Defective perlecan-associated basement membrane regeneration and altered modulation of transforming growth factor beta in corneal fibrosis

Wilson, Steven E.

doi:10.1007/s00018-022-04184-7

Cited by 17 publications

(10 citation statements)

References 121 publications

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“…Thus, in vivo, CALR treatment might decrease TGF‐β2 for a lesser effect on the conversion of keratocytes to myofibroblasts [associated with fibrosis] and in addition, block α‐SMA expression by keratocytes suggesting a double effect on decreasing the fibrotic response. Importantly, the amount of TGF‐β2, the number of cells that convert to myofibroblasts, and the duration of the presence of these cells during the wound healing response, control the severity of the fibrotic response and notably, myofibroblasts undergo apoptosis in the absence of TGF‐β2 8,49 . Therefore, the in vitro results support the general lack of fibrosis/scarring with topical CALR treatment of the cornea.…”

Section: Discussionmentioning

confidence: 53%

“…Importantly, the amount of TGF‐β2, the number of cells that convert to myofibroblasts, and the duration of the presence of these cells during the wound healing response, control the severity of the fibrotic response and notably, myofibroblasts undergo apoptosis in the absence of TGF‐β2. 8 , 49 Therefore, the in vitro results support the general lack of fibrosis/scarring with topical CALR treatment of the cornea.…”

Section: Discussionmentioning

confidence: 59%

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Calreticulin accelerates corneal wound closure and mitigates fibrosis: Potential therapeutic applications

Mishra,

Manzanares,

Prater

et al. 2023

J Cellular Molecular Medi

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The processes involved in regeneration of cutaneous compared to corneal tissues involve different intrinsic mechanisms. Importantly, cutaneous wounds involve healing by angiogenesis but vascularization of the cornea obscures vision. Previous studies showed that topically applied calreticulin (CALR) healed full‐thickness excisional animal wounds by a tissue regenerative process markedly enhancing repair without evoking angiogenesis. In the current study, the application of CALR in a rabbit corneal injury model: (1) accelerated full wound closure by 3 days (2) accelerated delayed healing caused by corticosteroids, routinely used to prevent post‐injury inflammation, by 6 days and (3) healed wounds without vascularization or fibrosis/hazing. In vitro, CALR stimulated proliferation of human corneal epithelial cells (CE) and corneal stromal cells (keratocytes) by 1.5‐fold and 1.4‐fold, respectively and induced migration of CE cells and keratocytes, by 72% and 85% compared to controls of 44% and 59%, respectively. As a marker of decreased fibrosis, CALR treated corneal wounds showed decreased immunostaining for α‐smooth muscle actin (α‐SMA) by keratocytes and following CALR treatment in vitro, decreased the levels of TGF‐β2 in human CE cells and α‐SMA in keratocytes. CALR has the potential to be a novel therapeutic both, to accelerate corneal healing from various injuries and in conjunction with corticosteroids.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 59%

Calreticulin accelerates corneal wound closure and mitigates fibrosis: Potential therapeutic applications

Mishra,

Manzanares,

Prater

et al. 2023

J Cellular Molecular Medi

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“…This was confirmed by experimental studies [26]. Corneal epithelial damage is accompanied by a release of cytokines, including interleukin-1 alpha (IL-1α) and FAS ligand, which can induce apoptosis in keratinocytes, support chronic inflammation and aggravate DES [27][28][29].…”

Section: Discussionmentioning

confidence: 81%

Assessing the early and late impact of excimer laser correction for myopia on the development of dry eye syndrome

Mogilevskyy¹,

Zhovtoshtan²

2022

Oftalmol Zh

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Background: Today, the global annual volume of excimer laser correction (ELC) is estimated to be 3.6 million procedures. Dry eye syndrome (DES) is a complication of ELC for myopia, and the frequency of DES at 1 month and 6 months after ELC for myopia has been reported to be 60% and 20%, respectively. Purpose: To assess the early and late impact of ELC for myopia on the development of DES. Material and Methods: Sixty-eight myopic patients (136 eyes) were prospectively divided into two groups, group 1 (a Laser-Assisted in Situ Keratomileusis (LASIK) group) and group 2 (a FemtoLASIK group). Patient age ranged from 20 to 44 years. Patients were assessed for DES (ocular surface, tear production, and tear film stability) preoperatively and postoperatively. Patients of group 1 received thin-flap LASIK using the Alcon Wavelight EX500 excimer laser. A 110-µm corneal flap was created by a Carriazo-Pendular microkeratome in group 1 and by an Alcon FS200 femto laser in group 2. Followup duration was 12 months. Results: Preoperative function tests showed mild dry eye in some patients of both groups. At 1 month and 3 months after ELC, the frequency of DES increased in group 1 by 75.5% and 63%, respectively, and in group 2, by 76.5% and 64.9%, respectively. At 6 months, the frequency of DES decreased in groups 1 and 2 by 38.7% and 40%, respectively, compared to the 3-month time point. However, 10% of the patients showing no signs of DES preoperatively had persistent DES after ELC. Conclusion: First, the baseline frequency of DES in patients with myopia was 10%. Second, at 1 month and 3 months after ELC for myopia, the frequency of DES increased by 75.5% and 63%, respectively, in the LASIK group, and by 76.5% and 64.9%, respectively, in the FemtoLASIK group. In addition, the frequency did not depend on the laser technique. Third, we noted a gradual decrease in the frequency of DES at late time points after ELC for myopia. At 6 months, the frequency of DES decreased by 38.7% and 40% in groups 1 and 2, respectively, compared to the 3-month time point. Finally, 10% of the patients showing no signs of DES preoperatively had persistent DES after ELC for myopia.

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“…This study also highlights the complexities of the overall corneal wound healing response that control corneal opacity versus transparency. Some of these factors include (1) the critical importance of timely and persistent healing of the epithelium (because no EBM regeneration is possible until the epithelium closes over a particular area of the cornea and opacity will occur after late breakdown of the epithelium), 15 , 16 (2) the regeneration of the EBM through the coordinated production of components by both the epithelial cells and the corneal fibroblasts/keratocytes that include laminins, perlecan, and collagen type IV is a key to transparency of the cornea, 17 – 19 (3) the downregulation of TGF-β effects on myofibroblasts/corneal fibroblasts because of decreased stromal passage of active TGF-β or inhibition of TGF-β effects, 6 , 7 (4) apoptosis or reversion to precursor cells by corneal fibroblasts and myofibroblasts, 6 , 7 (5) return of a normal cellularity with the affected stroma repopulated mostly with keratocytes, 6 , 7 and (6) normal keratocytes functioning over time to reabsorb/reorganize corneal stromal ECM and return the cornea to transparency. 14 A failure to return to normal in more than one of these factors, and likely others not well understood, is often involved in the development and persistent of vision compromising opacity.…”

Section: Discussionmentioning

confidence: 99%

Topical Losartan Decreases Myofibroblast Generation But Not Corneal Opacity After Surface Blast-Simulating Irregular PTK in Rabbits

Sampaio,

Villabona-Martinez,

Shiju

et al. 2023

Trans. Vis. Sci. Tech.

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Purpose To evaluate the efficacy of topical losartan after blast injury-simulating irregular phototherapeutic keratectomy (PTK) in rabbits. Methods Twelve NZW rabbits underwent 100 pulse 6.5 mm diameter PTK over a metal screen to generate severe surface irregularity and inhibit epithelial basement membrane regeneration. Corneas were treated with 0.8 mg/mL losartan in balanced salt solution (BSS) or BSS 50 µL six times per day for six weeks after PTK. All corneas had slit lamp photography, with and without 1% fluorescein at two, four, and six weeks after PTK, and were analyzed using immunohistochemistry for the myofibroblast marker α-smooth muscle actin (α-SMA), keratocyte marker keratocan, mesenchymal cell marker vimentin, transforming growth factor (TGF)–β1, and collagen type IV. Results Topical 0.8 mg/mL losartan six times a day significantly decreased anterior stromal α-SMA intensity units compared to BSS at six weeks after anterior stromal irregularity-inducing screened PTK ( P = 0.009). Central corneal opacity, however, was not significantly different between the two groups. Keratocan, vimentin, TGF-β1, or collagen type IV levels in the anterior stroma were not significantly different between the two groups. Conclusions Topical losartan effectively decreased myofibroblast generation after surface blast simulation irregular PTK. However, these results suggest initial masking-smoothing PTK, along with adjuvant topical losartan therapy, may be needed to decrease corneal stromal opacity after traumatic injuries that produce severe surface irregularity. Translational Relevance Topical losartan decreased scar-producing stromal myofibroblasts after irregular PTK over a metal screen but early smoothing of irregularity would also likely be needed to significantly decrease corneal opacity.

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Defective perlecan-associated basement membrane regeneration and altered modulation of transforming growth factor beta in corneal fibrosis

Cited by 17 publications

References 121 publications

Calreticulin accelerates corneal wound closure and mitigates fibrosis: Potential therapeutic applications

Calreticulin accelerates corneal wound closure and mitigates fibrosis: Potential therapeutic applications

Assessing the early and late impact of excimer laser correction for myopia on the development of dry eye syndrome

Topical Losartan Decreases Myofibroblast Generation But Not Corneal Opacity After Surface Blast-Simulating Irregular PTK in Rabbits

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