Ocular Surface Morbidities in Glaucoma

The tear film is essential for the integrity of the ocular surface. In ocular diseases such as dry eye syndrome (DES), tear film osmolarity is increased relative to normal physiological conditions. DES can be caused by deficiency in lachrymation, hyperevaporation, or surface alterations. Carnitines, shown to have osmoregulatory properties, are thought to regulate tear film osmolarity, thus protecting the corneal surface from damage. We investigated the presence of carnitine in tears, compared tear carnitine concentrations in healthy subjects and in DES patients and speculate on carnitine's potential role as a protective agent in the tear film. Tears were collected from 10 healthy subjects and 10 DES patients. Carnitine levels were assessed by high performance liquid chromatography-mass spectrometry. Carnitine and its derivatives were detected in the tear samples. In DES patients, concentrations were substantially lower than in healthy subjects; the mean concentrations were L-carnitine, 3.27 +/- 0.80 and 8.94 +/- 0.50 microMol/L; L-acetylcarnitine, 1.66 +/- 0.50 and 3.05 +/- 0.65 microMol/L; and L-propionylcarnitine, 0.30 +/- 0.11 and 0.57 +/- 0.13 microMol/L, in DES patients and healthy subjects, respectively. Although increased tear film osmolarity has been previously observed in DES patients, our study showed lower carnitine levels in DES patients than in healthy subjects, rather than the increased levels expected, although a causal relationship between carnitine levels and hyperosmolarity has not been established. The damage to ocular surface cells because of exposure to hypertonic tear film observed in DES may be partially because of an imbalance in the concentration of carnitine molecules in the tear film relative to the ocular surface cells. We propose, therefore, that carnitine solutions may have a role in preventing the adverse effects of observed hyperosmolarity and suggest that further studies are now warranted to investigate the clinical application of carnitine in the treatment of DES.

Background Glaucoma is a progressive optic neuropathy that may result in irreversible visual impairment and can diminish quality of life. Lowering intraocular pressure (IOP) through topical eyedrops is usually the primary approach to managing glaucoma. However, long-term treatment poses a risk to ocular surface health, leading to ocular surface disease (OSD). Preservative-containing eyedrops are implicated in OSD development due to their detrimental effects on the tear film and goblet cell density. OSD symptoms may impact patient compliance due to local side effects. This study aims to assess OSD in glaucoma patients receiving topical treatment, quantify symptoms and objective ocular surface parameters, and compare them to a control group not using topical glaucoma medications. Methodology Patients diagnosed with primary open-angle glaucoma receiving topical treatment and a control group were included in this study. To assess OSD, patients completed the Ocular Surface Disease Index (OSDI) questionnaire to evaluate symptoms and underwent objective measurements of ocular surface parameters using a keratograph. These parameters included assessments of bulbar redness and non-invasive keratograph tear break-up time (NIKTBUT). Results A cohort of 92 patients was subjected to examination, comprising 66 individuals diagnosed with glaucoma and 26 controls. Within the glaucoma patient subset, the mean number of IOP-lowering drugs administered was 2.42 ± 0.18, with 22.7% exclusively utilizing preservative-free eye drops. Our investigations unveiled a substantial prevalence of OSD symptoms, manifesting not only within the glaucoma cohort but also among the control group, with 72.7% and 53.8%, respectively (p = 0.224), reporting moderate-to-severe symptoms (OSDI > 23). Remarkably, OSDI scores exhibited higher values among female participants (p = 0.039) and glaucoma patients using prostaglandins (p<0.001) and were negatively correlated to the number of IOP-lowering drugs used (-0.448; p < 0.001). Furthermore, employing keratograph assessment, we discerned heightened bulbar redness (1.86 ± 0.07) in the glaucoma group compared to the control group (1.58 ± 0.07; p = 0.008). Glaucoma subgroup analyses further unveiled higher bulbar redness among glaucoma patients employing carbonic anhydrase inhibitors (p = 0.035) and applying medication preservatives (p = 0.045) but lower among individuals using beta-blockers (p = 0.018). However, the NIKTBUT did not show significant variance between the two groups (glaucoma group: 10.19 ± 0.85 seconds; control group: 10.96 ± 1.37 seconds; p = 0.499). Conclusions Our study revealed a significant prevalence of OSD in our sample, with the OSDI questionnaire showing limited specificity. The notable increase in bulbar redness pointed to an elevated prevalence of OSD among glaucoma patients, emphasizing the considerable impact of preservatives on ocular surface damage. Recognizing the potential damage to the tear film and ocular surface is crucial for glaucoma experts, who must employ comprehensive therapeutic strategies to mitigate symptoms, advocating for the preferential use of preservative-free medications, when possible, for optimizing long-term treatment.

Purpose: to evaluate the effectiveness of approaches to tear substitution in dry eye syndrome (DES) patients before cataract phacoemulsification (CPE). Material and methods. 60 DES and cataract patients who received preoperative therapy — tear substitute instillations (4 times a day, 1 month), were examined before CPE. They were divided into 2 groups each of which was subdivided into two subgroups. Group 1 included 30 mild DES patients with lipid deficiency who had a negative lipid interference test, meibomian gland dysfunction (MGD), and aqua deficiency absence (Schirmer-1 test &gt; 15 mm). The subgroup 1.1 (15 patients) received 0.18 % sodium hyaluronate (SH) instillations (Gilan comfort), while the other subgroup 1.2 received “fat-water” type emulsion instillations. Group 2 consisted of 30 moderate DES patients with lipid-aqua deficiency, who also had negative lipid interference test, MGD, and aqua deficiency presence. Subgroup 2.1 (15 patients) received 0.3 % sodium hyaluronate (SH) instillations (Gilan ultra comfort), while subgroup 2.2 patients received “fat-water” type emulsion instillations. We evaluated: the OSDI points, and tear break-up time (TBUT). Results. As a result of therapy, a positive effect of the therapy on OSDI and TBUT was observed in all subgroups. In group 1 , OSDI decrease and TBUT increase were more pronounced in subgroup 1.1 patients, however, this difference between subgroups was not statistically significant. In group 2, OSDI decrease and TBUT increase were more pronounced and statistically significant in subgroup 2.1 patients. Conclusion. In patients with mild DES and lipid deficiency, 0.18 % SH (Gilan comfort) demonstrated a positive effect on OSDI and TBUT comparable to the “fat-water” type emulsion. In moderate DES patients with lipid-aqua deficiency, 0.3 % SH (Gilan ultra comfort) demonstrated a statistically significant and more pronounced positive effect on OSDI and TBUT than the “fat-water” type emulsion.

PurposeInflammatory molecules have been demonstrated in the tear film of patients with severe dry eye disease (DED). However, little attention has been paid to the most frequent moderate forms of DED. This study analyzes tear cytokine levels and their clinical correlations in patients with moderate evaporative-type DED due to meibomian gland disease (MGD).MethodsTwenty three evaporative-type DED patients (46 eyes) of mild-to-moderate intensity and nine healthy subjects (18 eyes) were recruited. Two symptom questionnaires were self-answered and multiple DED-related clinical tests were performed. Unstimulated tears from each eye were isolated and were not pooled. Levels of 15 cytokines and chemokines were measured by multiplex bead analysis, compared with control levels, and correlated with clinical tests.ResultsFourteen out of the 15 molecules were reliably detected in 1 μl of unstimulated tears from DED patients. Epidermal growth factor (EGF), fractalkine/CX3CL1, interleukin (IL) 1-receptor antagonist (Ra), IL-8/CXCL8, interferon inducible protein (IP)-10/CXCL10, and vascular endothelial growth factor (VEGF) were found in 94%–100% of samples; IL-6 in 65% (significantly more detected in older patients); IL-1β, interferon gamma (IFN-γ), and IL-10 in 30%–48%; IL-17 in 13%; granulocyte macrophage colony stimulating factor (GM-CSF), IL-13, and tumor necrosis factor alpha (TNF-α) in 2%–9%; and IL-5 was never detected. EGF, fractalkine/CX3CL1, IL-1Ra, IP-10/CXCL10, and VEGF levels were significantly increased compared to normal controls. Pain was correlated with IL-6 and IL-8/CXCL8. Tear break-up time correlated inversely with IL1-Ra. Schirmer test and tear lysozyme levels negatively correlated with IL-1Ra, IL-8/CXCL8, fracktalkine/CX3CL1, IL-6, IP-10/CXCL10, and VEGF had the same tendency. Conjunctival staining correlated negatively with EGF and positively with IL-6.ConclusionsIn this sample of moderate evaporative-type DED patients, five inflammatory molecules were elevated. Fracktalkine was demonstrated to be present and elevated in tears in human DED. IL-1Ra, IL-6, IL-8/CXCL8, and EGF levels correlated with pain and with clinical parameters measuring tear stability, tear production or ocular surface integrity. These results suggest that inflammation plays a role not only in severe DED but also in moderate evaporative DED.

Purpose: To determine symptoms improvement in dry eye patients with short-term autologous serum (AS) eyedrops treatment using the standardized Ocular Surface Disease Index (OSDI) survey.Materials and methods: A double-blind randomized crossover clinical trial was conducted, comparing short-term (2 weeks) topical treatment with AS eyedrops diluted at 20% versus conventional artificial tears treatment in adult severe dry eye syndrome (DES) patients. The main outcome measure was assessment of symptoms with OSDI survey. Secondary outcomes were corneal and conjunctival fluorescein staining score of OXFORD and tear break up time (TBUT). The protocol was registered in www.clinicaltrials.gov, ID number: NCT00779987.Results: Twelve severe DES patients were included. Autologous serum treatment showed a statistically significant (p = 0.002) higher OSDI decrease (50%) versus conventional treatment (22%). There were no significant changes in objectives parameters (OXFORD and TBUT).Conclusions: Severe DES patients treated with AS achieve better symptoms improvement compared to artificial tears in a short-term treatment.

Seeing through tears: Understanding and managing dry eye disease.

Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are common gastrointestinal disorders with extraesophageal manifestations (EGERD). Studies showed a correlation between GERD/LPR and ocular discomfort. Our aim was to report the prevalence of ocular involvement in patients with GERD/LPR, describe clinical and biomolecular manifestations, and provide a treatment strategy for this novel EGERD comorbidity. Fifty-three patients with LPR and 25 healthy controls were enrolled in this masked randomized controlled study. Fifteen naive patients with LPR were treated with magnesium alginate eye drops and oral therapy (magnesium alginate and simethicone tablets) with a 1-month follow-up. Clinical ocular surface evaluation, Ocular Surface Disease Index questionnaire, tear sampling, and conjunctival imprints were performed. Tear pepsin levels were quantified by ELISA. Imprints were processed for human leukocyte antigen-DR isotype (HLA-DR) immunodetection and for HLA-DR, IL8, mucin 5AC (MUC5AC), nicotine adenine dinucleotide phosphate (NADPH), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY) transcript expression (PCR). Patients with LPR had significantly increased Ocular Surface Disease Index ( P < 0.05), reduced T-BUT ( P < 0.05), and higher meibomian gland dysfunction ( P < 0.001) compared with controls. After treatment, tear break-up time (T-BUT) and meibomian gland dysfunction scores improved to normal values. Pepsin concentration increased in patients with EGERD ( P = 0.01) and decreased with topical treatment ( P = 0.0025), significantly. HLA-DR, IL8, and NADPH transcripts were significantly increased in the untreated versus controls and comparable significant values were obtained after treatment ( P < 0.05). MUC5AC expression significantly increased with treatment ( P = 0.005). VIP transcripts were significantly higher in EGERD than in controls and decreased with the topical treatment ( P < 0.05). No significant changes were observed in NPY. We report an increase in prevalence of ocular discomfort in patients with GERD/LPR. The observations of VIP and NPY transcripts demonstrate the potential neurogenic nature of the inflammatory state. Restoration of the ocular surface parameters suggests the potential usefulness of topical alginate therapy.

The corneal contact bandage lens has gained clinicians acceptance for their wearing comfort and definite curative effects in ocular surface protection and damage reparation.Recently, application fields of contact bandage lens are still expanding with continuous exploration and development of new materials and function.To non-infectious ocular surface diseases, bandage lens obviously alleviate irritate symptoms and accelerate tissue healing.The application of bandage lens in infectious ocular surface diseases remains controversial.The bandage lens has become a routine intervention of ocular trauma and corneal perforation.It can also improve ocular surface microenvironment after the surgery of glaucoma, cataract, pterygium, corneal transplantation and refraction.It is an adjuvant therapy for aniridia, dry eye and children ocular surface diseases.This review summarized the history, current corneal contact bandage lens in preventing and treating ocular surface diseases. Key words: Corneal contact lens; Bandage lens; Ocular surface diseases; Clinical research

Objective To evaluate the dry eye status of nursing school students and understand their ocular surface health. Methods Using the convenience sampling method, a total of 90 nursing students studying in the Nursing College of Capital Medical University in March 2018 were selected as the research objects. The OCULUS Jenvis-OSDI dry eye questionnaire and OCULUS ocular surface comprehensive analyzer were used subjectively and objectively to analyze the heath of ocular surface. Results According to the OSDI dry eye questionnaire, mild dry eyes were 21 cases accounted for 23.3%, moderate dry eyes were 42 cases accounted for 46.7%, and severe dry eyes were 21 cases accounted for 23.3%. The main symptom of dry eye was foreign body sensation, accounting for 53.3%. The secondary symptoms were photophobia and blurred vision, which accounted for 46.7% and 40%, respectively. The OCULUS ocular surface comprehensive analyzer showed that the amount of tear secretion in both eyes was normal. In dry eye grading based on average tear film break-up time, critical dry eye accounted for about 60% and dry eye accounted for about 10%. Eye red analysis showed that 9 patients (10%) with hyperemia score>2.0 were dry eye caused by inflammation. Conclusions The nursing school students have a high incidence of dry eye and subjective symptoms. It indicates that the students overuse eye and do not pay attention to eye hygiene. It is the responsibility of the nursing teacher to carry out health education for students, popularize scientific and rational use of eye knowledge, and pay attention to eye health. Key words: Students, nursing; Dry eye; Ocular surface disease; Investigation

Background: Dry eye disease is a multifactorial disorder of the ocular surface and is a common cause of postoperative discomfort following cataract surgery, especially in the elderly population. Symptoms such as foreign body sensation, grittiness, ocular fatigue, and visual disturbance significantly affect the quality of life and patient satisfaction after surgery. Cataract surgery, being the most frequently performed ophthalmic procedure, particularly for senile cataract, can exacerbate pre-existing or subclinical ocular surface disease due to surgical trauma, corneal nerve damage, and postoperative topical medications. Early identification and management of dry eye are therefore essential to improve postoperative outcomes. Methods: This prospective comparative study included 160 patients undergoing cataract surgery, divided equally into two groups: 80 patients underwent manual Small Incision Cataract Surgery (SICS) and 80 underwent phacoemulsification. Patients were evaluated preoperatively (1 day before surgery) and postoperatively at 7, 30, and 90 days. Dry eye was assessed using the Ocular Surface Disease Index (OSDI) questionnaire, Tear Break-Up Time (TBUT), and Schirmer’s test. The incidence and severity of dry eye and ocular surface damage were compared between the two surgical techniques. Results: A significant increase in dry eye signs and symptoms was observed during the first postoperative week in both groups, evidenced by increased OSDI scores and reduced TBUT and Schirmer’s values. OSDI and TBUT showed better correlation with dry eye severity compared to Schirmer’s test. By 30 and 90 days postoperatively, tear film parameters gradually improved and returned to near-normal levels. Phacoemulsification was associated with a significantly lower incidence and severity of postoperative dry eye compared to manual SICS. Conclusion: Dry eye disease is a common but transient postoperative complication following both manual SICS and phacoemulsification. Symptoms are more pronounced in the early postoperative period, likely due to frequent use of topical medications and ocular surface toxicity and resolve as medications are tapered. OSDI and TBUT are more reliable indicators of postoperative dry eye than Schirmer’s test. Early postoperative ocular surface evaluation and the use of tear substitutes can reduce epithelial damage and improve patient comfort. Phacoemulsification causes less ocular surface disturbance and offers better postoperative patient well-being.

Matrix metalloproteinases (MMPs) are a group of endogenous protease which degrades extracellular matrix system. Their inhibitors, tissue inhibitor of metalloproteinases (TIMPs) and MMPs systems, degrade and restore the extracellular matrix (ECM). Expression level imbalance of MMPs and TIMPs system are closely related to the occurrence of ocular diseases, especially ocular surface diseases. It is believed that the excessive expression of MMPs, including MMP-1, MMP-3 and MMP-9 in fibroblasts in conjunctival stroma are key factors to cause imbalance between MMPs and TIMPs. Imbalance between MMPs and TIMPs leads to the melt of collagen fiber, elastic fiber degeneration, excessive degradation of conjunctival matrix and Tenon capsule, causing abnormal ocular surface tears. Ocular surface tear abnormality destroys the stability of the ocular surface environment, involved in many ocular surface diseases such as dry eye, conjunctival relaxation, pterygium, keratitis, and many other pathological changes of ocular surface diseases. (Int Rev Ophthalmol, 2017, 41: 32-37) Key words: matrix metalloproteinases; tissue inhibitor of metalloproteinases; ocular surface disease

Dry eye is a common inflammatory condition of the ocular surface. While oral omega-3 supplementation for its treatment has been extensively studied, recent large-scale studies have cast doubt on their efficacy. However, efficacy of topical omega-3 has yet to be reviewed. We performed a systematic search of PubMed, Embase, and Cochrane databases for all studies evaluating topical omega-3 in dry eye. Five human and five animal studies were included. Of the five human studies, two were on dry eye disease (DED), one was on contact lens discomfort, and two were on patients undergoing corneal collagen crosslinking. In humans, there is promising evidence for improved ocular surface staining and tear break-up time compared to controls, equivocal evidence for improvements to ocular surface symptoms and meibomian gland dysfunction, and no effect on increasing tear production. Data from animal models largely agree with these findings, and further reveal decreased inflammatory cytokines and monocyte infiltration. Our review suggests that topical omega-3 is a promising treatment for dry eye, but also points to the paucity of evidence in this field. Further trials in humans are required to characterize effects of topical omega-3 and optimize its dosage.

It is well-known that diabetes is one of the major causes of dry eye disease (DED). As DED can lead to serious ocular surface complications such as punctate keratitis, corneal erosion, corneal scarring, corneal perforation and visual loss, research is ongoing to investigate ways of improving the diagnosis of DED in patients with diabetes. This thesis investigated the role of inflammatory cytokines and metabolic proteins in tear fluid as a non-invasive, objective measure of inflammation in the diagnosis of type 2 diabetes (T2D)-related DED. In this thesis, a number of studies were performed to investigate potential tear fluid biomarkers and comparing them to the established clinical and laboratory measures used in DED diagnosis. It was important to evaluate the clinical behaviours of eye care professionals, such as ophthalmologists and optometrists with respect to the diagnosis and management of diabetes-related DED (Chapter 3). Thus, the online survey was conducted among 194 eye care professionals who work in the UK and Mongolia, to evaluate and compare their preferences for specific clinical procedures used to diagnose the presence of DED in diabetes. For example, how these may differ, depending on the practitioners' profession (ophthalmologist and optometrist) and the countries they work in. This study is the first time that the awareness of eye care professionals in the diagnosis and the management of diabetes-related DED in different regions of the world has been investigated. The results of the survey showed that eye care professionals in both countries have similar practice behaviours for diagnosing and treating diabetes-related DED. That is, ophthalmologists in the UK and in Mongolia have similar practice behaviours in diagnosing diabetes-related DED, and its severity, as for optometrists in the UK. Before commencing the studies to analyse protein biomarkers in tear fluids, it was important to establish the best possible means of sampling and storing tear samples, along with the optimal method of analysing them (Chapter 4). Therefore, a study was conducted to investigate the methodology of tear sampling, storage, analysis, sample centrifugation duration and speed. For tear biomarker assessment, a pilot study investigating the detectability of metabolic proteins in 1 μl tears was conducted (Chapter 5). This study is the first time that metabolic proteins such as Leptin, Insulin, C-peptide, GIP and active Ghrelin, have been shown to be detected in human tears collected from “healthy” individuals using Luminex Xmap technology. The results of this study showed that Leptin could be used in the future as a potential diagnostic biomarker of ocular surface disorders and, possibly, in determining the effects of metabolic disorders, as it has a low intra-subject confidence interval (CI) and a high intra-class correlation coefficient (ICC). A pilot study investigating the correlation between the presence of tear fluid inflammatory cytokines and tear fluid stability (assessed using tear evaporation rate [TER]; and non-invasive tear break-up time [NITBUT]) in healthy subjects was carried out (Chapter 6). This study also investigated the effect of time of day on TER and NITBUT values, and its possible correlation with tear cytokine concentrations in healthy subjects. The results revealed that the NITBUT and TER values had no significant variability over a day, or on different days, in healthy subjects, when the humidity and temperature of the examination room were constant. However, some tear fluid cytokine concentrations did show inter- and intra-day variability, without any consistent correlation with TER diurnal variation. Before commencing the study in a large cohort, a pilot study investigating the detectability of inflammatory cytokines and metabolic proteins in 1 μl tears collected from patients with type 2 diabetes (T2D; with and without DED) and DED-only (without T2D) was conducted (Chapter 7). The concentrations of 14 inflammatory cytokines, six metabolic proteins, ocular surface parameters, DED-related symptoms and quality of life (QoL) were evaluated and compared in a total of 122 subjects divided into four study groups as: T2D with DED, T2D-only (without DED), DED-only (without T2D) and healthy controls (Chapter 8). Overall, the results of this study showed that the ocular surface parameters and DED-related symptoms were similar for patients in the T2D+DED group and the DED-only group. In addition, patients in the T2D-only group had similar ocular surface parameters to healthy controls. Tear fluid Interleukin (IL)-6 and IL-8 concentrations were significantly higher in the T2D+DED group than the T2D-only group, DED-only group and healthy controls, which suggests that IL-6 and IL-8 could potentially be diagnostic biomarkers of T2D-related DED. These studies show that tear fluid biomarker analysis is feasible and it can be utilised in the objective diagnosis of T2D-related DED. This research helps to improve the understanding of the inflammatory mechanisms and markers of DED in T2D. However this complex process will require further research to identify the most appropriate biomarkers.

Purpose Ocular Surface Disease (OSD), recognized in 50% of glaucoma patients, can decrease anti‐glaucoma therapy compliance. Benzalkonium chloride (BAK) has been shown to induce OSD. Catioprost® is an unpreserved latanoprost 0.005% cationic emulsion. The design of a study comparing the efficacy and safety of Catioprost® versus a BAK‐free prostaglandin agonist, Travatan Z® (travoprost 0.004%) in patients with glaucoma and OSD is described.Methods Patients with elevated IOP at baseline requiring treatment with ocular anti‐hypertensive therapy were enrolled in this multicenter, phase II, investigator‐masked, randomized study. Following a washout period, patients demonstrating OSD symptoms and signs (corneal fluorescein staining, CFS, score≥1 on the modified Oxford scale and a tear film break up time, TFBUT, ≤10) in at least one eye at the baseline visit were randomized to either Catioprost® or Travatan Z® QD with follow‐up study evaluations at month 1 and 3.Results 105 patients were randomized. Change in diurnal IOP, a change in the global symptoms (ocular discomfort, burning, dryness, grittiness, stinging) and objective signs (CFS, TFBUT, conjunctival hyperemia) of OSD at month 1 and 3 will be presented. Safety outcomes will also be reported.Conclusion Preservative free prostaglandin agonists reduce the risk of ocular toxicity associated with BAK. However, their effect on restoring ocular surface damage is unclear. In this study, the efficacy and safety of an unpreserved latanoprost 0.005% cationic emulsion relative to BAK‐free travoprost 0.004% solution on reducing IOP and improving the signs and symptoms of OSD will be revealed. Commercial interest

Cystic fibrosis (CF) is an autosomal recessive genetic disorder. The disease affects all secretory epithelia including the eye and belongs to the group of ocular surface epithelial diseases, termed keratoconjunctivitis sicca that develop in dry eye. In the pathogenesis of dry eye, inflammation plays a crucial role. The aim of this study was to assess the potential role of MIP-1beta in the pathogenesis of dry eye syndrome in patients with CF. We assayed MIP-1beta levels in tear fluid and serum of 28 patients with CF and 27 controls by ELISA. The ophthalmic examinations including the tests for dry eye were used to study the ocular surface. The tear levels of MIP-1beta in the CF patients were significantly higher than those in the controls. Dry eye syndrome was observed in 10 (36%) CF patients. The tear fluid levels of MIP-1beta were significantly raised in CF patients with dry eye syndrome compared with CF patients without dry eye symptoms. Our results suggest a crucial role of CCL4/MIP-1beta in the development of dry eye syndrome in CF patients and immunopathogenesis of ocular surface changes in this disease. Clarification of the role of CCL4/MIP-1beta in the pathogenesis of ocular findings in CF patients will be useful in establishing immunotherapeutic strategies for this disease.