transforming-growth-factor-beta and Dry-Eye-Syndromes

Over the past 20 years it has become clear that dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) is a complex multifactorial disease characterized by an immune and inflammatory process that affects the lacrimal glands and ocular surface. In this paradigm, inflammation is seen as both the cause and consequence of conjunctival and corneal cell damage. In this chapter, we identify the unique characteristics of the lacrimal gland, the role of epithelial cells, regulatory T cells, and cytokines in maintaining ocular surface homeostasis and tear secretion function. We analyze the factors inducing loss of the lacrimal gland homeostasis and its consequences, and in so doing hope to provide a picture of the role of the immune system in the pathophysiology of KCS and useful information to help understand the complexity of DES.

Topics: Dry Eye Syndromes; Homeostasis; Humans; Lacrimal Apparatus; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Authors present one of the ocular diabetic complications--diabetic keratoepitheliopathy. The aim of this article is to summarize the knowledge about diabetic keratoepitheliopathy, its causes, manifestations and treatment options. Diabetes mellitus is associated with structural and functional disturbances in eyelids, conjunctiva and cornea. There are also changes in tear film present. Diabetic neuropathy resulting from the biochemical poor control of diabetes is the probable basic cause of the pathology. Mechanisms responsible for these changes are still not well understood. The corneal and conjunctival complications may occur spontaneously. But more often they arise from undue stress of intraocular surgery procedures. The incidence of diabetic keratoepitheliopathy in diabetic patients is high. However, it is rarely diagnosed. Effectiveness of symptomatic treatment with use of common medications is not satisfactory and it needs further investigation.

Topics: Adult; Aged; Causality; Comorbidity; Conjunctival Diseases; Corneal Diseases; Diabetes Complications; Dry Eye Syndromes; Endothelium, Corneal; Extracellular Matrix Proteins; Eyelid Diseases; Humans; Prevalence; Risk Factors; Tears; Transforming Growth Factor beta

Tears have antimicrobial, nourishing, mechanical, and optical properties. They contain components such as growth factors, fibronectin, and vitamins to support proliferation, migration, and differentiation of the corneal and conjunctival epithelium. A lack of these epitheliotrophic factors--for example, in dry eye, can result in severe ocular surface disorders such as persistent epithelial defects. Recently, the use of autologous serum in the form of eye drops has been reported as a new treatment for severe ocular surface disorders. Serum eye drops may be produced as an unpreserved blood preparation. They are by nature non-allergenic and their biomechanical and biochemical properties are similar to normal tears. In vitro cell culture experiments showed that corneal epithelial cell morphology and function are better maintained by serum than by pharmaceutical tear substitutes. Clinical cohort studies have reported its successful use for severe dry eyes and persistent epithelial defects. However, the protocols to prepare and use autologous serum eye drops varied considerably between the studies. As this can result in different biochemical properties protocol variations may also influence the epitheliotrophic effect of the product. Before the definitive role of serum eye drops in the management of severe ocular surface disease can be established in a large randomised controlled trial this has to be evaluated in more detail. In view of legislative restrictions and based upon the literature reviewed here a preliminary standard operating procedure for the manufacture of serum eye drops is proposed.

Topics: Cornea; Dry Eye Syndromes; Epidermal Growth Factor; Epithelial Cells; Epithelium, Corneal; Humans; Keratoconjunctivitis; Ophthalmic Solutions; Quality Control; Serum; Transforming Growth Factor beta

Topics: Cell Division; Conjunctiva; Dry Eye Syndromes; Epidermal Growth Factor; Epithelial Cells; Epithelium; Humans; Inflammation; Lacrimal Apparatus; Metaplasia; Models, Biological; Surface Properties; Tears; Transforming Growth Factor beta

Dry eye syndrome (DES) is a chronic ocular disease that induces epithelial damage to the cornea by decreasing tear production and quality. Adequate treatment options have not been established for severe DES such as Sjogren's syndrome due to complicated pathological conditions. To solve this problem, we focused on the conditioned medium of human adipose-derived mesenchymal stem cells (hAdMSC-CM), which have multiple therapeutic properties. Here, we showed that hAdMSC-CM suppressed Benzalkonium Chloride (BAC)-induced cytotoxicity and inflammation in human corneal epithelial cells (hCECs). In addition, hAdMSC-CM increased the expression level and regulated the localisation of barrier function-related components, and improved the BAC-induced barrier dysfunction in hCECs. RNA-seq analysis and pharmacological inhibition experiments revealed that the effects of hAdMSC-CM were associated with the TGFβ and JAK-STAT signalling pathways. Moreover, in DES model rats with exorbital and intraorbital lacrimal gland excision, ocular instillation of hAdMSC-CM suppressed corneal epithelial damage by improving barrier dysfunction of the cornea. Thus, we demonstrated that hAdMSC-CM has multiple therapeutic properties associated with TGFβ and JAK-STAT signalling pathways, and ocular instillation of hAdMSC-CM may serve as an innovative therapeutic agent for DES by improving corneal barrier function.

Topics: Animals; Cornea; Corneal Injuries; Culture Media, Conditioned; Dry Eye Syndromes; Humans; Mesenchymal Stem Cells; Rats; Transforming Growth Factor beta

Woundhealing disorders characterized by impaired or delayed re-epithelialization are a serious medical problem that is painful and difficult to treat. Gelsolin (GSN), a known actin modulator, supports epithelial cell regeneration and apoptosis. The aim of this study was to estimate the potential of recombinant gelsolin (rhu-pGSN) for ocular surface regeneration to establish a novel therapy for delayed or complicated wound healing. We analyzed the influence of gelsolin on cell proliferation and wound healing in vitro, in vivo/ex vivo and by gene knockdown. Gelsolin is expressed in all tested tissues of the ocular system as shown by molecular analysis. The concentration of GSN is significantly increased in tear fluid samples of patients with dry eye disease. rhu-pGSN induces cell proliferation and faster wound healing in vitro as well as in vivo/ex vivo. TGF-β dependent transcription of SMA is significantly decreased after GSN gene knockdown. Gelsolin is an inherent protein of the ocular system and is secreted into the tear fluid. Our results show a positive effect on corneal cell proliferation and wound healing. Furthermore, GSN regulates the synthesis of SMA in myofibroblasts, which establishes GSN as a key protein of TGF-β dependent cell differentiation.

Topics: Actins; Animals; Cell Differentiation; Cell Proliferation; Conjunctiva; Cornea; Dry Eye Syndromes; Epithelial Cells; Eyelids; Female; Gelsolin; Gene Expression Regulation; Humans; Lacrimal Apparatus; Male; Mice; Myofibroblasts; Nasolacrimal Duct; Re-Epithelialization; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; Wound Healing

TSP-1 is a physiologic activator of TGF-β, a critical induction factor for Th17-mediated immunity. The purpose of this study was to investigate the role of TSP-1 in the induction of the Th17 ocular surface response to DS. TSP-1KO and WT mice were subjected to DS5 and DS10), and parameters of ocular surface disease, including corneal barrier function, conjunctival CD4(+) T cell infiltration, and GC density, were evaluated. TSP-1KO mice subjected to DS had less corneal barrier disruption, reduced loss of PAS+ GC, and decreased CD4(+) T cell infiltration in the conjunctiva. In contrast to WT, TSP-1KO mice failed to up-regulate MMP-3 and MMP-9 mRNA transcripts in the cornea and IL-17A mRNA transcripts in the conjunctiva. RAG-1KO recipients of adoptively transferred CD4(+) T cells isolated from TSP-1KO mice subjected to DS5 showed milder dry-eye phenotype and less conjunctival inflammation than recipients of CD4(+) T cells from DS5 WT control. Reconstitution of TSP-1KO mice with WT DCs prior to DS reversed the resistance of the TSP-1KO to DS-induced immunopathology. In conclusion, DC-derived TSP-1 is critical for generating the Th17 ocular surface response to DS.

Topics: Animals; Conjunctiva; Cornea; Dendritic Cells; Dry Eye Syndromes; Eye Proteins; Humans; Mice; Mice, Knockout; Stress, Physiological; Th17 Cells; Thrombospondin 1; Time Factors; Transforming Growth Factor beta

TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII) mice. These mice have a truncated TGF-β receptor in CD4(+) T cells, rendering them unresponsive to TGF-β.. DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+) T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.. Our results showed that disruption of TGF-β signaling in CD4(+) T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress.

Topics: Adoptive Transfer; Aging; Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Movement; Cell Proliferation; Conjunctiva; Dry Eye Syndromes; Epithelium; Eye; Genes, Dominant; Homeodomain Proteins; Humans; Inflammation; Keratoconjunctivitis Sicca; Mice; Mice, Knockout; Mucous Membrane; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Chemokine; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

To investigate the efficacy of umbilical cord serum eyedrops for the treatment of severe dry eye syndrome.. Fifty-five eyes of 31 patients with severe dry eye syndrome were treated with umbilical cord serum eyedrops. Symptom scoring, tear film break-up time (BUT), Schirmer test, corneal sensitivity test, and corneal fluorescein staining were performed before and 1 and 2 months after treatment, and conjunctival impression cytology was performed before and 2 months after treatment. The concentrations of epidermal growth factor (EGF), vitamin A, and transforming growth factor-beta (TGF-beta) in umbilical cord serum and normal peripheral blood serum were measured.. Two months after treatment, significant improvement was observed in symptom score (from 3.07 +/- 0.54 to 0.96 +/- 0. 58), BUT (from 3.96 +/- 1.56 to 5.45 +/- 2.54 seconds), and keratoepitheliopathy score (from 4.87 +/- 3.22 to 1.71 +/- 1.84) (P < 0.01). There was no statistically significant change in Schirmer and corneal sensitivity tests. In impression cytology, the grade of squamous metaplasia (from 2.35 +/- 0.72 to 1.44 +/- 0.69) and goblet cell density (from 80.91 +/- 31.53 to 154.68 +/- 43.06 cell/mm) improved significantly (P < 0.01). The mean concentrations of EGF, TGF-beta, and vitamin A were 0.48 +/- 0.09, 57.14 +/- 18.98, and 230.85 +/- 13.39 ng/mL in umbilical cord serum and 0.14 +/- 0.03, 31.30 +/- 12.86, and 372.34 +/- 22.32 ng/mL in peripheral blood serum, respectively.. Umbilical cord serum contains essential tear components, and umbilical cord serum eyedrops are effective and safe for the treatment of severe dry eye syndrome.

Topics: Adult; Cornea; Dry Eye Syndromes; Epidermal Growth Factor; Female; Fetal Blood; Humans; Male; Middle Aged; Ophthalmic Solutions; Pregnancy; Prospective Studies; Tears; Transforming Growth Factor beta; Vitamin A

To evaluate the conjunctival cells by impression cytology with cellulose acetate membrane.. The expression of the TGF-beta 1 in conjunctival epithelium of 24 patients with dry eye were studied by impression cytology combined with immunohistochemical staining and observed by microscope.. The cellulose acetate membrane is very transparent under the microscope. Cell's membrane by TGF-beta 1 staining is clear, cytoplasm brown and nuclei blue.. The method of impression cytology with cellulose acetate membrane is simple and has no injury to the ocular surface. Combined with immunohistochemistry staining, it is suitable to observe the conjunctival cells by this technique which has an important value for the examination of the ocular surface disease.

Topics: Aged; Cellulose; Conjunctiva; Dry Eye Syndromes; Female; Humans; Immunohistochemistry; Male; Middle Aged; Transforming Growth Factor beta

To evaluate the efficacy of autologous serum application for the treatment of dry eye in Sjögren's syndrome.. The stability of essential components (EGF, vitamin A, and TGF-beta) in preserved serum were examined following preservation at 4 degrees C and -20 degrees C. In a primary clinical trial, 12 patients with Sjögren's syndrome were treated with autologous serum (diluted to 20% with sterile saline) for 4 weeks, and vital staining of the ocular surface was compared before and after treatment. The effects of serum on mucin (MUC-1) expression were observed in cultured conjunctival epithelial cells in vitro.. EGF, vitamin A, and TGF-beta were well preserved for up to 1 month in the refrigerator at 4 degrees C and up to 3 months in the freezer at -20 degrees C. Rose bengal and fluorescein scores improved significantly from the initial scores of 5.3 and 5.6 to 1.7 and 2.5 after 4 weeks, respectively. The additive effect of human serum for cultured conjunctival epithelial cells showed significant MUC-1 upregulation on the cell surface.. Autologous serum application is a safe and efficient way to provide essential components to the ocular surface in the treatment of dry eye associated with Sjögren's syndrome.

Topics: Blood; Dry Eye Syndromes; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Mucin-1; Ophthalmic Solutions; Sjogren's Syndrome; Tears; Transforming Growth Factor beta; Vitamin A

To evaluate the efficacy of autologous serum application for the treatment of persistent epithelial defect.. Prospective, clinical, noncomparative case series.. A total of 16 eyes were studied.. Autologous serum was prepared from the patients and diluted to 20% by saline. The patients were instructed to use the autologous serum six to ten times a day. The concentration of vitamin A, epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta) was measured at 1 week and 1 month stored in the refrigerator and 1 month and 3 months in the freezer.. Time to closure of epithelial defect.. Vitamin A, EGF, and TGF-beta were stable during the 1 month in the refrigerator and 3 months in the freezer. Among 16 persistent epithelial defects, 7 (43.8%) healed within 2 weeks, 3 (18.8%) healed within 1 month, and the remaining 6 (37.5%) did not respond within 1 month. No apparent side effect of autologous serum application was observed.. Autologous serum application healed 43.8% of persistent defect within 2 weeks and 62.5% within 1 month.

Topics: Adult; Aged; Blood; Cell Movement; Corneal Diseases; Dry Eye Syndromes; Epidermal Growth Factor; Epithelium, Corneal; Female; Humans; Male; Middle Aged; Prospective Studies; Transforming Growth Factor beta; Vitamin A; Wound Healing