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Davies EC, Pineda R.
Complications of Scleral-Fixated Intraocular Lenses. Semin Ophthalmol 2017;:1-6.
AbstractINTRODUCTION: Understanding the evolution of complications after scleral-fixated lens placement demonstrates advantageous surgical techniques and suitable candidates. MATERIALS/METHODS: A literature search in PubMed for several terms, including "scleral intraocular lens complication," yielded 17 relevant articles. RESULTS: Reviewing complication trends over time, lens tilt and suture erosion have decreased, cystoid macular edema has increased, and retinal detachment has remained the same after scleral-fixated lens placement. The successful reduction in complications are attributed to several alterations in technique, including positioning sclerotomy sites 180 degrees apart and using scleral flaps or pockets to bury sutures. Possible reduction in retinal risks have been proposed by performing an anterior vitrectomy prior to lens placement in certain settings. DISCUSSION: Complications after scleral-fixated lens placement should assist patient selection. Elderly patients with a history of hypertension should be counseled regarding risk of suprachoroidal hemorrhage, while young patients and postocular trauma patients should be considered for concurrent anterior vitrectomy.
Davies E.
Case Series: Novel Utilization of Rho-Kinase Inhibitor for the Treatment of Corneal Edema. Cornea 2021;40(1):116-120.
AbstractPURPOSE: To describe 3 cases of corneal clearance after the use of topical rho-kinase inhibitor, netarsudil, in the setting of endothelial cell dysfunction in comparison to one case without corneal clearance after the use of netarsudil. METHODS: Four patients presenting to a busy academic clinical corneal practice with visual complaints from corneal edema secondary to endothelial cell dysfunction were treated with topical netarsudil one drop daily in the affected eye. RESULTS: Corneal clearance was observed in 1) a case of peripheral corneal edema in the setting of iridocorneal endothelial syndrome after 4 weeks on netarsudil, 2) a case of corneal edema in the setting of early penetrating keratoplasty graft failure after 2-week use of netarsudil, and 3) a case of corneal edema in the setting of chronic penetrating keratoplasty graft failure after 4-week use of netarsudil. Corneal clearance was not observed in a case of corneal edema in the setting of pseudophakic bullous keratopathy from previous complicated intraocular lens exchange surgery with placement of an anterior chamber intraocular lens after the use of netarsudil for 12 weeks. CONCLUSIONS: Addition of topical rho-kinase inhibitor in the form of netarsudil can result in corneal clearance in a variety of certain cases of endothelial cell dysfunction, not previously documented in the literature.
Davies EC, Pavan-Langston D, Chodosh J.
Herpes zoster ophthalmicus: declining age at presentation. Br J Ophthalmol 2016;100(3):312-4.
AbstractOBJECTIVE: To investigate changes in the age of occurrence of herpes zoster ophthalmicus (HZO) in patients presenting to the Massachusetts Eye and Ear Infirmary (MEEI) from 2007 through 2013. DESIGN: Retrospective chart review. SETTING: Academic tertiary referral centre for ophthalmic conditions. PARTICIPANTS: 913 patients with acute HZO. METHODS: A total of 1283 potential cases were identified by searching the MEEI electronic medical record for patient charts with International Classification of Diseases 9 codes for herpes zoster, shingles and varicella from 2007 through 2013. The cases were reviewed to confirm diagnosis of acute HZO, requiring documentation of a skin rash or pain in the V1 distribution, resulting in inclusion of 913 cases. MAIN OUTCOME MEASURES: Number of HZO cases each year, mean age of HZO cases each year, number of HZO cases with an immunodeficiency state. RESULTS: The number of patients with HZO presenting to MEEI increased from 71 cases in 2007 to 195 cases in 2013. The mean age of patients with acute HZO reduced significantly from 61.2 years in 2007 to 55.8 years in 2013 (p=0.0119). The number of patients with acute HZO in the setting of an immunodeficiency state did not change significantly over the study period. CONCLUSIONS: Ever since the introduction of varicella vaccination in children, there has been debate regarding its effect on zoster epidemiology, particularly regarding the potential to reduce population exposure and limit repeated immunological boosts against varicella zoster virus in adults. Patients presenting to MEEI with HZO were younger on average in 2013 than in 2007. Although a population-based study is necessary to test the hypothesis, our study suggests that varicella vaccination of children remains a possible explanation for the increased number of cases and reduction in mean age of newly diagnosed patients.
De Arrigunaga S, Akpek EK, Aldave AJ, Mian SI, Zurakowski D, Ciolino JB, Ciolino JB.
Prospective, Randomized, Multicenter, Double-Masked, Clinical Trial of Corneal Cross-Linking for Boston Keratoprosthesis Carrier Tissue. Am J Ophthalmol 2023;249:39-48.
AbstractPURPOSE: To assess whether cross-linking the carrier donor cornea of the Boston Keratoprosthesis (BKPro) improves retention of the device in participants at high risk for keratolysis. DESIGN: Prospective, double-masked, randomized clinical trial. METHODS: In this multicenter study, 68 adult participants who were scheduled for BKPro implantation were enrolled. Masked participants were randomized to receive either a cross-linked (CXL) or non-cross-linked (non-CXL) donor corneal carrier. The Kaplan-Meier event-free survival was determined by the product-limit method and compared by the log-rank test to examine whether survival curves were different between the CXL and non-CXL groups. The primary outcome of the study was time from surgery to BKPro removal. The secondary endpoint was 12-month retention rate. RESULTS: A total of 68 participants were enrolled and randomized 1:1 to each group. The average age at the time of surgery was 62 (range = 24-89) years, and 42 participants (62%) were male. The overall BKPro retention rate was 70% during a mean follow-up time of 93 (range = 6-201) weeks. Twenty BKPros were removed, 10 in the CXL group and 10 in the non-CXL group, with 18 requiring removal because of sterile keratolysis. There was no difference in the time to removal between the groups during the study (P = .910). At 12 months, there was no significant difference in the retention rate in the CXL group (94%) vs the non-CXL group (82%, P = .150). CONCLUSIONS: In this prospective study, cross-linking of the carrier cornea prior to BKPro implantation did not reduce the incidence of sterile keratolysis or increase device retention among participants at high risk for retention failure.
Deiner MS, McLeod SD, Wong J, Chodosh J, Lietman TM, Porco TC.
Google Searches and Detection of Conjunctivitis Epidemics Worldwide. Ophthalmology 2019;126(9):1219-1229.
AbstractPURPOSE: Epidemic and seasonal infectious conjunctivitis outbreaks can impact education, workforce, and economy adversely. Yet conjunctivitis typically is not a reportable disease, potentially delaying mitigating intervention. Our study objective was to determine if conjunctivitis epidemics could be identified using Google Trends search data. DESIGN: Search data for conjunctivitis-related and control search terms from 5 years and countries worldwide were obtained. Country and term were masked. Temporal scan statistics were applied to identify candidate epidemics. Candidates then were assessed for geotemporal concordance with an a priori defined collection of known reported conjunctivitis outbreaks, as a measure of sensitivity. PARTICIPANTS: Populations by country that searched Google's search engine using our study terms. MAIN OUTCOME MEASURES: Percent of known conjunctivitis outbreaks also found in the same country and period by our candidate epidemics, identified from conjunctivitis-related searches. RESULTS: We identified 135 candidate conjunctivitis epidemic periods from 77 countries. Compared with our a priori defined collection of known reported outbreaks, candidate conjunctivitis epidemics identified 18 of 26 (69% sensitivity) of the reported country-wide or island nationwide outbreaks, or both; 9 of 20 (45% sensitivity) of the reported region or district-wide outbreaks, or both; but far fewer nosocomial and reported smaller outbreaks. Similar overall and individual sensitivity, as well as specificity, were found on a country-level basis. We also found that 83% of our candidate epidemics had start dates before (of those, 20% were more than 12 weeks before) their concurrent reported outbreak's report issuance date. Permutation tests provided evidence that on average, conjunctivitis candidate epidemics occurred geotemporally closer to outbreak reports than chance alone suggests (P < 0.001) unlike control term candidates (P = 0.40). CONCLUSIONS: Conjunctivitis outbreaks can be detected using temporal scan analysis of Google search data alone, with more than 80% detected before an outbreak report's issuance date, some as early as the reported outbreak's start date. Future approaches using data from smaller regions, social media, and more search terms may improve sensitivity further and cross-validate detected candidates, allowing identification of candidate conjunctivitis epidemics from Internet search data potentially to complementarily benefit traditional reporting and detection systems to improve epidemic awareness.
DeLoss KS, Le H-G, Gire A, Chiu GB, Jacobs DS, Carrasquillo KG.
PROSE Treatment for Ocular Chronic Graft-Versus-Host Disease as a Clinical Network Expands. Eye Contact Lens 2016;42(4):262-6.
AbstractBACKGROUND: Keratoconjunctivitis sicca occurs in 40% to 90% of patients with ocular chronic graft-versus-host disease (cGVHD). Ocular symptoms can have profound effects in both the visual function and quality of life of patients with GVHD. We report the impact of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in patients with cGVHD as a clinical network expands. METHODS: We queried the BostonSight PROSE manufacturing database from January 2002 to December 2011. Patients treated for ocular cGVHD were reported by age, gender, year, and network site where the treatment was undertaken. The baseline and six-month follow-up scores of visual function using a standardized validated instrument, the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), were evaluated for a period in 2006 and again in 2010 after network expansion had occurred. RESULTS: A total of 407 patients with a male:female ratio of 226:181, mean age was 51 years with ocular cGVHD underwent PROSE treatment from January 2002 to December 2011. By 2011, 67% of all cases were treated at network clinics. Baseline characteristics of patients treated throughout the network in 2010 were similar to that of 2006 and 2010 cohorts from the main center. There was a significant improvement of 41 points (P<0.001) in composite NEI VFQ score among patients treated across the network in 2010, similar to the improvement of 30 points (P<0.001) seen among the patients treated at the main center in 2010. There was a trend toward lower baseline self-reported general health status (SRGHS) and VFQ scores among patients treated at network clinics, suggesting that expansion of the network allows treatment of sicker patients (lower general health status) or those more severely affected by ocular cGVHD. CONCLUSIONS: PROSE treatment of ocular cGVHD has increased in the last decade with the establishment of BostonSight network clinics across the United States. Patients treated at network clinics showed similar levels of baseline visual function and SRGHS, and achieved a similar high level of improvement in visual function as those treated at the main center. Patient-reported measures of functional status are useful in evaluating treatment options for patients with cGVHD. PROSE treatment has significant positive impact on the visual function of patients with ocular cGVHD regardless of whether the patient is treated at the main center or at a network site.
Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE.
Reply. Cornea 2019;38(12):e56-e57.
Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE, and Group TILSCDW.
Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea 2019;38(3):364-375.
AbstractPURPOSE: Despite extensive knowledge gained over the last 3 decades regarding limbal stem cell deficiency (LSCD), the disease is not clearly defined, and there is lack of agreement on the diagnostic criteria, staging, and classification system among treating physicians and research scientists working on this field. There is therefore an unmet need to obtain global consensus on the definition, classification, diagnosis, and staging of LSCD. METHODS: A Limbal Stem Cell Working Group was first established by The Cornea Society in 2012. The Working Group was divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to obtain agreement on a strategic plan and methodology from all participants after a comprehensive literature search, and final agreement was reached on the definition, classification, diagnosis, and staging of LSCD. A writing group was formed to draft the current manuscript, which has been extensively revised to reflect the consensus of the Working Group. RESULTS: A consensus was reached on the definition, classification, diagnosis, and staging of LSCD. The clinical presentation and diagnostic criteria of LSCD were clarified, and a staging system of LSCD based on clinical presentation was established. CONCLUSIONS: This global consensus provides a comprehensive framework for the definition, classification, diagnosis, and staging of LSCD. The newly established criteria will aid in the correct diagnosis and formulation of an appropriate treatment for different stages of LSCD, which will facilitate a better understanding of the condition and help with clinical management, research, and clinical trials in this area.
Deng SX, Kruse F, Gomes JAP, Chan CC, Daya S, Dana R, Figueiredo FC, Kinoshita S, Rama P, Sangwan V, Slomovic AR, Tan D, and Group TILSCDW.
Global Consensus on the Management of Limbal Stem Cell Deficiency. Cornea 2020;39(10):1291-1302.
AbstractPURPOSE: In recent decades, the medical and surgical treatment of limbal stem cell deficiency (LSCD) has evolved significantly through the incorporation of innovative pharmacological strategies, surgical techniques, bioengineering, and cell therapy. With such a wide variety of options, there is a need to establish a global consensus on the preferred approaches for the medical and surgical treatment of LSCD. METHODS: An international LSCD Working Group was established by the Cornea Society in 2012 and divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to reach agreement on a strategic plan and methods after a comprehensive literature search. A writing group drafted the current study. RESULTS: A consensus in the medical and surgical management of LSCD was reached by the Working Group. Optimization of the ocular surface by eyelid and conjunctival reconstruction, antiinflammatory therapy, dry eye and meibomian gland dysfunction treatment, minimization of ocular surface toxicity from medications, topical medications that promote epithelialization, and use of a scleral lens is considered essential before surgical treatment of LSCD. Depending on the laterality, cause, and stage of LSCD, surgical strategies including conjunctival epitheliectomy, amniotic membrane transplantation, transplantation of limbal stem cells using different techniques and sources (allogeneic vs. autologous vs. ex vivo-cultivated), transplantation of oral mucosal epithelium, and keratoprosthesis can be performed as treatment. A stepwise flowchart for use in treatment decision-making was established. CONCLUSIONS: This global consensus provides an up-to-date and comprehensive framework for the management of LSCD.
Di Zazzo A, Micera A, Coassin M, Varacalli G, Foulsham W, De Piano M, Bonini S.
InflammAging at Ocular Surface: Clinical and Biomolecular Analyses in Healthy Volunteers. Invest Ophthalmol Vis Sci 2019;60(5):1769-1775.
AbstractPurpose: To assess the ocular surface in volunteers who consider themselves as healthy, in order to evaluate how para-inflammatory mechanisms fail with age, and thus investigate the phenomenon of "InflammAging." Methods: In this observational prospective cohort study, volunteers were categorized into three groups according to age: young (19-40 years), middle-aged (41-60 years), and older adults (61-93 years). Clinical assessments included tear breakup time (T-BUT) and Schirmer test type I. Dry eye symptoms were evaluated by the Ocular Surface Disease Index (OSDI) questionnaire. Conjunctival mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), MUC5AC, and IL-8 were measured by real-time PCR and immunofluorescence. Results: A total of 82 volunteers (38 males and 44 females) were enrolled. T-BUT decreased significantly with increasing age (young: 11.13 ± 0.18 seconds; middle-aged: 10.83 ± 0.56 seconds; older: 9.00 ± 1.00 seconds, P < 0.05). Schirmer test values decreased significantly with age (young: 20.6 ± 1.0 mm; middle-aged: 19.2 ± 1.2 mm; older: 16.0 ± 1.1 mm, P < 0.05). OSDI scores increased with age in both groups, but they were substantially higher in women. Conjunctival expression of inflammatory markers ICAM-1, IL-8, and MUC5AC increased with age. Conclusions: Clinical signs, symptoms, and biomarkers of chronic inflammation increased with age in a cohort of volunteers who considered themselves healthy, indicating an age-related progressive impairment of ocular surface system function.
Di Zazzo A, Gaudenzi D, Yin J, Coassin M, Fernandes M, Dana R, Bonini S.
Corneal angiogenic privilege and its failure. Exp Eye Res 2021;204:108457.
AbstractThe cornea actively maintains its own avascular status to preserve its ultimate optical function. This corneal avascular state is also defined as "corneal angiogenic privilege", which results from a critical and sensitive balance between anti-angiogenic and pro-angiogenic mechanisms. In our review, we aim to explore the complex equilibrium among multiple mediators which prevents neovascularization in the resting cornea, as well as to unveil the evolutive process which leads to corneal angiogenesis in response to different injuries.
Di Zazzo A, Tahvildari M, Florakis GJ, Dana R.
Ocular Manifestations of Inherited Phospholipase-Cγ2-Associated Antibody Deficiency and Immune Dysregulation. Cornea 2016;
AbstractPURPOSE: To report the ocular manifestations of phospholipase-Cγ2-associated antibody deficiency and immune dysregulation (PLAID). METHODS: Case report and literature review. RESULTS: A 21-year-old woman diagnosed with PLAID was referred for evaluation of repeated episodes of ocular inflammation resulting in bilateral peripheral corneal pannus with episcleritis and corneal scarring accompanied by systemic manifestations including epidermolysis bullosa and interstitial lung disease. Systemic immunosuppression with corticosteroids and interleukin-1 (IL-1) receptor antagonist (anakinra) was supplemented with topical anakinra to avoid systemic side effects, which resulted in partial improvement of the ocular symptoms. Oral prednisone was restarted to treat active lesions during bouts of inflammation. CONCLUSIONS: Ocular PLAID is a bilateral chronic or recurrent inflammatory disease of the ocular surface leading to severe and early cicatricial ocular surface and corneal involvement because of high IL-1 production. Management of PLAID may require both topical and systemic immunomodulatory treatments, potentially including targeted local anti-IL-1 therapy.
Di Zazzo A, Kheirkhah A, Abud TB, Goyal S, Dana R.
Management of High-risk Corneal Transplantation. Surv Ophthalmol 2016;
AbstractThe cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal grafting has a high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates because of a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered.; however, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been employed for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use, as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments, as well as tolerance-inducing methods, show promising horizons in the management of high-risk corneal transplantation in near future.
Di Zazzo A, Tahvildari M, Subbarayal B, Yin J, Dohlman TH, Inomata T, Mashaghi A, Chauhan SK, Dana R.
Proangiogenic Function of T Cells in Corneal Transplantation. Transplantation 2017;101(4):778-785.
AbstractBACKGROUND: Corneal neovascularization increases the risk of T cell-mediated allograft rejection. Here, we investigate whether T cells promote angiogenesis in transplantation. METHODS: Conventional effector T cells were collected from draining lymph nodes of allogeneic or syngeneic corneal transplanted BALB/c mice. T cells were either cocultured with vascular endothelial cells (VECs) to assess VEC proliferation or used in a mixed lymphocyte reaction assay. Messenger RNA (mRNA) expression of vascular endothelial growth factor (VEGF)-A, -C, and VEGF receptor 2 (VEGF-R2) in VECs was assessed by real-time PCR. VEGF-A protein expression was determined by enzyme-linked immunosorbent assay. Flow cytometry was used to analyze VEGF-R2 expression in corneal CD31 cells, and VEGF-A and IFNγ expression in corneal CD4 T cells. RESULTS: Allogeneic T cells from high-risk (HR) grafted mice induced more VEC proliferation than those from syngeneic transplant recipients (P = 0.03). Vascular endothelial growth factor-A mRNA and protein expression were higher in T cells from draining lymph nodes (P = 0.03 and P = 0.04, respectively) and cornea (protein; P = 0.04) of HR compared with low-risk (LR) grafted hosts. Vascular endothelial growth factor-A, VEGF-C, and VEGF-R2 mRNA expression were increased in VECs when cocultured with T cells from HR transplants compared with LR transplants and naive mice. In addition, IFNγ blockade in T cell/VEC coculture increased VEC proliferation and VEGF-A protein expression, whereas blocking VEGF-A significantly reduced VEC proliferation (P = 0.04). CONCLUSIONS: Allogeneic T cells from corneal transplant hosts promote VEC proliferation, probably via VEGF-A signaling, whereas IFNγ shows an antiangiogenic effect. Our data suggest that T cells are critical mediators of angiogenesis in transplantation.
Diel RJ, Mehra D, Kardon R, Buse DC, Moulton E, Galor A.
Photophobia: shared pathophysiology underlying dry eye disease, migraine and traumatic brain injury leading to central neuroplasticity of the trigeminothalamic pathway. Br J Ophthalmol 2021;105(6):751-760.
AbstractBACKGROUND: Photophobia is a potentially debilitating symptom often found in dry eye disease (DE), migraine and traumatic brain injury (TBI). METHODS: We conducted a review of the literature via a PubMed search of English language articles with a focus on how photophobia may relate to a shared pathophysiology across DE, migraine and TBI. RESULTS: DE, migraine and TBI are common conditions in the general population, are often comorbid, and share photophobia as a symptom. Across the three conditions, neural dysregulation of peripheral and central nervous system components is implicated in photophobia in various animal models and in humans. Enhanced activity of the neuropeptide calcitonin gene-related peptide (CGRP) is closely linked to photophobia. Current therapies for photophobia include glasses which shield the eyes from specific wavelengths, botulinum toxin, and inhibition of CGRP and its receptor. Many individuals have persistent photophobia despite the use of these therapies, and thus, development of new therapies is needed. CONCLUSIONS: The presence of photophobia in DE, migraine and TBI suggests shared trigeminothalamic pathophysiologic mechanisms, as explained by central neuroplasticity and hypersensitivity mediated by neuropeptide CGRP. Treatment strategies which target neural pathways (ie, oral neuromodulators, transcutaneous nerve stimulation) should be considered in patients with persistent photophobia, specifically in individuals with DE whose symptoms are not controlled with traditional therapies.
Ding J, Sullivan DA.
Aging and dry eye disease. Exp Gerontol 2012;47(7):483-90.
AbstractDry eye disease is a prevalent eye disorder that in particular affects the elderly population. One of the major causes of dry eye, meibomian gland dysfunction (MGD), shows increased prevalence with aging. MGD is caused by hyperkeratinization of the ductal epithelium of meibomian gland and reduced quantity and/or quality of meibum, the holocrine product that stabilizes and prevents the evaporation of the tear film. Of note, retinoids which are used in current anti-aging cosmetics may promote the development of MGD and dry eye disease. In this review, we will discuss the possible mechanisms of age-related MGD.
Ding J, Kam WR, Dieckow J, Sullivan DA.
The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci 2013;54(6):4341-50.
AbstractPURPOSE: Meibomian gland dysfunction (MGD) is a primary cause of dry eye disease. One of the risk factors for MGD is exposure to 13-cis retinoic acid (13-cis RA), a metabolite of vitamin A. However, the mechanism is not well understood. We hypothesize that 13-cis RA inhibits cell proliferation, promotes cell death, alters gene and protein expressions, and attenuates cell survival pathways in human meibomian gland epithelial cells. METHODS: To test our hypotheses, immortalized human meibomian gland epithelial cells were cultured with or without 13-cis RA for varying doses and time. Cell proliferation, cell death, gene expression, and proteins involved in proliferation/survival and inflammation were evaluated. RESULTS: We found that 13-cis RA inhibited cell proliferation, induced cell death, and significantly altered the expression of 6726 genes, including those involved in cell proliferation, cell death, differentiation, keratinization, and inflammation, in human meibomian gland epithelial cells. Further, 13-cis RA also reduced the phosphorylation of Akt and increased the generation of interleukin-1β and matrix metallopeptidase 9. CONCLUSIONS: Exposure to 13-cis RA inhibits cell proliferation, increases cell death, alters gene expression, changes signaling pathways, and promotes inflammatory mediator and protease expression in meibomian gland epithelial cells. These effects may be responsible, at least in part, for the 13-cis RA-related induction of MGD.
Ding J, Wirostko B, Sullivan DA.
Human growth hormone promotes corneal epithelial cell migration in vitro. Cornea 2015;34(6):686-92.
AbstractPURPOSE: Corneal wound healing is a highly regulated process that requires the proliferation and migration of epithelial cells and interactions between epithelial cells and stromal fibroblasts. Compounds that can be applied topically to the ocular surface and that have the capability of activating corneal epithelial cells to proliferate and/or migrate would be useful to promote corneal wound healing. We hypothesize that human growth hormone (HGH) will activate signal transducers and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial cell and fibroblast proliferation and/or migration in vitro. The purpose of this study was to test these hypotheses. METHODS: We studied cell signaling, proliferation, and migration using an immortalized human corneal epithelial cell line and primary human corneal fibroblasts in vitro. We also examined whether insulin-like growth factor-1 (IGF-1), a hormone known to mediate many of HGH's growth promoting actions, may play a role in this effect. RESULTS: We show that HGH activates STAT5 signaling and promotes corneal epithelial cell migration in vitro. The migratory effect requires an intact communication between corneal epithelia and fibroblasts and is not mediated by IGF-1. CONCLUSIONS: HGH may represent a topical therapeutic to promote corneal epithelial wound healing. This warrants further investigation.
Ding J, Sullivan DA.
The effects of insulin-like growth factor 1 and growth hormone on human meibomian gland epithelial cells. JAMA Ophthalmol 2014;132(5):593-9.
AbstractIMPORTANCE: A phase 1 study has reported that dry eye disease is the most common adverse effect of human exposure to the antibody figitumumab, an anticancer drug that prevents insulin-like growth factor 1 (IGF-1) from binding to its receptor. We hypothesized that the mechanism underlying this effect is the inhibition of IGF-1 action in epithelial cells of the meibomian gland. OBJECTIVES: To test the hypothesis that IGF-1 stimulates meibomian gland function in vitro and to examine whether growth hormone, a closely related hormone of IGF-1, has the same effect. DESIGN, SETTING, AND MATERIAL: Immortalized human meibomian gland epithelial cells were cultured in the presence or the absence of IGF-1, growth hormone, and an IGF-1 receptor-blocking antibody. Signaling pathways, cell proliferation, neutral lipid staining, and a key protein involved in lipid biogenesis were evaluated. INTERVENTION: Application of IGF-1 and growth hormone to human meibomian gland epithelial cells. MAIN OUTCOMES AND MEASURES: Immunoblotting, cell counting, and neutral lipid staining. RESULTS Insulin-like growth factor 1 activated the phosphoinositol 3-kinase/Akt and forkhead box O1 pathways (showing a dose-dependent effect on immunoblotting), stimulated cellular proliferation (about 1.8-fold increase in cell number), increased sterol regulatory element-binding protein 1 expression (about 3-fold increase on immunoblotting), and promoted lipid accumulation in human meibomian gland epithelial cells (about 2-fold increase in lipid staining). These IGF-1 actions, which may be blocked by cotreatment with the anti-IGF-1 antibody, were accompanied by inconsistent effects on extracellular signal-regulated kinase phosphorylation. We were not able to demonstrate activation of Akt, forkhead box O1, extracellular signal-regulated kinase, Janus kinase 2, or signal transducers and activators of transcription 5, induced cell proliferation, or lipid accumulation in these cells by growth hormone application. CONCLUSIONS AND RELEVANCE: Our results support the hypothesis that IGF-1 acts on human meibomian gland epithelial cells and may explain why treatment with figitumumab, the IGF-1 inhibitor, causes dry eye disease. Ophthalmic care for dry eye disease may be needed when patients with cancer undergo treatment with drugs that inhibit IGF-1 action.
