TGFβ1 and TGFβ2 proteins in corneas with and without stromal fibrosis: Delayed regeneration of apical epithelial growth factor barrier and the epithelial basement membrane in corneas with stromal fibrosis

Interleukin-1 and Transforming Growth Factor Beta: Commonly Opposing, but Sometimes Supporting, Master Regulators of the Corneal Wound Healing Response to Injury

“…81 Fibrocytes (not shown) attracted from limbal blood vessels by chemokines produced by corneal fibroblasts also begin TGFβ1-and TGFβ2-driven development into myofibroblasts. 12,116 Limited amounts of TGFβ1 and TGFβ2 are also produced by both vimentin-positive and vimentin-negative stromal cells 9 (not shown). (C) In corneas that heal without scarring fibrosis, the EBM is regenerated by the coordinated action of the healed epithelium and cooperating keratocytes/corneal fibroblasts (that produce EBM components such as perlecan and nidogens), and epithelial barrier function is re-established.…”

“…Inactive TGFβ1 is produced in small amounts by corneal epithelial and endothelial cells, while small amounts of inactive TGFβ1 and TGFβ2 are also present in the tears-restricted from passage through the epithelium by an epithelial barrier function. 9 The EBM and Descemet's membrane prevent passage of TGFβ1 or TGFβ2 into the stroma, although small amounts of TGFβ1 or TGFβ2 below the level of IHC detection may be sequestered in the stromal matrix (not shown). IL-1α [76][77][78] (and also inactive IL-1β 81 ) are within corneal epithelial cells.…”

“…(B) Within minutes to hours of epithelial-stromal injury, including the EBM, inactive TGFβ1 production is upregulated in the epithelium, and TGFβ1 and TGFβ2 are present at increased levels in the tears (from the lacrimal gland and possibly conjunctiva, goblets cells and other cells), and enter the stroma in high levels in the absence of EBM. 9 TGFβ1 and TGFβ2 are activated by collagenases and metalloproteinases (and thrombospondin-1) in the stroma, and integrins in the epithelium (as well as possibly other activators). [58][59][60] IL-1α (and pro-IL-1β) are released from injured corneal epithelial cells (IL-1β is activated by neutrophil serine proteases and other enzymes 34,35 ) and high concentrations of IL-1α and IL-1β trigger apoptosis of subepithelial keratocytes 1,5 via upregulation of Fas ligand by keratocytes (that constitutively express Fas).…”

“…55,171 Surrounding keratocytes that escape the wave of apoptosis transition to corneal fibroblasts and, driven by TGFβ1 and TGFβ2, begin development into myofibroblasts. 9 IL-1α and IL-1β also upregulate surviving corneal fibroblast production of HGF and KGF that modulate corneal epithelial cell migration, proliferation and differentiation to heal the epithelial defect. 81 Fibrocytes (not shown) attracted from limbal blood vessels by chemokines produced by corneal fibroblasts also begin TGFβ1-and TGFβ2-driven development into myofibroblasts.…”

“…(C) In corneas that heal without scarring fibrosis, the EBM is regenerated by the coordinated action of the healed epithelium and cooperating keratocytes/corneal fibroblasts (that produce EBM components such as perlecan and nidogens), and epithelial barrier function is re-established. 9 Deprived of sufficient epithelial and tear TGFβ1 and TGFβ2 by the regenerated EBM, myofibroblast precursors and corneal fibroblasts either undergo apoptosis or revert to keratocytes. 9 Little disordered extracellular matrix is produced and stromal opacity is limited.…”