A new perspective on the pathobiology of keratoconus: interplay of stromal wound healing and reactive species‐associated processes

Abstract

Severe loss of vision manifests from the corneal protrusion, thinning and distortion that characterises keratoconus, which in its most severe form is still treated primarily by lamellar or penetrating keratoplasty. Unfortunately, alternative therapeutic options targeting the underlying pathobiology remain limited, attributable to an incomplete understanding of the biological mechanisms instigating stromal deterioration and other disease processes. We postulate that underlying abnormalities in stromal repair and reactive species-linked activities and the interaction between these phenomena are implicated in the development of keratoconus. This revised interpretation of the pathophysiology may, with further investigation, advance our knowledge and the clinical management of this prevalent ectatic disorder.

Keratoconus: an inflammatory disorder?

“…84 There is also a report of an increase in type IX collagen and a dysregulation in type XVIII collagen expression posterior to the healing process in patients with keratoconus. 85 Cheung et al, 74,86 analyzing ex vivo the modulation of the healing process of corneas with keratoconus and of non-keratoconic corneas, found that fibroblast growth factor 2 (FGF-2), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) were found to be upregulated in keratoconic corneas in comparison with normal uninjured corneas, but following an ex vivo secondary injury EGF, FGF-2, and PDGF were found to be downregulated in both non-keratoconic and keratoconic corneas, but they were decreased further in the later ones (FGF-2 was reduced to undetectable levels). According to those results, the authors concluded that dysregulation of reparative pathways in keratoconus causes on the one hand keratoconic corneas to appear in a perpetually injured state, but on the other hand they also produce a weakened repair response to a secondary lesion (eg, eye rubbing or contact lens wear and oxidative damage), which further supported what the authors had previously postulated: that underlying abnormalities in stromal repair and activities linked to oxygen reactive species along with the interaction between these phenomena were implicated in the development of keratoconus.…”

“…Recent technological advances have enabled more sophisticated molecular studies of the keratoconic condition, which changed some of the previously conceived theories for its pathogenesis. 3,24,25,[73][74][75][76] Pathophysiologic components of keratoconus can be largely classified into the following: alterations of the stroma composition, imbalance of pro-inflammatory and anti-inflammatory molecules, imbalance of the enzymes that cause extracellular matrix degradation and their corresponding inhibitors, oxidative stress, and cellular hypersensitivity. These events occur simultaneously and may present positive feedback between one another.…”

“…There are over 21 types of collagen in the human body; however, type I corresponds to 75% of the amount present in the cornea, 77 although cornea also contains collagen types III, V, and VI regularly interwoven into lamellae, and collagen type XII in epithelium basement membrane and sub-epithelial stroma. 74,78 Although the reduction in the number of lamellae within the affected region could correspond simply to a redistribution of the collagen within the cornea by slippage between the lamellae, as suggested by Polack 79 almost 40 years ago, this explanation by itself does not seem to be enough to account for the stromal thinning, especially in light of more recent studies showing that the collagen lamellae in keratoconus corneas exhibit a significant decrease in number compared with controls, 80 and that keratoconus diminishes the amount of types I, III, V, and XII collagen, as well as lumican and keratocan proteins, as determined using highly sensitive mass spectrometric analysis. 78 Additional researchers have reported the reduction of the interfibrillar distance of collagen sheets and the increase of proteoglycans with abnormalities in their configuration as the condition evolves.…”

“…According to those results, the authors concluded that dysregulation of reparative pathways in keratoconus causes on the one hand keratoconic corneas to appear in a perpetually injured state, but on the other hand they also produce a weakened repair response to a secondary lesion (eg, eye rubbing or contact lens wear and oxidative damage), which further supported what the authors had previously postulated: that underlying abnormalities in stromal repair and activities linked to oxygen reactive species along with the interaction between these phenomena were implicated in the development of keratoconus. 74,86 Inflammation ILs are secreted proteins and signaling molecules (cytokines), which function as important mediators of immune responses, cell proliferation, and inflammatory reactions. 87,88 As early as 1991, Girard et al 89 found that two cytokines, transforming growth factor-β (TGFβ) and IL-1, modulated the expression of metalloproteinases by cultured corneal stromal cells.…”

“…ICAM-1 has been shown to participate in corneal inflammation. 74 Lema et al 20 concluded that a higher level of inflammatory response to contact lens wearing was present in keratoconus in comparison with normal corneas.…”