Stromal interleukin-1 expression in the cornea after haze-associated injury
Introduction
Corneal injury, including surgery or infection, may trigger a loss of corneal transparency associated with the generation of stromal myofibroblasts that produce disordered matrix components such as collagen and glycosaminoglycans (Masur et al., 1996, Jester et al., 1999a, Wilson et al., 1999, Netto et al., 2006). TGFβ and PDGF have been shown to have important roles in modulating the development of corneal myofibroblasts from precursor cells (Masur et al., 1996, Jester et al., 1999b, Jester et al., 2002, Kaur et al., 2009b). The appearance and persistence of the myofibroblasts has been hypothesized to occur when structural and/or functional defects in the regenerated epithelial basement membrane allows penetration of TGFβ and PDGF from the epithelium into the stroma at sufficient levels required for receptor activation (Netto et al., 2006, Kaur et al., 2009b).
Over a period of years following surgery, many cases of corneal haze that occur after photorefractive keratectomy resolve spontaneously (Rajan et al., 2004). Recent work demonstrated that myofibroblast apoptosis has an important role in the resolution of corneal haze through the removal of the cellular contribution to the opacity (Wilson et al., 2007). Remaining anomalous extracellular matrix is subsequently removed by keratocytes that repopulate the anterior stroma. In a recent in vitro study, Kaur et al. (2009a) demonstrated that exogenous interleukin (IL)-1 alpha or IL-1 beta triggers apoptosis of corneal myofibroblasts and that TGFβ blocks this effect. The current study examines potential in situ sources of IL-1 alpha or IL-1 beta in the corneal stroma following haze-generating photorefractive keratectomy in a rabbit model.
Section snippets
Animals and surgery
All animals were treated in accordance with the tenets of the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. The Animal Control Committee at the Cleveland Clinic approved the animal studies included in this work. Anaesthesia was obtained by intramuscular injection of ketamine hydrochloride (30 mg/kg) and xylazine hydrochloride (5 mg/kg). In addition, topical proparacaine hydrochloride 1% (Alcon, Ft. Worth, TX, USA) was applied to each eye at the time of photorefractive
Results
In response to -9 diopter PRK in the rabbit, little haze can be noted in corneas 1 week or 2 weeks after PRK (not shown). At week 3, a significant haze response to the PRK is present (not shown). By 4 weeks after the PRK there is dense haze that obscures iris details (Fig. 1).
Immunocytochemistry (Fig. 2) and cell counts performed on double-stained slides (Table) from the areas of the stroma with dense haze in all of the corneas treated with PRK revealed the presence of SMA+ and SMA- stromal
Discussion
Severe haze (or opacity) sometimes develops in the corneal stroma after photorefractive keratectomy (PRK) and other surgeries or injuries. Myofibroblasts have an important role in the development of haze after they are generated following injury to some corneas. Large numbers of these cells result in altered transparency through the production of disordered collagen and other extra cellular matrix materials produced by these cells and the opacity of the cells themselves (Jester et al., 1999a,
Acknowledgements
This study was supported by EY10056, EY015638, and Research to Prevent Blindness, New York, NY.
References (24)
- et al.
Corneal myofibroblast generation from bone marrow-derived cells
Exp. Eye Res.
(2010) - et al.
Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury
Exp. Eye Res.
(2009) - et al.
TGF beta induced myofibroblast differentiation of rabbit keratocytes requires synergistic TGF beta, PDGF and integrin signaling
Exp. Eye Res.
(2002) - et al.
Corneal stromal wound healing in refractive surgery: the role of myofibroblasts
Prog. Retinal Eye Res.
(1999) - et al.
Corneal myofibroblast viability: opposing effects of IL-1 and TGF beta-1
Exp. Eye Res.
(2009) - et al.
Corneal stroma PDGF blockade and myofibroblast development
Exp. Eye Res.
(2009) - et al.
Apoptosis, necrosis, proliferation, and myofibroblast generation in the stroma following LASIK and PRK
Exp. Eye Res.
(2003) - et al.
Apoptosis in the cornea: further characterization of Fas-Fas ligand system
Exp. Eye Res.
(1997) - et al.
Stromal haze, myofibroblasts, and surface irregularity after PRK
Exp. Eye Res.
(2006) - et al.
A long-term study of photorefractive keratectomy; 12-year follow-up
Ophthalmology
(2004)
Myofibroblast differentiation is induced in keratinocyte-fibroblast co-cultures and is antagonistically regulated by endogenous transforming growth factor-beta and interleukin-1
Am. J. Pathol.
Topical interleukin-1 receptor antagonist inhibits inflammatory cell infiltration into the cornea
Exp. Eye Res.
Cited by (47)
Applications of hydrogel materials in different types of corneal wounds
2023, Survey of OphthalmologyCorneal epithelial biomechanics: Resistance to stress and role in healing and remodeling
2023, Journal Francais d'OphtalmologieCorneal haze post photorefractive keratectomy
2021, Journal Francais d'OphtalmologieCitation Excerpt :TGF-β is a decisive modulator in the expression and differentiation of myofibroblasts. It decreases the production of collagenases and suppresses the IL-1-mediated apoptosis of mature myofibroblasts and their precursors [7]. Keratocytes and myofibroblasts synthesise MMPs which are a family of proteolytic enzymes responsible for extracellular matrix remodelling, cell-matrix interaction, the recruitment of inflammatory cells and the activation of cytokines [10].
The anti-scarring role of Lycium barbarum polysaccharide on cornea epithelial-stromal injury
2021, Experimental Eye ResearchCorneal myofibroblasts and fibrosis
2020, Experimental Eye ResearchCitation Excerpt :Once mature myofibroblasts develop, they persist until the requisite source of TGFβ1 and/or TGFβ2 to maintain viability is sufficiently reduced by repair or replacement of the injured EBM and/or DBM. Once the levels of these TGFβ isotypes drop in the stroma, then IL-1 produced by surrounding cells (keratocytes, corneal fibroblasts, or bone marrow-derived cells) or the myofibroblasts themselves (autocrine), unopposed by TGFβ1 or TGFβ2, triggers increased apoptosis of the myofibroblasts, and results in a decrease in myofibroblast density in the stroma (Kaur et al., 2009: Barbosa et al., 2010b; Barbosa et al., 2012). Myofibroblasts may also regulate their own viability via autocrine IL-1 production once TGFβ declines (Barbosa et al., 2010b).
Corneal wound healing
2020, Experimental Eye ResearchCitation Excerpt :Less study has been devoted to corneal wound healing in chronic injuries associated with dystrophies, degenerations, and systemic diseases affecting the cornea, but presumably ongoing, low-grade profibrotic processes, perhaps involving injury to EBM or DBM, or which directly trigger alterations in the normal stromal collagen lamellae or lead to deposition of excess or defective extracellular matrix components underlie the pathophysiology of these diseases. In the case of ongoing development versus apoptotic disappearance of myofibroblasts and their precursors, a balance between extra-stromal TGFβ (epithelial, tear film, endothelial and aqueous humor) and paracrine/autocrine IL-1 appears to be a key determinate of the fate of individual myofibroblasts (Kaur et al., 2009a; Barbosa et al., 2010b, 2012; Wilson and Esposito, 2009). Corneal epithelial and stromal cells also produce interleukin-1 receptor antagonist (IL-1RA) that controls IL-1-modulated processes (Torres et al., 1994; Huer et al., 2009; Ko et al., 2010), but how this IL-1RA production is regulated in coordination with the production of the cytokines themselves by these cells is poorly understood.