Injury and defective regeneration of the epithelial basement membrane in corneal fibrosis: A paradigm for fibrosis in other organs?

Abstract

Myofibroblast-mediated fibrosis is important in the pathophysiology of diseases in most organs. The cornea, the transparent anterior wall of the eye that functions to focus light on the retina, is commonly affected by fibrosis and provides an optimal model due to its simplicity and accessibility. Severe injuries to the cornea, including infection, surgery, and trauma, may trigger the development of myofibroblasts and fibrosis in the normally transparent connective tissue stroma. Ultrastructural studies have demonstrated that defective epithelial basement membrane (EBM) regeneration after injury underlies the development of myofibroblasts from both bone marrow- and keratocyte-derived precursor cells in the cornea. Defective EBM permits epithelium-derived transforming growth factor beta, platelet-derived growth factor, and likely other modulators, to penetrate the stroma at sustained levels necessary to drive the development of vimentin+ alpha-smooth muscle actin+ desmin+ (V+A+D+) mature myofibroblasts and promote their persistence. Defective versus normal EBM regeneration likely relates to the severity of the stromal injury and a resulting decrease in fibroblasts (keratocytes) and their contribution of EBM components, including laminin alpha-3 and nidogen-2. Corneal fibrosis may resolve over a period of months to years if the inciting injury is eliminated through keratocyte-facilitated regeneration of normal EBM, ensuing apoptosis of myofibroblasts, and reorganization of disordered extracellular matrix by repopulating keratocytes. We hypothesize the corneal model of fibrosis associated with defective BM regeneration and myofibroblast development after epithelial or parenchymal injury may be a paradigm for the development of fibrosis in other organs where chronic injury or defective BM underlies the pathophysiology of disease.

Fibrocytes, Wound Healing, and Corneal Fibrosis

“…The cornea is the transparent anterior wall of the eye that, along with the lens, focuses light on the retina. 82 Fibrocytes have been shown to participate in the cornea wound healing response to injury that can lead to stromal fibrosis. The immunohistochemical study of fibrocytes in the cornea is challenging since an important marker for detection of fibrocytes is collagen type I, 6 and the normal corneal stroma itself contains large amounts of collagen type I.…”

“…After many types of injuries of the cornea, including trauma, infection and surgery, depending on the severity, induced surface irregularity, and likely genetic factors, the wound healing process results in development of mature myofibroblasts and fibrosis in the normally transparent connective tissue stroma. 82 Damage of basement membrane (epithelial basement membrane or Descemet's endothelial basement membrane) and delayed or aborted regeneration underlies the development of corneal fibrosis. 81 Defective BM permits TGF-β 1 , PDGF, and likely other modulators, derived from tears and epithelium or aqueous humor and endothelium, to penetrate the stroma at sustained levels necessary to drive the development of precursor cells into myofibroblasts that generate disordered extracellular matrix and fibrosis.…”

“…78,84 Normal versus defective BM regeneration likely relates to the type and severity of the stromal injury and results from inadequate production or incorrect localization of BM components-including laminins, nidogens, perlecan, and collagen type IV. 82,91 Corneal epithelial injury triggers release of IL-1 and apoptosis of the underlying keratocytes mediated by Fas-Fas ligand system in a manner that is proportional to the size of the original injury. 92 Extensive loss of keratocytes delays BM regeneration because of a deficiency or inadequate localization of some BM components contributed by keratocytes to the EBM.…”

“…92 Extensive loss of keratocytes delays BM regeneration because of a deficiency or inadequate localization of some BM components contributed by keratocytes to the EBM. 82,93 Bianchetti et al 71 suggest that fibrocytes may also contribute to a thickening of the EBM by also producing BM components; however, more work is needed to validate this contribution to corneal BM regeneration. In addition, injuries that produce corneal stromal surface irregularity promote fibrosis by mechanically impeding BM regeneration-and thereby augmenting TGFβ 1 and PDGF penetration into the stroma to drive myofibroblast development and their persistence.…”

“…In addition, injuries that produce corneal stromal surface irregularity promote fibrosis by mechanically impeding BM regeneration-and thereby augmenting TGFβ 1 and PDGF penetration into the stroma to drive myofibroblast development and their persistence. 82,94 After corneal infection, trauma or surgery, keratocytes in proximity to the injury are "activated" by released growth factors, such as TGF-β 1 to transform into "corneal fibroblasts" that neither express the keratocyte marker keratocan nor the myofibroblast marker αSMA. 82 Moreover, bone marrow progenitors cells are also stimulated by growth factors to differentiate into fibrocytes.…”