Successful treatment of diabetic keratopathy with punctal occlusion

Sakamoto, Akiko; Sekiya, Hiroshi; Kitagawa, Kazuko

doi:10.1111/j.1395-3907.2004.0189h.x

Cited by 9 publications

(5 citation statements)

References 7 publications

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“…The hallmarks of this disorder include epitheliopathy (keratopathy) and neuropathy 1,51. Despite wide occurrence, the diabetic corneal disease treatment remains symptomatic 52,53. Experimental therapies including aldose reductase inhibitors, thymosin β 4 , insulin, and opioid growth factor antagonist, naltrexone, have been only tested in animals or early phase clinical trials 54–56.…”

Section: Discussionmentioning

confidence: 99%

Normalization of Wound Healing and Diabetic Markers in Organ Cultured Human Diabetic Corneas by Adenoviral Delivery ofc-MetGene

Saghizadeh¹,

Kramerov²,

et al. 2010

Invest. Ophthalmol. Vis. Sci.

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Purpose Diabetic corneas display altered basement membrane and integrin markers, increased expression of proteinases, decreased hepatocyte growth factor receptor, c-met proto-oncogene, and impaired wound healing. Recombinant adenovirus (rAV) driven c-met overexpression in human organ-cultured corneas was tested for correction of diabetic abnormalities. Methods Forty-six human autopsy corneas from twenty-three long-term diabetic donors (five with diabetic retinopathy) were organ-cultured and transduced with rAV expressing c-met gene (rAV-cmet) under the cytomegalovirus promoter at about 108 plaque-forming units per cornea for 48 hr. Each control fellow cornea received control rAV (rAV expressing β-galactosidase gene or vector alone). After additional 4-5 days incubation, 5-mm epithelial wounds were created with n-heptanol, and healing was monitored. Corneas were analyzed afterwards by immunohistochemistry and Western blotting. Signaling molecule expression and role was examined by immunostaining, phosphokinase antibody arrays, Western blotting, and inhibitor analysis. Results rAV-cmet transduction led to increased epithelial staining for c-met (total, extracellular and phosphorylated) and normalization of the patterns of select diabetic markers compared to rAV-vector transduced control fellow corneas. Epithelial wound healing time in c-met transduced diabetic corneas decreased two-fold compared to rAV-vector transduced corneas and became similar to normal. C-met action apparently involved increased activation of p38 mitogen-activated protein kinase. C-met transduction did not change tight junction protein patterns suggesting unaltered epithelial barrier function. Conclusions rAV-driven c-met transduction into diabetic corneas appears to restore HGF signaling, normalize diabetic marker patterns, and accelerate wound healing. C-met gene therapy could be useful for correcting human diabetic corneal abnormalities.

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Section: Discussionmentioning

confidence: 99%

Normalization of Wound Healing and Diabetic Markers in Organ Cultured Human Diabetic Corneas by Adenoviral Delivery ofc-MetGene

Saghizadeh¹,

Kramerov²,

et al. 2010

Invest. Ophthalmol. Vis. Sci.

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“…However, patients with clinically manifested corneal diabetes only receive topical symptomatic treatment including artificial tears, autologous serum possibly supplying adhesive and growth factors for healing, contact lenses as a corneal bandage, punctal occlusion to increase tear production, topical antibiotics to control infection in case of persistent epithelial defects [7,23,46]. Naltrexone (opioid growth factor antagonist), insulin, aldose reductase inhibitors, and substance P have been tested with varying degree of success for alleviating diabetic keratopathy, but they are still in various phases of preclinical and clinical testing [33,35,37].…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-driven overexpression of proteinases in organ-cultured normal human corneas leads to diabetic-like changes

Saghizadeh

Kramerov

Yaghoobzadeh

et al. 2010

Brain Research Bulletin

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Our previous data suggested the involvement of matrix metalloproteinase-10 (MMP-10) and cathepsin F (CTSF) in the basement membrane and integrin changes occurring in diabetic corneas. These markers were now examined in normal human organ-cultured corneas upon recombinant adenovirus (rAV)-driven transduction of MMP-10 and CTSF genes. Fifteen pairs of normal autopsy human corneas were used. One cornea of each pair was transduced with rAV expressing either CTSF or MMP-10 genes. 1–2 × 108 plaque forming units of rAV per cornea were added to cultures for 48 hr with or without sildenafil citrate. The fellow cornea of each pair received control rAV with vector alone. After 6–10 days incubation without rAV, corneas were analyzed by Western blot or immunohistochemistry, or tested for healing of 5-mm circular epithelial wounds caused by topical application of n-heptanol. Sildenafil significantly increased epithelial transduction efficiency, apparently through stimulation of rAV endocytosis through caveolae. Corneas transduced with CTSF or MMP-10 genes or their combination had increased epithelial immunostaining of respective proteins compared to fellow control corneas. Staining for diabetic markers integrin α3β1, nidogen-1, nidogen-2, and laminin γ2 chain became weaker and irregular upon proteinase transduction. Expression of phosphorylated Akt was decreased in proteinase-transduced corneas. Joint overexpression of both proteinases led to significantly slower corneal wound healing that became similar to that observed in diabetic ones. The data suggest that MMP-10 and CTSF may be responsible for abnormal marker patterns and impaired wound healing in diabetic corneas. Inhibition of these proteinases in diabetic corneas may alleviate diabetic keratopathy symptoms.

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“…Even with improved surgical techniques individuals with diabetes account for 80% of cases of corneal complications after cataract and refractive surgery, vitrectomy for non-clearing vitreous hemorrhage, and PRP (Foulks et al, 1979; Chung et al, 1988; Hiraoka et al, 2001; Chiambo et al, 2004; Dogru et al, 2004; Wylegała et al, 2006; Chen et al, 2009; Bikbova et al, 2012; Vieira-Potter et al, 2016). In some patients, diabetic keratopathy may develop following ocular surgery (Sakamoto et al, 2004; Chen et al, 2009). These problems arise as a consequence of epithelial debridement usually performed during both procedures to improve intraoperative visualization (Schulze et al, 2006; Chen et al, 2009).…”

Section: General Manifestations Of Diabetes In the Corneamentioning

confidence: 99%

Diabetic complications in the cornea

2017

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Diabetic corneal alterations, such as delayed epithelial wound healing, edema, recurrent erosions, neuropathy/loss of sensitivity, and tear film changes are frequent but underdiagnosed complications of both type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. The disease affects corneal epithelium, corneal nerves, tear film, and to a lesser extent, endothelium, and also conjunctiva. These abnormalities may appear or become exacerbated following trauma, as well as various surgeries including retinal, cataract or refractive. The focus of the review is on mechanisms of diabetic corneal abnormalities, available animal, tissue and organ culture models, and emerging treatments. Changes of basement membrane structure and wound healing rates, the role of various proteinases, advanced glycation end products (AGEs), abnormal growth and motility factors (including opioid, epidermal, and hepatocyte growth factors) are analyzed. Experimental therapeutics under development, including topical naltrexone, insulin, inhibitors of aldose reductase and AGEs, as well as emerging gene and cell therapies are discussed in detail.

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Successful treatment of diabetic keratopathy with punctal occlusion

Cited by 9 publications

References 7 publications

Normalization of Wound Healing and Diabetic Markers in Organ Cultured Human Diabetic Corneas by Adenoviral Delivery ofc-MetGene

Normalization of Wound Healing and Diabetic Markers in Organ Cultured Human Diabetic Corneas by Adenoviral Delivery ofc-MetGene

Adenovirus-driven overexpression of proteinases in organ-cultured normal human corneas leads to diabetic-like changes

Diabetic complications in the cornea

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