are key regulators of stromal cellularity through their modulation of TGFβ. After injury to the cornea, depending on the severity of the insult, and possibly genetic factors, trace opacity to severe scarring fibrosis develops. Stromal cellularity, and the functions of different cell types, are the major determinants of the level of the stromal opacity.

Therapeutic potential of topical administration of acriflavine against hypoxia-inducible factors for corneal fibrosis

“…(de Oliveira et al, 2021). The α-SMA expressing myofibroblast is mainly responsible for corneal fibrosis, and sometimes is differentiated from other cells (e.g., bone marrow-derived fibrocytes) in the stroma (Kempuraj and Mohan, 2022;Wilson et al, 2022). Corneal hypoxia caused by contact lens wear or inflammation, usually results in corneal neovascularization (CNV), which often severely compromises vision by decreasing the transparency of corneal stroma (Safvati et al, 2009).…”

“…Corneal hypoxia caused by contact lens wear or inflammation, usually results in corneal neovascularization (CNV), which often severely compromises vision by decreasing the transparency of corneal stroma (Safvati et al, 2009). The CNV-associated pericytes are α-SMA positive and have been found to have the capacity to transdifferentiate into myofibroblasts (Kostallari and Shah, 2019;Wilson et al, 2022). Therefore, under hypoxia conditions or serious corneal damage, multiple studies focused on the inhibition of CNV to prevent corneal opacity by blocking vascular endothelial growth factor (VEGF) receptors, attenuating inflammation or targeting the VEGF upstream regulator of HIF-1α (Peral et al, 2022).…”

The NLRP3 Activation in Infiltrating Macrophages Contributes to Corneal Fibrosis by Inducing TGF-β1 Expression in the Corneal Epithelium

“…Recent studies provide increasing evidence indicating that the enhanced TGF-β1 synthesis after a corneal injury is closely associated with the progression of ocular fibrosis. 41 – 43 Moreover, TGF-β1 and its receptors can inhibit the proliferation of corneal epithelial cells and stimulate the proliferation of mesenchymal fibroblasts. 44 – 46 Therefore, the increased synthesis of TGF-β1 at the injury site leads to increased myofibroblast differentiation, 47 delayed re-epithelialization, 48 , 49 and increased collagen gel contraction.…”

Advanced surgeries, medicines and materials for corneal regeneration

“…The ECM is composed of collagens and proteoglycans. The main type of collagen found in the corneal stroma is type I, but smaller amounts of type V, XI and XII collagens are also found 8 . The collagen fibres are organized in bundles called fibrils which are closely packed together in a parallel manner, to form a thin sheet called a lamella.…”

“…The collagen fibrils in the corneal stroma are highly organized and very small in diameter (25-30nm). The major fibrilforming collagens found in the corneal stroma are type I (80%-90%) and V (10%-20%) 8 . Each collagen fibril has both type I and V collagens, while collagen type V is important in initiating fibril assembly and regulating fibril diameter 11 .…”