epidermal-growth-factor and Corneal-Ulcer

Healing of ocular surface wounds is a complex process involving migration, mitosis, and differentiation of epithelial and stromal cells. Endogenously produced peptide growth factors such as epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), or transforming growth factor beta (TGF-beta) may play key roles in the natural wound healing process. Lacrimal gland cells were reported to synthesize and secrete EGF into tear fluid where it may enhance healing of corneal epithelial and stromal injuries by an exocrine pathway. EGF stimulated DNA synthesis of epithelial cells and stromal fibroblasts in culture, stimulated synthesis of fibronectin by epithelial cells and was chemotactic for human epithelial and stromal cells. Human corneal epithelial cells also synthesized TGF-alpha which may influence epithelial cells by an autocrine pathway. TGF-beta, which is a potent inducer of lysyl oxidase mRNA levels in cultures of human scleral fibroblasts, may be the factor most responsible for inducing synthesis of corneal extracellular matrix components after an injury. Treatment of epithelial injuries ocular surface wounds with exogenous peptide growth factors also accelerated healing in rabbits and primates. Treatment of severe ocular surface injuries caused by alkali with a combination of EGF, fibronectin, a synthetic collagenase inhibitor, and Aprotinin significantly blocked ulceration and enhanced epithelial regeneration. Clinical trials of topical treatment of EGF for ocular surface wounds suggest that peptide growth factors may be a valuable adjuvant for treatment of ocular surface wounds.

Topics: Animals; Cell Differentiation; Cell Movement; Cornea; Corneal Stroma; Corneal Ulcer; Epidermal Growth Factor; Epithelium; Humans; Mitosis; Transforming Growth Factor alpha; Transforming Growth Factor beta; Wound Healing

Numerous recent research results stress the importance of the epidermal growth factor (EGF) for the growth and differentiation of corneal tissues. EGF, a physiological ingredient in the tears, plays a predominant role in the regeneration of corneal epithelium. Furthermore, EGF has been shown to increase the proliferation and differentiation of corneal keratocytes and endothelial cells. Topically applied EGF significantly enhances both the re-epithelialization of denuded areas and the tear strength of stromal cicatrices. These results may lead to interesting pharmacological management procedures for numerous corneal disorders. Thus, the clinical feasibility of EGF therapy is currently the subject of intensive evaluation. A better understanding of its mode of action, both on the molecular and cellular level, and increasing knowledge of the pharmacokinetics, together with the development of suitable application media, may all make EGF an integral part of the next generation of ophthalmic drugs. This survey reviews basic molecular-pharmacological and biochemical findings on EGF and evaluates its possible value for therapeutical use.

Topics: Animals; Corneal Diseases; Corneal Ulcer; Epidermal Growth Factor; ErbB Receptors; Humans; Signal Transduction; Wound Healing

The tolerability and efficacy of epidermal growth factor (EGF) in the topical treatment of herpetic corneal ulcers in addition to topical acyclovir have been evaluated in a double-blind, placebo-controlled, randomized study in two groups of patients. The time required for complete reepithelialization of the cornea was recorded, and the data obtained were analyzed statistically. In the EGF group, the reepithelialization was significantly faster than in the control group. Tolerability of EGF was always excellent. These results indicate that EGF is safe and effective in reducing the healing time of herpetic corneal ulcers.

Topics: Acyclovir; Administration, Topical; Adult; Aged; Corneal Ulcer; Double-Blind Method; Epidermal Growth Factor; Female; Humans; Keratitis, Herpetic; Male; Middle Aged; Ophthalmic Solutions

The tolerability and efficacy of epidermal growth factor (EGF) in the topical treatment of traumatic corneal ulcers have been evaluated in a double-blind, placebo-controlled, randomized study in two groups of patients. The time required for complete reepithelialization of the cornea was recorded, and the data obtained were analyzed statistically. In the EGF group the reepithelialization was significantly faster than in the control group. Tolerability of EGF was always excellent. These results indicate that EGF is safe and effective in reducing the healing time in the management of superficial corneal lesions.

Topics: Administration, Topical; Adolescent; Adult; Aged; Cornea; Corneal Injuries; Corneal Ulcer; Double-Blind Method; Epidermal Growth Factor; Epithelium; Female; Humans; Male; Middle Aged; Ophthalmic Solutions; Wound Healing

Platelet-rich plasma (PRP) harbors high concentrations of growth factors related to the promotion of wound healing. We evaluated the efficacy of PRP eyedrops in the treatment of persistent epithelial defects (PEDs).. Autologous PRP and autologous serum (AS) were prepared from whole blood. The concentrations of transforming growth factor (TGF)-β1, TGF-β2, epidermal growth factor (EGF), vitamin A and fibronectin in the PRP and AS were analyzed and compared. The corneal epithelial healing efficacy of PRP was compared with that of AS in patients with PED induced by post-infectious inflammation.. The concentrations of TGF-β1, TGF-β2, EGF, vitamin A and fibronectin in the PRP and AS were not statistically different. However, the concentrations of EGF in the PRP were significantly greater than in the AS. AS was used in 17 and PRP in 11 eyes of 28 patients. The healing rates of the corneal epithelia of the PRP-treated eyes were significantly higher than those treated with AS.. The PRP was effective in the treatment of PEDs. This may be attributable to its high concentration of platelet-contained growth factors, most notably EGF. PRP could be an effective, novel treatment option for chronic ocular surface disease.

Topics: Adult; Aged; Aged, 80 and over; Cell Proliferation; Chromatography, High Pressure Liquid; Corneal Diseases; Corneal Ulcer; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epithelium, Corneal; Eye Infections, Bacterial; Female; Fibronectins; Humans; Male; Middle Aged; Ophthalmic Solutions; Platelet Count; Platelet-Rich Plasma; Retrospective Studies; Serum; Transforming Growth Factor beta; Vitamin A; Wound Healing

Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.

Topics: Antigens, CD; Antigens, Neoplasm; Basigin; Cell Line; Cholera Toxin; Coculture Techniques; Cornea; Corneal Ulcer; DNA Primers; Epidermal Growth Factor; Epithelium, Corneal; Fibroblasts; Humans; Immunohistochemistry; Insulin; Microscopy, Confocal; Polymerase Chain Reaction; Reference Values; Transforming Growth Factor beta; Transforming Growth Factor beta1

Healing of corneal alkali injuries remains a severe clinical challenge. The authors evaluated the effect of a new synthetic inhibitor of matrix metalloproteinases (GM6001 or N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-L-tryptophane methylamide) on preventing ulceration of rabbit corneas after alkali injury. Topical treatment of corneas with severe alkali injuries with 400 micrograms/ml or 40 micrograms/ml GM6001 alone prevented ulceration for 28 days, although 8 of 10 corneas treated with vehicle perforated. Corneas treated with 4 micrograms/ml GM6001 had midstromal depth ulcers. Corneas treated with 400 micrograms/ml of GM6001 contained very few inflammatory cells and had significantly reduced vessel ingrowth compared with vehicle-treated corneas. Epithelial regeneration after moderate alkali injuries also was investigated. Persistent epithelial defects developed 4 days after moderate alkali injury in rabbit corneas treated with vehicle and progressively increased to an average of 20% of the original 6 mm diameter wound by 27 days after moderate alkali injury. By contrast, epithelial regeneration was complete and persisted for 21 days for corneas treated with a formulation containing GM6001 (400 micrograms/ml), epidermal growth factor (10 micrograms/ml), fibronectin (500 micrograms/ml), and aprotinin (400 micrograms/ml). Sporadic punctate staining developed in 20% of the corneas treated with the combination of agents between days 21-28 after moderate alkali injury. These results demonstrate that topical application of GM6001 prevented corneal ulceration after severe alkali injury and that a combination containing GM6001, epidermal growth factor, fibronectin, and aprotinin promoted stable regeneration of corneal epithelium after moderate alkali injury.

Topics: Alkalies; Animals; Aprotinin; Burns, Chemical; Cornea; Corneal Injuries; Corneal Ulcer; Dipeptides; Dose-Response Relationship, Drug; Epidermal Growth Factor; Extracellular Matrix; Eye Burns; Fibronectins; Metalloendopeptidases; Rabbits; Regeneration

Epidermal growth factor (EGF) is known to promote corneal epithelial wound healing in experimental scrape and keratectomy models. We studied its efficacy in treating alkali-burned epithelial ulceration. EGF induced hyperplasia and cell proliferation to resurface the denuded and denatured corneal stroma, but it did not prevent recurrent erosions. A combination of EGF with fibronectin (Fn) was noted to enhance epithelial defect closure after alkali burns of the cornea and was seen to prevent recurrent erosions. Histopathologic examination of these corneas revealed marked leukocytic infiltration of the alkali-burned corneal stroma. To find ways to retard this inflammatory response, we studied the role of topical steroids and their efficacy when used with EGF, Fn, and laminin (Ln) in the management of alkali-burned corneas. Use of steroids decreased the incidence of recurrent erosions and corneal perforations. Histologically, steroids markedly decreased the leukocytic infiltration of stromal tissue, thereby retarding the collagenolysis. Topical steroids used with EGF and fibronectin were seen to promote epithelial wound closure and to prevent recurrent erosions in alkali-burned corneas. Combinations of EGF, fibronectin, and steroids may have a place in the treatment of clinical corneal alkali burns.

Topics: Adrenal Cortex Hormones; Animals; Cell Division; Corneal Injuries; Corneal Ulcer; Epidermal Growth Factor; Epithelium; Eye Burns; Fibronectins; Ophthalmic Solutions; Rabbits; Recurrence; Sodium Hydroxide; Wound Healing

Ten rabbits with the right eye burnt by 1 N NaOH were treated 5 times daily with epidermal growth factor (EGF) eyedrops or placebo. The epithelium seemed to heal better under EGF treatment than with placebo. Also, ulceration and secondary calcification of the cornea were reduced in the EGF-treated group. The vascularisation was slightly diminished by EGF. The lactate dehydrogenase and N-acetylglucose aminidase activities and the lactate and glucose levels in the corneae were not different between the EGF and the placebo groups. The results showed that there was a beneficial effect of EGF in these experiments with most severe eye burn disease. But the improved regeneration of the epithelium seemed to be counteracted and partly abolished by the severe inflammatory reaction in these eyes.

Topics: Animals; Blood Vessels; Burns, Chemical; Cornea; Corneal Ulcer; Epidermal Growth Factor; Epithelium; Eye Burns; Microscopy, Electron, Scanning; Rabbits; Regeneration; Sodium Hydroxide

Epidermal Growth Factor is a polypeptide isolated from mouse submaxillary glands and evaluated by histological studies. The healing of 7.3 mm diameter central corneal epithelial wounds after treatment with epidermal Growth Factor was measured by standardized photography. The results suggest that topically-administrated Epidermal Growth Factor, at a frequency of four (p less than 0.02) and six (p less than 0.001) times daily, significantly increases the corneal epithelial healing rate compared to the vehicle control. Histological examination of the control eyes enucleated after seven days of treatment showed an epithelium four to five layers in thickness. The basal cells had a round shape and round, centrally-positioned nuclei. The Epidermal Growth Factor treated group (six times daily) had an epithelial thickness of five to six layers. The basal cells were taller and more tightly-packed with oval nuclei oriented towards the apex of the cell.

Topics: Animals; Cornea; Corneal Ulcer; Disease Models, Animal; Epidermal Growth Factor; Epithelium; Female; Male; Ophthalmic Solutions; Rabbits; Wound Healing

Topics: Adrenal Cortex Hormones; Animals; Antibody Formation; Conjunctiva; Cornea; Corneal Ulcer; Epidermal Growth Factor; Epithelium; Female; Humans; Immunity, Cellular; Male; Mice; Peptides; Rabbits; Regeneration; Skin; Tears