Distinct Inflammatory and Oxidative Effects of Diabetes Mellitus and Hypothyroidism in the Lacrimal Functional Unit.

Diabetes mellitus (DM) and hypothyroidism (HT) are prevalent diseases associated with dry eye (DE). Their impact on the lacrimal functional unit (LFU) is poorly known. This work evaluates the changes in the LFU in DM and HT. Adult male Wistar rats had the disease induced as follows: (a) DM: streptozotocin and (b) HT: methimazole. The tear film (TF) and blood osmolarity were measured. Cytokine mRNA was compared in the lacrimal gland (LG), trigeminal ganglion (TG), and cornea (CO). Oxidative enzymes were evaluated in the LG. The DM group showed lower tear secretion (p = 0.02) and higher blood osmolarity (p < 0.001). The DM group presented lower mRNA expression of TRPV1 in the cornea (p = 0.03), higher Il1b mRNA expression (p = 0.03), and higher catalase activity in the LG (p < 0.001). The DM group presented higher Il6 mRNA expression in the TG (p = 0.02). The HT group showed higher TF osmolarity (p < 0.001), lower expression of Mmp9 mRNA in the CO (p < 0.001), higher catalase activity in the LG (p = 0.002), and higher expression of Il1b mRNA in the TG (p = 0.004). The findings revealed that DM and HT induce distinct compromises to the LG and the entire LFU.

Focal lymphocytic sialadenitis and ectopic germinal centers in oral reactive lesions and primary Sjögren's syndrome: a comparative study.

Focal lymphocytic sialadenitis (FLS), an important diagnostic criterion for Sjögren's syndrome (SS) diagnosis, can also be observed when assessing minor salivary gland (mSG) biopsies from healthy asymptomatic individuals (non-SS patients). Fifty cases of primary SS (pSS group) and 31 cases of oral reactive lesions (non-SS non-sicca group) containing also typical FLS features, were assessed by morphological and immunohistochemical (CD10, CD23 and Bcl-6) analysis, aiming at the detection of GCs. All pSS cases showed FLS with focus score (FS) ≥ 1. In the non-SS non-sicca group, 12, 10 and 9 cases showed FLS with FS ≥ 1, FLS with FS < 1 and FLS associated with chronic sclerosing sialadenitis with FS < 1, respectively. The morphological analysis revealed similar frequency of GCs in pSS (20%) and non-SS non-sicca group (19%). The area (p = 0.052) and largest diameter (p = 0.245) of GCs were higher in pSS than non-SS non-sicca group. The FS and number of foci were significantly higher in pSS than non-SS non-sicca group with FS < 1. Immunohistochemistry confirmed all morphological findings (GCs showing CD23 and Bcl-6 positivity, with variable CD10 expression) and additionally in 3 and 1 cases of the pSS and non-SS non-sicca group, respectively. Moreover, another 6 and 2 cases of the pSS and non-SS non-sicca group with FS ≥ 1, respectively, showed positivity only for CD23. FLS can also be observed when assessing oral reactive lesions, which showed similar frequency of GCs with those found in pSS patients. Further studies, including functional analysis of lymphocytic populations and GCs in FLS, are encouraged.

Neurological and Inflammatory Manifestations in Sjögren's Syndrome: The Role of the Kynurenine Metabolic Pathway.

For decades, neurological, psychological, and cognitive alterations, as well as other glandular manifestations (EGM), have been described and are being considered to be part of Sjögren's syndrome (SS). Dry eye and dry mouth are major findings in SS. The lacrimal glands (LG), ocular surface (OS), and salivary glands (SG) are linked to the central nervous system (CNS) at the brainstem and hippocampus. Once compromised, these CNS sites may be responsible for autonomic and functional disturbances that are related to major and EGM in SS. Recent studies have confirmed that the kynurenine metabolic pathway (KP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating indoleamine 2,3-dioxygenase (IDO) in SS. This pathway interferes with serotonergic and glutamatergic neurotransmission, mostly in the hippocampus and other structures of the CNS. Therefore, it is plausible that KP induces neurological manifestations and contributes to the discrepancy between symptoms and signs, including manifestations of hyperalgesia and depression in SS patients with weaker signs of sicca, for example. Observations from clinical studies in acquired immune deficiency syndrome (AIDS), graft-versus-host disease, and lupus, as well as from experimental studies, support this hypothesis. However, the obtained results for SS are controversial, as discussed in this study. Therapeutic strategies have been reexamined and new options designed and tested to regulate the KP. In the future, the confirmation and application of this concept may help to elucidate the mosaic of SS manifestations.

Sjögren syndrome: what and where are we looking for?

PURPOSE OF REVIEW: Sjögren's syndrome affects exocrine glands leading to a dry mouth and dry eyes. Dry eye manifestations can precede the diagnosis of Sjögren's syndrome by many years. Innumerous spontaneous and inducible Sjögren's syndrome models have been used to study the pathogenesis of Sjögren's syndrome. This review focuses on recent human data, ocular and extraglandular manifestations of animal models, what is known, what is still unknown and how we need to look, and their correlation correspondence to human disease. RECENT FINDINGS: Hallmarks of dry eye in Sjögren's syndrome include increased corneal staining, goblet cell loss and low tear volume. Confocal microscopy and impression cytology are able to clarify new markers of the ocular disease. Extraglandular manifestations should be an alert more severe complications in the eye. Some models have strong sex and exocrine gland predilection, whereas aging generally worsens the disease phenotype. Although most models do not display a significant increase in corneal staining or tear secretion impairment, conjunctival infiltration and decrease in goblet cells are frequently seen. SUMMARY: We have seen great advances in the role of inflammation in ocular, oral and extra-glandular manifestations of Sjögren's syndrome. Several mechanisms and mediators of Sjögren's syndrome have been elucidated in animal model studies.

Topical anti-glaucoma medications effects on meibomian glands: Systematic review and meta-analysis.

Meibomian gland (MG) dysfunction and glaucoma are very prevalent ocular conditions that significantly impact patients' quality of life. A growing number of clinical and experimental studies have reported an association between the use of topical eye drops to reduce intraocular pressure and the development or exacerbation of MG dysfunction. Studies investigating the impact of glaucoma eyedrops on MG diagnostic parameters have shown variable results, particularly regarding the morphology and function of MG and tear film instability. Herein, we corroborated the findings of greater changes in morphological and functional variables related to MG in patients treated with antiglaucoma eye drops through a systematic review and meta-analysis.

Hormones and dry eye syndrome: an update on what we do and don't know.

PURPOSE OF REVIEW: Dry eye syndrome (DES) prevalence is large and its relationship with hormonal diseases is becoming clearer, although more complex. This review provides insight to this association as well as clarifying what remains unanswered about how to interpret and treat findings common to both DES and hormonal diseases. RECENT FINDINGS: Several sex hormone-related diseases are associated with DES. Hormone replacement therapy to correct such conditions has conflicting outcomes based on epidemiologic studies and clinical trials. Thyroid-associated diseases are frequently involved in DES and must be investigated in cases where the cause of the ocular disease is undetermined. Diabetes mellitus is one of the major causes of DES, whereas correcting the metabolic imbalance minimizes its ocular symptomology. Gene therapy to treat DES-related hormonal diseases is a promising option based on animal studies. SUMMARY: Diagnosis and management of hormonal diseases can minimize the ocular surface damage and severity of DES. Clinical care of DES includes patient evaluation of hormonal status. Future research requires clarification of the underlying disease mechanisms and identifying novel strategies to reprogram the endocrine system rather than chronic medication usage.

Dry eye disease treatment: a systematic review of published trials and a critical appraisal of therapeutic strategies.

Dry eye disease (DED) treatment is an area of increasing complexity, with the emergence of several new treatment agents in recent years. Evaluation of the efficacy of these agents is limited by heterogeneity in outcomes definition and the small number of comparative studies. We provide a systematic review of clinical trials (CTs) related to DED treatment and a critical appraisal of CT public databases. CT reports obtained from eight databases were reviewed, as well as public free-access electronic databases for CT registration. Data evaluation was based on endpoints such as symptoms, Schirmer test, ocular surface staining scores, recruitment of patients, type and efficacy of the drug, and the design and site of performance of the study. Forty-nine CTs were evaluated involving 5,189 patients receiving DED treatment. Heterogeneity in study design prevented meta-analysis from yielding meaningful results, and a descriptive analysis of these studies was conducted. The most frequent categories of drugs for DED in these studies were artificial tears, followed by anti-inflammatory drugs and secretagogues. Although 116 studies have been completed, according to the registration database for clinical trials, only 17 of them (15.5%) were published. Out of 185 registered CTs related to DED, 72% were performed in the USA. The pharmaceutical industry sponsored 78% of them. The identification of effective DED treatment strategies is hindered by the lack of an accepted set of definitive criteria for evaluating disease severity.

Topical Brazilian propolis improves corneal wound healing and inflammation in rats following alkali burns.

BACKGROUND: The objective of this study was to investigate the effects of the Brazilian Scaptotrigona sp propolis, a widely used folk medicine, in corneal wound healing and inflammation. METHODS: Corneal epithelial defects of 1 mm in diameter were made in the right eyes of Wistar male adult rats by cauterization with silver nitrate sticks. Subsequently, they were divided in two groups (n = 40 rats/group): Brazilian propolis (BP) group was topically treated with a microemulsion containing 1% Brazilian propolis; vehicle (VH) group received the same formulation without propolis. The epithelial defect area was photographed and measured at t = 0 (wound induction), and after 12, 24, 48 and 120 h of treatment. The inflammatory response was evaluated based on counting of neutrophils. Epithelial regeneration rates were determined based on Ki-67 expression in basal epithelial cells. Comparisons were made using the Kruskal-Wallis and the Mann-Whitney U test. RESULTS: The BP group presented both smaller epithelial defect areas at 12, 24 and 48 h and fewer corneal infiltrating neutrophils at 24 and 48 h (P < 0.01) than the VH group. These effects were associated with more pervasive Ki-67 staining in the BP group at 12 and 24 h (P < 0.05). CONCLUSIONS: Topically applied BP accelerated wound healing and reduced the inflammatory response to silver nitrate-induced corneal alkali burns in rats.

Natural history and predictors for progression in pediatric keratoconus.

We studied the demographic and clinical predictors associated with keratoconus progression in a pediatric population. Retrospective cohort study. We evaluated 305 eyes without previous surgeries from 168 patients, 9 to < 18 years old, and with a minimum 36-month follow-up in a hospital corneal ambulatory. We used Kaplan-Meyer survival curves; the dependent variable (main outcome measure) was the interval time (months) until the event, defined as an increase of 1.5 D in the maximum keratometry (Kmax), obtained with Pentacam. We evaluated the predictors: age (< or ≥ 14 years), sex, keratoconus familial history, allergy medical history, and the baseline tomographic parameters: mean keratometry (Km), Kmax (< or ≥ 55 D); and thinnest pachymetry (TP). We used log-rank tests and compared median survival times for right (RE)/left eyes (LE) and better (BE)/worse eyes (WE). A p value < 0.05 was considered significant. The patients' mean ± SD age was 15.1 ± 2.3 years old; 67% were boys, 30% were < 14 years, 15% had keratoconus familial history, and 70% were allergic. The general Kaplan-Meyer curves showed no differences between RE/LE or BE/WE. RE with allergy and LE with Kmax ≥ 55 D had smaller survival times ((95%CI 9.67-32.1), p 0.031 and (95%CI 10.1-44.1), p 0.042, respectively). For BE and WE, Kmax ≥ 55 D had smaller survival times ((95% CI 6.42- ), p 0.031 and (95%CI 8.75-31.8), p 0.043, respectively). Keratoconus progression was similar between RE/LE and BE/WE. Steepest corneas are predictors of faster progression. Allergy is also a predictor of keratoconus progression in RE.

Age-dependent changes in rat lacrimal gland anti-oxidant and vesicular related protein expression profiles.

PURPOSE: Anti-oxidation and exocytosis are important for maintaining exocrine tissue homeostasis. During aging, functional and structural alterations occur in the lacrimal gland (LG), including oxidative damage to proteins, lipids, and DNA. The aims of the present study were to determine in the aging LG: a) the effects of aging on LG structure and secretory activity and b) changes in the expression of oxidative stress markers. METHODS: To address these goals, tear secretion composition and corneal impression cytology were compared between male Wistar rats of 2 (control) and 24 (aged) months. LG morphology and the expression levels of vitamin E and malonaldehyde (MDA) were evaluated to determine the anti-oxidant activity and lipid peroxidation, respectively. RT-PCR and western blot analysis were used for the analysis of Ras related in brain GTPase protein (Rab) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins of the secretory machinery (i.e.; Rab 3d, Rab 27, vesicle-associated membrane protein-2 (Vamp-2), and syntaxin). RESULTS: Histological analysis of aged rats revealed a higher frequency of corneal epithelia metaplasia. In the acinar cells, organelles underwent degeneration, and lipofucsin-like material accumulated in the cytoplasm along with declines in the anti-oxidant marker vitamin E. Rab3d and Rab27b mRNA levels fell along with Rab3d protein expression, whereas syntaxin levels increased. CONCLUSIONS: These findings indicate that exocytotic and anti-oxidant mechanisms become impaired with age in the rat LG. In parallel with these structural alterations, functional declines may contribute to the pathophysiology caused by tear film modification in dry eye disease.

Clinical and laboratory evaluation of sicca complaints: distinctive aspects of primary, secondary and non-Sjogren syndrome.

BACKGROUND: Sjögren Syndrome (SS) is a systemic autoimmune disease with a wide spectrum of manifestations that can lead to misdiagnosis. This study describes and compares demographic, clinical, serological, and histopathological data from subjects with SS and non-Sjögren Syndrome (NSS). It also details specific features within the primary SS (pSS) and secondary SS (sSS) groups identifying sub-groups. METHODS: The sample included individuals referred to an academic medical center in Brazil for investigation of SS from 2012 to 2020. Patients were retrospectively classified as primary SS (pSS), secondary SS (sSS), or NSS, based on the American-European Consensus Group criteria (AECG-2002), after multi-professional clinical and laboratory evaluation. RESULTS: A total of 676 individuals were screened and 510 (75.4%) completed the assessments; 198 patients were classified as pSS, 149 as sSS, and 163 as NSS. Symptoms and glandular dysfunction tests were similar in the groups. Concerning pSS, extraglandular manifestations were present in 59% of patients; the elderly had more dry symptoms and peripheral neurological disorders; and 2.5% developed non-Hodgkin lymphoma. In sSS, each overlap promoted distinct clinical and laboratory variants. Several alternative diagnoses were identified as a cause of sicca complex in NSS group. CONCLUSIONS: The diagnosis of SS remains a challenge behind dryness. Up to 31% of the suspected cases had other conditions associated to the symptoms. Histopathological analysis of LSG and SSa determined the diagnostic. Aging in pSS and overlap disease in sSS were responsible for distinct phenotypes and characteristic sub-groups in SS.

Oxidative Stress in the Protection and Injury of the Lacrimal Gland and the Ocular Surface: are There Perspectives for Therapeutics?

Oxidative stress (OS) is a major disruption in the physiology of the lacrimal functional unit (LFU). Antioxidant enzymes have dual protective activities: antioxidant and antimicrobial activities. Peroxidases have been indistinctly used as markers of the secretory activity of the LFU and implicated in the pathophysiology, diagnosis and treatment of dry eye disease (DED), even though they comprise a large family of enzymes that includes lactoperoxidase (LPO) and glutathione peroxidase (GPO), among others. Assays to measure and correlate OS with other local LFU phenomena have methodological limitations. Studies implicate molecules and reactions involved in OS as markers of homeostasis, and other studies identify them as part of the physiopathology of diseases. Despite these conflicting concepts and observations, it is clear that OS is influential in the development of DED. Moreover, many antioxidant strategies have been proposed for its treatment, including calorie restriction to nutritional supplementation. This review offers a critical analysis of the biological mechanisms, diagnostic outcomes, drug use, dietary supplements, and life habits that implicate the influence of OS on DED.

Comparison of the effects of corneal and lacrimal gland denervation on the lacrimal functional unit of rats.

PURPOSE: This study aimed to compare the changes in the lacrimal functional unit in the following two models of neurogenic dry eye syndrome: sensory denervation of the cornea versus autonomic denervation of the lacrimal gland. METHODS: The neural network supports the lacrimal functional unit. It can be divided into afferent (sensory) and efferent (autonomic) pathways and is affected by severe diseases that compromise the lacrimal functional unit. Male Wistar, 8-week-old rats were divided into the following three groups: 1) control naïve (n=16 animals); 2) autonomic denervation: where rats were subjected to right lacrimal gland nerve ablation and evaluated after 1 and 2 months (1M and 2M) after the procedure (n=7 animals per subgroup, autonomic denervation 1M and autonomic denervation 2M, respectively); 3) sensory denervation induced by 0.2% benzalkonium chloride eye drops, twice a day for 7 days in the right eye (n=10 animals). The corneal sensitivity was measured using the eye wipe test with capsaicin (10 µM). The quantitative real-time PCR was performed to compare the mRNA expressions of proinflammatory cytokines, such as Il-1ß, Il-6, Tnf, Mmp9, in the cornea, trigeminal ganglion, and lacrimal gland. In addition, the mRNA of the promitotic factors in the lacrimal gland, such as Bmp7, Runx1, Runx3, Fgf10, and Smad1, was compared. RESULTS: Sensory denervation induced corneal hyperalgesia (p=0.001). Sensory denervation and autonomic denervation increased the mRNA of proinflammatory cytokines in the cornea and lacrimal gland (p<0.05), but only sensory denervation increased the mRNA levels of Il-1ß and Tnf in the trigeminal ganglion (p<0.05) compared with the control naïve. CONCLUSIONS: Autonomic denervation and sensory denervation models can have common features, such as inflammation of different parts of the lacrimal functional unit. However, hyperesthesia and inflammatory markers in the trigeminal ganglion because of sensory denervation and the expression of regenerative mediators in the lacrimal gland owing to autonomic denervation are the distinguishing features of these diseases that can be explored in future studies assessing dry eye syndrome secondary to neural damage of the lacrimal functional unit.

Multicenter prospective validation study for international chronic ocular graft-versus-host disease consensus diagnostic criteria.

PURPOSE: To validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD. METHODS: Between 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD. RESULTS: The relation between the ICCGVHD score (0-11) and NIH2014 eye score (0-4) was relatively high (r = 0.708, 95% CI: 0.637-0.767, p < 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%-98.1%) and 71.7% (95% CI: 63.0-79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%-82.1%), and the negative predictive value was 87.0% (95% CI:81.6-92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859-0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673-1.000). CONCLUSIONS: Good sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research.

Ocular findings among patients surviving COVID-19.

To describe the medium-term ophthalmological findings in patients recovering from COVID-19. Patients recovered from the acute phase of COVID-19 underwent a complete ophthalmological evaluation, including presenting and best-corrected visual acuity (BCVA), refractometry, biomicroscopy, tonometry, break-up time and Schirmer tests, indirect ophthalmoscopy, color fundus picture, and retinal architecture evaluation using optical coherence tomography. Socio-demographic data and personal medical history were also collected. According to the severity of systemic manifestations, patients were classified into mild-to-moderate, severe, and critical. Sixty-four patients (128 eyes) were evaluated 82 ± 36.4 days after the onset of COVID's symptoms. The mean ± SD duration of hospitalization was 15.0 ± 10.7 days. Seven patients (10.9%) had mild-to-moderate, 33 (51.5%) severe, and 24 (37.5%) critical disease. Median [interquartile ranges (IQR)] presenting visual acuity was 0.1 (0-0.2) and BCVA 0 (0-0.1). Anterior segment biomicroscopy was unremarkable, except for dry eye disease, verified in 10.9% of them. The mean ± SD intraocular pressure (IOP) in critical group (14.16 ± 1.88 mmHg) was significantly higher than in severe group (12.51 ± 2.40 mmHg), both in the right (p 0.02) and left eyes (p 0.038). Among all, 15.6% had diabetic retinopathy, and two patients presented with discrete white-yellowish dots in the posterior pole, leading to hyporreflective changes at retinal pigment epithelium level, outer segment, and ellipsoid layers. The present study identified higher IOP among critical cases, when compared to severe cases, and discrete outer retina changes 80 days after COVID-19 infection. No sign of uveitis was found.

Lacrimal gland atrophy and dry eye related to isotretinoin, androgen, and prolactin: differential diagnosis for Sjögren's syndrome.

This report is of three cases of sicca syndrome, initially suspected to be Sjögren's syndrome, which was ruled out by clinical and laboratory investigations. The patients were a 24-year-old woman, a 32-year-old man, and a 77-year-old woman with chronic symptoms of sicca syndrome, including dry eye syndrome. The first case was associated with the use of isotretinoin, a retinoic acid. The second was associated with the use of anabolic androgenic steroids, and the third was related to a prolactin- secreting pituitary adenoma. All cases manifested sicca, including dry eye syndrome, after those events, and the manifestations persisted. Magnetic resonance imaging revealed bilateral atrophy of the lacrimal gland. The medical history, ocular examinations, laboratory exams, and magnetic resonance images confirmed dry eye syndrome; however, the exams were all negative for Sjögren's syndrome. The lacrimal gland was absent on magnetic resonance imaging in all three cases. The clinical history revealed that the signs and symptoms appeared after chronic exposure to retinoic acid, anabolic androgenic steroids, and a prolactin-secreting pituitary adenoma, respectively. Chronic isotretinoin, anabolic androgenic steroids, and prolactin-secreting pituitary adenoma or, in this last case, its inhibitory treatment, can cause lacrimal gland atrophy, sicca syndrome, and dry eye syndrome, and a differential diagnosis of Sjögren's syndrome. Further studies on doses, time, and other susceptibilities to the long-lasting adverse effects of retinoic acid, anabolic androgenic steroids, and the repercussions of prolactin-secreting pituitary adenoma are necessary to confirm and expand upon these associations.

Lacrimal Gland as a Target Organ for Adenovirus Gene Therapy Encoding Erythropoietin for Dry Eye Induced by Benzalkonium Chloride.

Purpose: The aims of this work were a) to describe the histology of the lacrimal gland (LG) and cornea induced by an adenovirus (Ad) vector encoding the human erythropoietin (Epo) gene delivered to the LG and b) to evaluate the therapeutic potential of this strategy to prevent benzalkonium chloride (BAK) corneal toxicity.Methods: Structure and function of male Wistar rats LG were compared in the groups: 1) naïve control and 2) Ad-hEpo in the right LG (RLG). The protective response against BAK eye drops was compared among the groups 1) naïve control, 2) BAK in the right eye, 3) Ad-hEpo RLG + BAK and 4) Ad-hEpo in the right salivary gland (RSG)+BAK. Ad-hEpo groups received an injection of AdLTR2EF1a-hEPO (25 ul, 1010 particles/ml) in the right LG or SG (positive control). The BAK groups received 0.2% BAK in the right cornea twice a day. The tests applied after 7 days, included tear secretion, hEPO mRNA detection by qRT-PCR, LG and cornea histology, LG ELISA for cytokines and hematocrit.Results: hEPO mRNA was present in the Ad-hEpo RLG and RSG, but not kidney or liver samples (negative controls). TNF-α and IL-1ß increased in the LG exposed to Ad-hEpo compared to naïve control (p = .0115 and p = .0397, respectively). BAK reduced tear secretion, but this reduction was prevented by Ad-hEpo RLG+BAK and Ad-hEpo RSG+BAK (p = .017). The corneal epithelia were thinner in the BAK-treated groups independent of Ad-hEpo (p = .0009). Hematocrit increased only in the Ad-hEpo RSG group (p = .01).Conclusions: Ad-hEpo infection of rat LG and SG induces local, but only the SG infection induced systemic changes in rats. Importantly, Ad-hEpo attenuated the BAK-mediated toxic reduction in tear flow. Future studies must consider viral vector tissue tropism, biodistribution and effective therapeutic gene products for ocular surface diseases.

Limitations and advances in new treatments and future perspectives of corneal blindness.

This review is intended to describe the therapeutic approaches for corneal blindness, detailing the steps and elements involved in corneal wound healing. It also presents the limitations of the actual surgical and pharmacological strategies used to restore and maintain corneal transparency in terms of long-term survival and geographic coverage. In addition, we critically review the perspectives of anabolic agents, including vitamin A, hormones, growth factors, and novel promitotic and anti-inflammatory modulators, to assist corneal wound healing. We discuss the studies involving nanotechnology, gene therapy, and tissue reengineering as potential future strategies to work solely or in combination with corneal surgery to prevent or revert corneal blindness.