Materiały źródłowe

• #1 The Pathophysiology, Diagnosis, and Treatment of Dry Eye Disease (30.01.2015)

  https://di.aerzteblatt.de/int/archive/article/167472

  Dry eye disease (DED) is common; its prevalence around the world varies from 5% to 34%. Its putative pathogenetic mechanisms include hyperosmolarity of the tear film and inflammation of the ocular surface and lacrimal gland. […] Recent studies have shown that dry eye is an inflammatory disease that has many features in common with autoimmune disease. Stress to the ocular surface (environmental factors, infection, endogenous stress, antigens, genetic factors) is postulated as the pathogenetic triggering mechanism. Proinflammatory cytokines, chemokines, and matrix metalloproteinases lead to the expansion of autoreactive T helper cells which infiltrate the ocular surface and lacrimal gland. The result is a vicious circle of damage to the ocular surface and inflammation. […] Dry eye disease is defined as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and subacute inflammation of the ocular surface.

• #1 The pathophysiology of dry eye disease: What we know and future directions for research

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5657523/

  Clinical and laboratory studies performed over the past few decades have discovered that dry eye is a chronic inflammatory disease that can be initiated by numerous extrinsic or intrinsic factors that promote an unstable and hyperosmolar tear film. […] These changes in tear composition, in some cases combined with systemic factors, lead to an inflammatory cycle that causes ocular surface epithelial disease and neural stimulation. […] Acute desiccation activates stress signaling pathways in the ocular surface epithelium and resident immune cells. […] This triggers production of innate inflammatory mediators that stimulate the production of matrix metalloprotease, inflammatory cell recruitment, and dendritic cell maturation. […] These mediators combined with exposure of autoantigens can lead to an adaptive T-cell mediated response.

• #1 Pathophysiology of dry eye disease and novel therapeutic agents

  https://scielo.org.za/scielo.php?script=sci_arttext&pid=S2410-15162024000100021&lang=es

  Dry eye disease (DED) is one of the most common ocular surface diseases, which is caused by decreased tear production or increased evaporation. […] All reviewed papers showed that DED is characterised by the loss of homeostasis, resulting in tear film instability, hyperosmolarity and inflammation of the ocular surface. […] The causes of DED are complicated and multifactorial but currently, inflammation of the ocular surface is believed to be the main cause. […] Dysfunction of more than one tear producing cells and/or glands leads to unstable tear film. Increased tear osmolarity (hyperosmolarity) is the hallmark or core mechanism of DED that activates stress signalling pathways in the ocular surface epithelium and triggers production of innate inflammatory molecules that initiate a vicious cycle that leads to decline in tear function and worse symptoms.

• #1 Pathogenesis and Classification of Dry Eye Disease | Ento Key

  https://entokey.com/pathogenesis-and-classification-of-dry-eye-disease/

  Global features of dry eye include the following: An unstable tear film, Tear film hyperosmolarity, Ocular surface damage, Symptoms of ocular surface distress. […] Causes of ocular surface disease in dry eye include the following: Chronic hyperosmotic stress, An unstable tear film, Inflammation, Alterations in tear and surface mucins, Tear lipid abnormalities, Evaporative tear loss, Decreased lubricity between the lids and the ocular surface. […] Several pathogenetic mechanisms of dry eye have been proposed during a period spanning 40 years. […] The concept of the mucin-deficient dry eye was introduced. In these patients there was evidence of extensive inflammation of the conjunctiva with a loss of the mucin-producing goblet cells of the conjunctiva. […] The hallmark of the mucin-deficient dry eye was very rapid breakup of the tear film.

• #1 The pathophysiology of dry eye disease: What we know and future directions for research

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5657523/

  Hyperosmolar stress has a direct pro-inflammatory effect on the ocular surface epithelium. […] It has been shown to activate mitogen-activated protein kinases (MAPKs), stimulate secretion of pro-inflammatory cytokines (e.g. IL-1, TNF-, and IL-6), chemokines and matrix metalloproteinases such as MMP-3 and MMP-9 and induce apoptosis. […] The interaction of these inflammatory mediators is complex and they have been shown to upregulate each other; thus amplifying the inflammatory cascade. […] MMP-9 contributes to corneal barrier disruption by lysing tight junctions in the superficial epithelium. […] Increased tear MMP-9 has also been detected in other ocular surface diseases, such as atopic and vernal keratoconjunctivitis, corneal ulceration, recurrent corneal erosions and ocular burns that also have corneal barrier disruption.

• #1 Dry Eye Disease (Keratoconjunctivitis Sicca): Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1210417-overview

  Various proinflammatory cytokines that may cause cellular destruction, including interleukin (IL)1, IL-6, IL-8, TGF-, tumor necrosis factor alpha (TNF-), and chemokine ligand 5 (CCL5 or RANTES), are altered in patients with dry eye disease. […] Inflammatory cytokines, in addition to inhibiting neural function, also may convert androgens into estrogens, resulting in meibomian gland dysfunction. An increased rate of apoptosis also is seen in conjunctival and lacrimal acinar cells, perhaps owing to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) also are present in the epithelial cells. […] Mucin deficiency leads to poor wetting of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production.

• #1 The pathophysiology of dry eye disease: What we know and future directions for research

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5657523/

  Evidence indicates that the initial innate immune response to dryness is followed by an adaptive CD4+ T cell autoimmune response in mice exposed to desiccating stress and patients with Sjgren syndrome (SS) and non-SS associated aqueous tear deficiency. […] While the target autoantigen(s) in this autoimmune reaction have not been identified, members of the kallikrein family have been implicated as putative antigens in some studies. […] Disrupted immune tolerance in dry eye elicits leads to dendritic cell maturation and generation of autoreactive T effector cells in mouse dry eye models. […] Human dry eye patients have an increased number of conjunctival dendritic cells and a higher percentage of cells expressing the dendritic cell maturation marker HLA-DR. […] Depletion of dendritic cells prevented the development of dry eye disease in mice subjected to desiccating stress.

• #1 The pathophysiology of dry eye disease: What we know and future directions for research

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5657523/

  Mature dendritic cells prime antigen-specific Th1 and Th17 effector T cells in the conjunctival draining lymph nodes. […] Several laboratories have identified interferon gamma (IFN-) and IL-17, produced by Th1 and Th-17 cells respectively, as critical effector cytokines in dry eye. […] IFN- promotes conjunctival goblet cell loss and lacrimal gland acinar loss, while IL-17 cause corneal barrier disruption and lymphangiogenesis in mouse dry eye models. […] The disruption of immune tolerance and generation of effector T cells suggests inadequate suppression by regulatory T cells (Tregs). […] Indeed, dysfunctional Tregs that cannot suppress T effector activity, but produce IFN- and IL-17 have been observed in mouse models of dry eye induced by desiccating stress or associated with aging. […] These studies suggest that similar to the ocular surface, a vicious cycle of inflammation and apoptosis involving infiltrating cells and glandular acinar cells perpetuates LG inflammation leading to glandular dysfunction in SS and age-related dry eye.

• #1 Dry Eye Disease (Keratoconjunctivitis Sicca): Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1210417-overview

  Tear hyperosmolarity and instability are the principal components of the primary drivers of dry eye disease. The 2 major types of DED, aqueous deficient dry eyes (ADDE) and evaporative dry eyes (EDE), can both be related to tear hyperosmolarity and instability. […] In EDE, tear film lipid deficiency from meibomian gland dysfunction results in excessive evaporation of the tear film. This leads to tear hyperosmolarity in the presence of normal lacrimal function. […] In ADDE, reduced tear secretion from the lacrimal glands due to lacrimal gland damage (for example, in Sjgren disease) leads to the hyperosmolarity of the tear film despite a normal evaporation rate of the tear film. […] Both EDE and ADDE often co-exist and contribute to the mixed type of dry eye disease. Tear hyperosmolarity, which is present in both EDE and ADDE, eventually enters into a vicious cycle that leads to chronic inflammation, loss of conjunctival goblet cells, ocular surface damage, and self-perpetuating disease.

• #1 Etiology of Dry Eye | IntechOpen

  https://www.intechopen.com/chapters/86159

  Tear film hyperosmolarity causes an increase in osmolarity of the ocular surface epithelium and stimulates a cascade of inflammatory events involving MAP kinases and NFkB signaling pathways and the secretion of inflammatory cytokines. […] The major groups and subgroups of dry eye are described below. […] Dysfunction in the lacrimal gland leads to the aqueous-deficient dry eye that reduces lacrimal tear secretion and volume. […] Tear-deficient dry eye causes tear hyperosmolarity. […] Sjogren syndrome is an exocrinopathy that involves the lacrimal and salivary glands targeted by an autoimmune process. […] The inflammatory process in the glands leads to the expression of autoantigens in the epithelium of the ocular surface with the homing of tissue-specific CD4 and CD8 T-cells. […] A neurosecretory block influences the hyposecretion of the tears due to the effects of immune cell influx and secretion of inflammatory cytokines or the presence of circulating antibodies directed against muscarinic receptors within the glands.

• #1 Etiology of Dry Eye | IntechOpen

  https://www.intechopen.com/chapters/86159

  Non-Sjogren syndrome dry eye is a type of ADDE caused due to lacrimal dysfunction but not with the characteristics of systemic autoimmunity; age-related dry eye is the most common. […] Evaporative dry eye is caused due to increased water loss (evaporation) from the tear film in the presence of normal lacrimal secretory function. […] The loss of the tear film lipid layer due to meibomian gland dysfunction (MGD) is the leading cause of evaporative dry eye.

• #1 Dry Eye treatments in Escondido|R. Bernardo| San Diego

  https://beyondoptometry.com/dry-eye/

  Dry Eye Disease (DED), is a multi factorial disease of the ocular surface with loss of tear film stability often times from unhealthy or insufficient barrier oil later. As a result, variety of symptoms such as itchy, red, and strained eyes are common. […] The pathogenesis of Meibomian Gland Dysfunction and Dry Eye Disease has been described as a vicious cycle in which inflammation is the essential factor. MGD happens for different reasons such as skin disorders, eyelid inflammation, and microbial infections, resulting in thickening of the glands, reducing their normal function, and increased meibum viscosity. MGD results in instability of the tear film which increases exposure of the corneal nerve plexus, stimulating more inflammation. The result is a vicious DED cycle that feeds back to the MGD cycle.

• #1 Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction | British Journal of Ophthalmology

  https://bjo.bmj.com/content/100/3/300

  The International Workshop on MGD proposed a complex pathway involved in the self-enforcing vicious circles of MGD. […] It is likely that MGD is a heterogeneous complex condition arising from any combination of the following five separate pathophysiological mechanisms: eyelid inflammation, conjunctival inflammation, corneal damage, microbiological changes and tear film instability-associated DED. […] The following four sequential events comprise the MGD loop: stasis of the meibum, bacterial proliferation, release of lipases and esterases, and increased meibum melting temperature. […] Skin diseases (eg, ocular rosacea) are also believed to play a role in MGD pathology; approximately 90% of patients with ocular rosacea show eyelid changes that are similar to those observed in patients with MGD.

• #1 The pathophysiology of dry eye disease: What we know and future directions for research

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5657523/

  Cornea barrier disruption develops by protease-mediated lysis of epithelial tight junctions leading to accelerated cell death, desquamation, an irregular poorly lubricated cornea surface and exposure and sensitization of epithelial nociceptors. […] Conjunctival goblet cell dysfunction and death are promoted by the T helper 1 cytokine interferon gamma (IFN-). […] These epithelial changes further destabilize the tear film, amplify inflammation and create a vicious cycle. […] The numerous extrinsic (e.g. desiccating environment, exposure) and intrinsic (e.g. aging, autoimmunity, drying medications) factors that can contribute to this inflammatory cycle demonstrate why it is often difficult to ascribe a single cause for most cases of dry eye disease and the importance of addressing all modifiable risk factors.

• #1 The Role of Neuropeptides in Pathogenesis of Dry Eye

  https://www.mdpi.com/2077-0383/10/18/4248

  Neuropeptides are thought to be important factors in the pathogenesis of dry eye disease, as suggested by the well-known role between the nervous and immune systems, and several recently published studies have elucidated the previously unknown pathogenic mechanisms involved in the role of the neuropeptides secreted from the corneal nerves in dry eye disease. […] The current concept of immunopathogenesis of DED is summarized as follows. Hyperosmolar stress caused by desiccating stress (DS) can hijack the physical barrier system through the activation of intracellular signaling pathways, mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) stress signaling pathways and can initiate proinflammatory cytokine production. […] In DED-induced corneas, decreased density and altered morphologic structure of the subbasal nerves have been reported.

• #1 Dry Eye Syndrome – EyeWiki

  https://eyewiki.org/Dry_Eye_Syndrome

  Dry eye syndrome is a general term that describes the state of the front of the eye in response to a breakdown in the natural layer of tears that coats the front of the eye, called the tear film. […] When the tear film becomes unhealthy, it breaks down in different places on the cornea and conjunctiva, leading not only to symptoms of irritation, but also to unstable and intermittently changing vision. […] Corneal hyperesthesia and/or reduced sensation may be present in severe and chronic dry eye disease. Sensory denervation may cause dry eye by reducing the afferent signaling of tear production, reducing the blink rate, and by altering trigeminal nerve influences on ocular epithelial health. Decreased corneal sensation can also result from chronic dry eye. […] Tear hyperosmolarity can induce tear film instability by modifying the interaction between tear film lipids and proteins, damaging the epithelial cell membranes, triggering inflammation, and stimulating corneal nerves.

• #1 TRPV1 in Dry Eye Disease

  https://www.imrpress.com/journal/FBL/29/5/10.31083/j.fbl2905175/htm

  Dry eye disease (DED) is a prevalent ophthalmic ailment with intricate pathogenesis and that occurs primarily due to various factors which affect the ocular surface. DED is characterized by the disruption of tear film homeostasis, inflammatory reaction, and neuroparesthesia. […] There is accumulating evidence that implicates TRPV1 in the initiation and progression of DED through its detection of hypertonic conditions and modulation of inflammatory pathways. […] Increased expression or activity of Transient receptor potential vanilloid 1 (TRPV1) was recently associated with the pathogenesis of DED. Over the past 30 years, TRPV1 was shown to have crucial functions in sensing hypertonic environments and ocular surface injury, as well as in regulating inflammatory pathways. […] The aim of this paper was therefore to provide a comprehensive overview of TRPV1 expression and function in ocular tissues and cells, as well as its importance in the pathophysiology of DED.

• #1 TRPV1 in Dry Eye Disease

  https://www.imrpress.com/journal/FBL/29/5/10.31083/j.fbl2905175/htm

  Research has demonstrated that TRPV1 functions as a hypertonic osmotic sensor. Therefore, inhibition of TRPV1 could provide osmotic protection and minimize ocular surface damage caused by hyperosmolality. […] TRPV1 perceives a range of environmental stimuli and is triggered by these to stimulate cellular Ca2+ influx, which in turn induces the activation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB, leading to increased production of pro-inflammatory cytokines. […] Neurogenic inflammation is a particularly important mechanism by which TRPV1 causes inflammation of the ocular surface in DED. […] The corneal epithelium is most susceptible to damage during dry eye conditions. It serves as a protective shield against damaging stimuli, and epithelial cells are maintained by the migration of basal cells to the upper layers of the tissue to replace terminally differentiated cells at the surface. […] The loss or blocking of TRPV1 expression in mice with alkali burns inhibits the production of TGFβ and other proinflammatory factors, resulting in severe and long-lasting corneal inflammation and scarring.

• #1 How dry eye disease can become a complex vicious cycle

  https://europe.ophthalmologytimes.com/view/how-dry-eye-disease-can-become-a-complex-vicious-cycle

  The vicious cycle theory is a new way of understanding dry eye disease and may help improve prevention and treatment strategies. […] Dry eye is a very complex disease. It is not just a question of lack of water and so it is impossible to treat patients just by lubricating the eye with water. It is a disease that involves a series of self-stimulating biological events, and the lack of tears, insufficient tear quality or their instability results in direct mechanical and/or osmotic stress, which causes further damage. […] In addition, goblet cell loss results in further tear film instability or imbalance and thus, dryness. The drier the eyes become, the more inflammatory they become and the greater the inflammation, the more the eyes continue to dry out, i.e., a vicious cycle occurs. […] To give more context on the vicious cycle theory, the dryness of the eye stimulates the nerves, the inflammatory reaction and inflammatory cells, and those act as stimulation for further damage, and so tears and their quality are reduced further, resulting in the disease becoming chronic.

• #1 Dry eye syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Dry_eye_syndrome

  Dry eye syndrome can lead to blurred vision, instability of the tear film, increased risk of damage to the ocular surface such as scarring of the cornea, and changes in the eye including the neurosensory system. […] Dry eye occurs when either the eye does not produce enough tears or when the tears evaporate too quickly. […] The most common cause of dry eye is increased evaporation of the tear film, typically as a result of meibomian gland dysfunction (MGD). […] Any abnormality of any one of the three layers of tears produces an unstable tear film, resulting in symptoms of dry eyes. […] In advanced cases, the epithelium undergoes pathologic changes, namely squamous metaplasia and loss of goblet cells. […] Some severe cases result in thickening of the corneal surface, corneal erosion, punctate keratopathy, epithelial defects, corneal ulceration (sterile and infected), corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation. […] Another contributing factor may be lacritin monomer deficiency. […] The ocular surface microbiome, composed of a diverse community of microorganisms, has been implicated in the pathogenesis of dry eye syndrome, potentially influencing ocular surface inflammation and homeostasis.

• #1 What is the impact of microbiota on dry eye: a literature review of the gut-eye axis | BMC Ophthalmology | Full Text

  https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-024-03526-2

  Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. […] However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease. […] Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects.

• #1 Dry Eye Disease (Keratoconjunctivitis Sicca): Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1210417-overview

  Normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin, and phospholipase A2, is decreased in dry eye disease. […] Androgens are believed to be trophic for the lacrimal and meibomian glands. They exert potent anti-inflammatory activity via production of transforming growth factor beta (TGF-), suppressing lymphocytic infiltration. […] SS-associated dry eye disease leads to a chronic inflammatory state, with the production of autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF), fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (eg, anti-RO [SS-A] and anti-LA [SS-B]); inflammatory cytokine release; and focal lymphocytic infiltration of the lacrimal and salivary gland, with glandular degeneration and induction of apoptosis in the conjunctiva and lacrimal glands.

• #1

  https://journals.lww.com/jomh/fulltext/2017/08020/dry_eye_syndrome_in_menopause_and_perimenopausal.1.aspx

  Dry eye disease (DED) is a multifactorial ocular surface disease that causes symptoms of ocular pain, discomfort, and decreased visual acuity. […] It is more prevalent in the females and is being specifically in the menopausal and postmenopausal age group. This is believed to be due to the changes in balance of sex hormones. Sex hormones estrogens and androgens influence production of all components of the tear film including aqueous layer, lipid, and mucin. Various mechanisms such as decrease in hormonal levels, shift in feedback mechanisms, and changes in receptor receptivity interplay to alter the ocular surface homeostasis and subsequently result in DED. […] The tear film has three major components the aqueous layer secreted by the lacrimal gland, the lipid layer secreted by the meibomian glands, and mucin secreted by the conjunctival goblet cells. Tear production, evaporation, drainage, health of corneal epithelial cells, corneal subbasal nerve plexus and corneal inflammatory and immune status interplay to maintain ocular surface homeostasis. By influencing the above-mentioned mechanisms, sex hormones play a role in pathogenesis of DED.

• #1

  https://visivite.com/blogs/dry-eye/mechanisms-of-dry-eye?srsltid=AfmBOopTg-bTLl_SP5YISG–s11EsyH3esrNwEtR17KrSdHX_HfYpMvS

  Dry Eye Syndrome is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort. […] Examples of Dry Eye Syndrome due to excessive tear evaporation include blepharitis, lid abnormalities and contact lens use. […] Low bioavailability of androgens is a common feature of Primary Lacrimal Gland Deficiency. Androgens increase secretory factor and IgA secretion by the lacrimal gland. […] Sjogren’s Syndrome is associated with extensive lacrimal gland inflammation. This inflammation may then cause loss of neuronal innervation. […] It is the composition of tears, more than the actual quantity of tears, that is of greater importance in the comfort and health of the ocular surface.

• #1 Research progress on the immune mechanism of thyroid-related eye disease combined with dry eye | Journal of Ophthalmic Inflammation and Infection | Full Text

  https://joii-journal.springeropen.com/articles/10.1186/s12348-025-00477-7

  Thyroid associated eye disease combined with dry eyes is a common clinical disease and has gradually received clinical attention. Its onset is caused by various factors such as eyelid dynamic change and immune inflammation, involving tear secretion, tear discharge, tear quality and other aspects. […] Studies have shown that dry eye is particularly common in patients with thyroid diseases. About 65-85% of patients with thyroid associated ophthalmopathy (TAO) have dry eye. […] Dry eyes are not simply caused by a decrease in tear volume. Abnormal tear quality also plays an important role in the occurrence of dry eyes. […] Relevant studies have shown that the occurrence of TAO dry eye is closely related to increased ocular surface exposure and immune-inflammatory factors. […] Some studies have shown that the lacrimal gland of TAO patients are also affected, suggesting that lacrimal gland as tear secretion organs, may be an important cause of TAO combined with dry eyes.

• #1 Research progress on the immune mechanism of thyroid-related eye disease combined with dry eye | Journal of Ophthalmic Inflammation and Infection | Full Text

  https://joii-journal.springeropen.com/articles/10.1186/s12348-025-00477-7

  The lacrimal gland of TAO patients become the target of autoantibody attack, resulting in lacrimal gland damage and reduced tear production. […] During the course of TAO, ocular surface damage is the main cause of dry eye symptoms in patients, and the cornea is the most direct and sensitive effector organ of ocular surface damage. […] Current studies have found that corneal changes are mainly reflected in corneal inflammation and decreased nerve sensitivity. […] The immune inflammatory edema of the extraocular muscles and orbital fat in TAO causes increased orbital pressure. […] The cornea is rich in nerve endings, which not only maintain the sensation of the cornea, but also play an important role in ion transport between corneal layers, cell division, wound healing, and maintaining the stability of the ocular surface microenvironment.

• #1 The shared mechanism and potential diagnostic markers for premature ovarian failure and dry eye disease | Scientific Reports

  https://www.nature.com/articles/s41598-024-67284-3

  Premature ovarian failure (POF), which is often comorbid with dry eye disease (DED) is a key issue affecting female health. […] The diminished estrogen levels resulting from ovarian hypoplasia adversely affect lacrimal gland secretion, leading to the characteristic symptoms of DED. […] Investigating these comorbid mechanisms is crucial for understanding the development and progression of both POF and DED. […] The comorbidity mechanism of POF and DED was predominantly related to DNA replication, cell cycle, and the IL-17 signaling pathway. […] The functionality of these genes, whether in the activation or inhibition of metabolic pathways, is emblematic of the metabolic versatility integral to the pathogenesis of DED and POF.

• #1 International Journal of Leprosy and other Mycobacterial Diseases

  http://ijl.ilsl.br/detalhe_artigo.php?id=MjI1

  Dry eye is characterized by the ocular surface disease that results from any condition or circumstance that decreases tear secretion or increases tear film evaporation. […] Studies conducted by Hodges, el al. indicate that a patient with leprosy is at risk for developing keratoconjunctivitis sicca, and they suggest that the aqueous layer of the tear film may be decreased due to reduced secretion of tears from the accessory lacrimal glands of the conjunctiva. The decrease could also be due to a diseased afferent arc to the lacrimal gland or to a diseased lacrimal gland. […] Previous studies have shown that low tear production is the main cause of dry eye in leprosy and just lubrication prevents dryness in the majority of them. […] The lower tear BUT indicates that a significant number shows a deficiency of mucous component which is produced by the goblet cells of the conjunctiva. The mucous coat is important in the stability of the tear film. Although the quantity of tears produced are not affected in this study, the tear film seems to be unstable in many leprosy patients.

• #1 International Journal of Leprosy and other Mycobacterial Diseases

  http://ijl.ilsl.br/detalhe_artigo.php?id=MjI1

  In leprosy, the eyes may be affected primarily by direct invasion or infiltration of the eyes by Mycobacterium leprae or abnormal exposure of the eyes secondary to involvement of the 5th and 7th cranial nerves. […] Based on this study, Lamba et al. have postulated that an autonomic denervation may play a similar role in producing an abnormality of the mucin layer, resulting in subclinical dry eyes.

• #1 Chapman University Digital Commons

  https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/9/

  Allogenic hematopoietic stem cell transplantation is a procedure that offers a possible cure for hematologic cancers and other hematologic disorders. […] GVHD is a complex, multi-organ disease resulting from an immunological attack by donor engrafted immune cells to host organs, including the eye surface. […] Several pathological mechanisms likely contribute to the etiology of ocular GVHD-associated dry eye disease. […] Despite the high frequency of ocular surface involvement in patients experiencing GVHD, little is known about the underlying pathogenesis responsible for ocular GVHD-associated dry eye. […] Our data showed that topical treatment by mucin secretagogue, rebamipide, partially attenuates GVHD-associated damage to ocular surface. […] Immune-mediated ocular surface damage in GVHD can initiate a wound healing response leading to fibrosis in the conjunctiva, a fibroblast-rich tissue.

• #1 Chapman University Digital Commons

  https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/9/

  Conjunctival fibrosis may underlie the noted decrease in goblet cells and ocular surface mucins, thus contributing to GVHD-associated dry eye. […] Our results demonstrated that ocular GVHD causes a significant increase in expression of -smooth muscle actin (SMA), a marker of myofibroblasts, in the conjunctiva. […] An increase in the components of renin-angiotensin system component (RAS), angiotensinogen and angiotensin converting enzyme, was also noted in the conjunctiva suggesting that ocular GVHD causes conjunctival fibrosis by myofibroblast formation and activation of conjunctival RAS.

• #1 TFOS DEWS II REPORT – Iatrogenic Dry Eye – TFOS – Tear Film & Ocular Surface Society

  https://www.tfosdewsreport.org/report-iatrogenic_dry_eye/121_36/en/

  Dry eye can be caused by a variety of iatrogenic interventions. […] The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. […] Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. […] Preservatives, such as benzalkonium chloride, may further aggravate DED. […] A variety of systemic drugs can also induce DED secondary to multiple mechanisms. […] Moreover, the use of contact lens induces or is associated with DED. […] However, one of the most emblematic situations is DED caused by surgical procedures such as corneal refractive surgery as in laser-assisted in situ keratomileusis (LASIK) and keratoplasty due to mechanisms intrinsic to the procedure (i.e. corneal nerve cutting) or even by the use of postoperative topical drugs.

• #1 TFOS DEWS II REPORT – Iatrogenic Dry Eye – TFOS – Tear Film & Ocular Surface Society

  https://www.tfosdewsreport.org/report-iatrogenic_dry_eye/121_36/en/

  Cataract surgery, lid surgeries, botulinum toxin application and cosmetic procedures are also considered risk factors to iatrogenic DED, which can cause patient dissatisfaction, visual disturbance and poor surgical outcomes. […] This report also presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries. […] Multiple different mechanisms have been proposed to describe the effect of drugs on dry eye symptoms and are unique to the particular class of drug being administered. […] A large segment of systemic drugs that have an effect on dry eye symptoms are those with anticholinergic activity. […] More specifically, G-protein coupled muscarinic receptors in the lacrimal gland acini and conjunctival mucus-producing cells can be affected, thereby reducing aqueous and mucous tear component production and resultant tear film stability.

• #1 TFOS DEWS II REPORT – Iatrogenic Dry Eye – TFOS – Tear Film & Ocular Surface Society

  https://www.tfosdewsreport.org/report-iatrogenic_dry_eye/121_36/en/

  The anti-cholinergic class comprises a wide range of therapeutic drug categories including antidepressants, antipsychotics or neuroleptics, anti-Parkinson’s, H1 antihistamines, decongestants and antispasmodics. […] Additionally, adrenergic agents, including both beta-blockers and alpha agonists, elicit changes in both tear production and tear film quality (i.e., mucus and protein secretion), likely mediated by protein kinase C production and intracellular Ca++ concentration. […] Several drugs such as amiodarone, aspirin, bisphosphonates, chloroquine, ibuprofen and clofazimine are secreted in the tears and may aggravate existing sicca conditions, due to either mechanical irritation or an increased evaporative form of dry eye caused by the presence of drug crystals or deposits in the tears or cornea.

• #1 TFOS DEWS II REPORT – Iatrogenic Dry Eye – TFOS – Tear Film & Ocular Surface Society

  https://www.tfosdewsreport.org/report-iatrogenic_dry_eye/121_36/en/

  The systemic drugs identified by large epidemiological studies as increasing the risk for DED together with their associated ORs are listed in Table 2. […] The evaluation of DED induced by topical drugs is complicated, as clinical trials typically exclude patients prone to ocular surface disease (OSD), and thus, dry eye symptoms may not be interpreted and reported as such. […] Topical drugs may act at the level of the ocular surface through various mechanisms, exerting allergic, toxic and/or immuno-inflammatory effects or by chemical interaction with the lacrimal film, either by disrupting the lipid layer through detergent tensioactive effects, by reducing aqueous secretion, or by damaging: goblet cells; the conjunctival and corneal epithelia; corneal nerves through neurotoxic effects; or even eyelids at the skin or meibomian gland level.

• #1 Lacrimal Hypofunction as a New Mechanism of Dry Eye in Visual Display Terminal Users | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011119

  Dry eye has shown a marked increase due to visual display terminal (VDT) use. […] To address this issue that potentially affects the life quality, we conducted a large-scale epidemiological study of VDT users and an animal study. […] These data suggest that lacrimal gland hypofunction is associated with VDT use and may be a critical mechanism for VDT-associated dry eye. […] In order to prevent the occurrence of dry eyes as well as maintain the ocular surface health, attention needs to be paid to the total lifetime working hours. […] The mechanism(s) underlying the observed association between VDT and decreased tear secretion are not defined in the present human study. […] In our rat VDT user model, persistent strain by riding on the swing in combination with exposure to an evaporative environment showed persistent decrease in tear secretion.

• #1 New Dry Eye Drug is First That Aims to Treat Cause, Rather Than Symptoms | UVA Today

  https://news.virginia.edu/content/new-dry-eye-drug-first-aims-treat-cause-rather-symptoms

  University of Virginia Health System researchers have developed a potential therapeutic treatment for dry eye, with human testing to start in March. The drug differs from other treatments of dry eye in that it aims to treat the cause of dry eye instead of masking the symptoms. […] Lacripep aims to eliminate inflammatory triggers by restoring the natural basal tearing mechanism and health of cells in contact with tears. This includes restoration of the nerves on the cornea of the eye, which signal the brain to produce more tears. […] But these are temporary fixes that do not treat what may be the root cause of the disease a shortage of the tear protein lacritin and often lead to frustration and pain for people with the condition. Lacripep is a short synthetic fragment of lacritin. If successful, Lacripep would be the first drug to treat that cause of dry eye. […] With lacritin deficient in dry-eye tears, topical Lacripep is a replacement therapy, which will probably not cure the disease. You would still have to keep treating your eyes, but maybe just once a day.

• #2 Dry Eye Disease: Pathophysiology, Classification, and Diagnosis

  https://www.ajmc.com/view/apr08-3141ps079-s087

  Dry eye disease (DED) is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort, visual disturbance, and often ocular surface damage. […] Although recent research has made progress in elucidating DED pathophysiology, currently there are no uniform diagnostic criteria. […] DED is a multifactorial disorder involving multiple interacting mechanisms. Dysfunction of any LFU component can lead to DED by causing alterations in the volume, composition, distribution, and/or clearance of the tear film. Two mutually reinforcing global mechanisms, tear hyperosmolarity and tear film instability, have been identified. […] Tear hyperosmolarity can arise from either low aqueous flow or excessive tear film evaporation. Hyperosmolar tears can damage the ocular surface epithelium by activating an inflammatory cascade, with release of inflammatory mediators into the tears.

• #2 Dry Eye Disease (Keratoconjunctivitis Sicca): Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1210417-overview

  Tear hyperosmolarity and instability are the principal components of the primary drivers of dry eye disease. The 2 major types of DED, aqueous deficient dry eyes (ADDE) and evaporative dry eyes (EDE), can both be related to tear hyperosmolarity and instability. […] In EDE, tear film lipid deficiency from meibomian gland dysfunction results in excessive evaporation of the tear film. This leads to tear hyperosmolarity in the presence of normal lacrimal function. […] In ADDE, reduced tear secretion from the lacrimal glands due to lacrimal gland damage (for example, in Sjgren disease) leads to the hyperosmolarity of the tear film despite a normal evaporation rate of the tear film. […] Both EDE and ADDE often co-exist and contribute to the mixed type of dry eye disease. Tear hyperosmolarity, which is present in both EDE and ADDE, eventually enters into a vicious cycle that leads to chronic inflammation, loss of conjunctival goblet cells, ocular surface damage, and self-perpetuating disease.

• #2 Etiology of Dry Eye | IntechOpen

  https://www.intechopen.com/chapters/86159

  A functional Reflex arc is the key to controlling the tear flow and maintaining the homeostasis of tear osmolarity. […] Therefore, dysfunction of LFU has been identified to be prominent in the development of various forms of dry eye. There are two major divisions of dry eye (discussed later in this chapter): 1. Aqueous-deficient dry eye and 2. Evaporative dry eye. Both lead to tear hyperosmolarity. […] Hyperosmolarity is regarded as the central mechanism for various forms of dry eye as a response to reduced tear flow or increased tear evaporation. Tear film instability and thinning of the tear film with excessive aqueous evaporation are the events that influence tear hyperosmolarity. […] Tear hyperosmolarity stimulates a sequence of inflammatory events in the ocular surface epithelium, involving NF-kB signaling and MAP kinases pathways with the secretion of inflammatory cytokines (IL-1, IL-1, and TNF-) and matrix metalloproteinases (e.g., MMP9).

• #2 Dry Eye Syndrome – EyeWiki

  https://eyewiki.org/Dry_Eye_Syndrome

  Dry eye syndrome is a general term that describes the state of the front of the eye in response to a breakdown in the natural layer of tears that coats the front of the eye, called the tear film. […] When the tear film becomes unhealthy, it breaks down in different places on the cornea and conjunctiva, leading not only to symptoms of irritation, but also to unstable and intermittently changing vision. […] Corneal hyperesthesia and/or reduced sensation may be present in severe and chronic dry eye disease. Sensory denervation may cause dry eye by reducing the afferent signaling of tear production, reducing the blink rate, and by altering trigeminal nerve influences on ocular epithelial health. Decreased corneal sensation can also result from chronic dry eye. […] Tear hyperosmolarity can induce tear film instability by modifying the interaction between tear film lipids and proteins, damaging the epithelial cell membranes, triggering inflammation, and stimulating corneal nerves.

• #2

  https://www.healio.com/clinical-guidance/dry-eye/pathophysiology-overview

  Several factors contribute to the development of DES, including: […] The core mechanism and hallmark feature of DES pathogenesis is tear film hyperosmolarity. Both aqueous tear deficient dry eye (ADDE) and EDE involve tear hyperosmolarity: in ADDE, it occurs because less solvent (water) is produced by the lacrimal glands and in evaporative dry eye (EDE) because too much water is lost by evaporation. The hyperosmolarity causes both direct and indirect (i.e., inflammatory) damage to the ocular surface, particularly to epithelial and goblet cells. This activates epithelial stress signaling, mediated by mitogen activated protein kinase (MAPK) and nuclear factor B (NFB), which in turn stimulates release of pro-inflammatory factors, including cytokines (e.g., IL-1), tumor necrosis factor (TNF) and matrix metalloproteases (MMPs).

• #2 Dry Eye: Master the Science Beneath the Surface

  https://www.reviewofoptometry.com/article/dry-eye-master-the-science-beneath-the-surface

  Inflammation plays a significant role in the etiopathogenesis of dry eye. It promotes ocular surface disruption and symptoms of irritation. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Once investigators identified inflammation’s role in dry eye development, research could target treatment using anti-inflammatory agents that inhibit the expression of inflammatory mediators on the ocular surface. By doing so, these agents help restore a healthy tear film and reduce signs and symptoms of afflicted patients. […] Growing evidence shows dry eye-related ocular surface inflammation is mediated by lymphocytes. Based on earlier immunohistopathological evaluations, patients with both Sjögren’s syndrome (SS) related and non-SS dry eye have identical conjunctival inflammation manifested by T-cell infiltrates and upregulation of CD3, CD4 and CD8, as well as lymphocyte activation markers CD11a and HLA-DR. These results suggested that clinical symptoms and signs of dry eye may be dependent on T-cell activation and resultant autoimmune inflammation. Multiple other studies demonstrated the role of proinflammatory cytokines and matrix metalloproteinases (MMPs) in the pathogenesis of dry eye.

• #2 CRSToday | The Evolution of Treatment of Dry Eye Disease

  https://crstoday.com/articles/the-evolution-of-treatment-of-dry-eye-disease/the-evolution-of-treatment-of-dry-eye-disease-2

  In 1995, the National Eye Institute, together with industry, organized a workshop with the intent to solidify a definition for dry eye disease (DED). The definition they generated stated, Dry eye is a disorder of the tear film due to tear deficiency or excessive evaporation, which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort. Since that time, understanding of the etiology, pathology, and treatment has increased considerably. […] We now know that while multifactorial, DED is a chronic, immune-mediated inflammatory disease.1 When the delicate homeostatic balance of the ocular surface system is disturbed, it triggers the activation of a stress response that progresses from mitogen-activated protein kinases to transcription factors, and then production of proinflammatory cytokines and matrix metalloproteinases.2 This leads to the activation of T-cells that infiltrate the ocular surface and secrete additional proinflammatory cytokines.3,4 Thus begins a self-perpetuating cycle of inflammation and epithelial damage across the entire ocular surface, regardless of the origin of the disruption. […] It is now well understood that inflammation is one of the most important aspects of DED pathogenesis,20,21 and no matter the trigger, untreated or undertreated, established disease can lead to severe refractory disease.22

• #2 The Role of Neuropeptides in Pathogenesis of Dry Eye

  https://www.mdpi.com/2077-0383/10/18/4248

  The induction of neurogenic inflammation within the ocular surface and lacrimal glands through the release of neuropeptides has been suggested to be a contributor to the pathogenesis of DED. […] The concept of the lacrimal functional unit was presented in 1998, and this unit is composed of lacrimal glands (both main and accessory), the ocular surface, and interconnecting innervation. […] The abundant supply of sensory and autonomic nerve fibers on the ocular surface plays an important role in maintaining healthy epithelia and serves as the main source of neurogenic inflammation. […] The experimental evidence for this immunopathogenesis theory of DED, based on T-cell-associated adaptive immunity, is based on animal studies using adoptive transfer and studies on memory Th17 cells. […] The presence of monocytic cells stained with the lymphatic endothelium-specific marker, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) in the conjunctiva has been described and is associated with the growth of lymphatic vessels into the cornea.

• #2 Helper T Cells May Play Role in Pathogenesis of Dry Eye – Ophthalmology Advisor

  https://www.ophthalmologyadvisor.com/news/helper-t-cells-may-play-role-in-pathogenesis-of-dry-eye/

  Helper T cells may be associated with more severe conjunctival and corneal staining. […] These findings may indicate that helper T cells play a role in inflammation leading to ocular surface damage, according to the report. […] Helper T cells showed a significant positive association with conjunctival and corneal staining score, possibly indicating their role in inflammation that leads to damage of the ocular surface. […] The DREAM study enrolled a population of real-world subjects with moderate to severe DED who had both symptoms and signs of ocular surface disease at baseline, despite ongoing DED treatment, according to the researchers. Helper T cells showed a significant positive association with conjunctival and corneal staining score, possibly indicating their role in inflammation that leads to damage of the ocular surface.

• #2 Etiology of Dry Eye | IntechOpen

  https://www.intechopen.com/chapters/86159

  Tear film hyperosmolarity causes an increase in osmolarity of the ocular surface epithelium and stimulates a cascade of inflammatory events involving MAP kinases and NFkB signaling pathways and the secretion of inflammatory cytokines. […] The major groups and subgroups of dry eye are described below. […] Dysfunction in the lacrimal gland leads to the aqueous-deficient dry eye that reduces lacrimal tear secretion and volume. […] Tear-deficient dry eye causes tear hyperosmolarity. […] Sjogren syndrome is an exocrinopathy that involves the lacrimal and salivary glands targeted by an autoimmune process. […] The inflammatory process in the glands leads to the expression of autoantigens in the epithelium of the ocular surface with the homing of tissue-specific CD4 and CD8 T-cells. […] A neurosecretory block influences the hyposecretion of the tears due to the effects of immune cell influx and secretion of inflammatory cytokines or the presence of circulating antibodies directed against muscarinic receptors within the glands.

• #2 Dry Eye Disease (Keratoconjunctivitis Sicca): Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1210417-overview

  Normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin, and phospholipase A2, is decreased in dry eye disease. […] Androgens are believed to be trophic for the lacrimal and meibomian glands. They exert potent anti-inflammatory activity via production of transforming growth factor beta (TGF-), suppressing lymphocytic infiltration. […] SS-associated dry eye disease leads to a chronic inflammatory state, with the production of autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF), fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (eg, anti-RO [SS-A] and anti-LA [SS-B]); inflammatory cytokine release; and focal lymphocytic infiltration of the lacrimal and salivary gland, with glandular degeneration and induction of apoptosis in the conjunctiva and lacrimal glands.

• #2 Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction | British Journal of Ophthalmology

  https://bjo.bmj.com/content/100/3/300

  Meibomian gland dysfunction (MGD) is the most frequent cause of dry eye disease (DED). […] It is probable that MGD is a heterogeneous condition arising from any combination of the following five separate pathophysiological mechanisms: eyelid inflammation, conjunctival inflammation, corneal damage, microbiological changes and DED resulting from tear film instability. […] The pathogenesis of both MGD and DED can be described in terms of a vicious circle: the underlying pathophysiological mechanisms of DED and MGD interact, resulting in a double vicious circle. […] MGD-associated tear film instability provides an entry point into the vicious circle of DED and leads to hyperosmolarity and inflammation, which are both a cause and consequence of DED. […] MGD is associated with multiple pathological mechanisms including inflammation, microbial factors and lipid deficiencies.

• #2 Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction | British Journal of Ophthalmology

  https://bjo.bmj.com/content/100/3/300

  The absence of normal meibum reduces the lipid content of the tear film, allowing entry into the DED loop of the vicious circle, in which the lipid-deficient tear film promotes increased tear evaporation, hyperosmolarity and inflammation. […] Meibomian gland blockage, dropout and inflammation directly link the DED and MGD vicious circles.

• #2 Dry eye syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Dry_eye_syndrome

  Dry eye syndrome can lead to blurred vision, instability of the tear film, increased risk of damage to the ocular surface such as scarring of the cornea, and changes in the eye including the neurosensory system. […] Dry eye occurs when either the eye does not produce enough tears or when the tears evaporate too quickly. […] The most common cause of dry eye is increased evaporation of the tear film, typically as a result of meibomian gland dysfunction (MGD). […] Any abnormality of any one of the three layers of tears produces an unstable tear film, resulting in symptoms of dry eyes. […] In advanced cases, the epithelium undergoes pathologic changes, namely squamous metaplasia and loss of goblet cells. […] Some severe cases result in thickening of the corneal surface, corneal erosion, punctate keratopathy, epithelial defects, corneal ulceration (sterile and infected), corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation. […] Another contributing factor may be lacritin monomer deficiency. […] The ocular surface microbiome, composed of a diverse community of microorganisms, has been implicated in the pathogenesis of dry eye syndrome, potentially influencing ocular surface inflammation and homeostasis.

• #2 Dry Eye Disease: Pathophysiology, Classification, and Diagnosis

  https://www.ajmc.com/view/apr08-3141ps079-s087

  Chronic inflammation may result in reduced corneal sensation and decreased reflex activity, leading to increased evaporation and tear film instability. Inflammation can also result in goblet cell loss and decreased mucin production, which further contributes to tear film instability. […] There are 2 major etiologic categories of DED: aqueous-deficient and evaporative. […] Aqueous-deficient DED is classified as either Sjögren or non-Sjögren. […] Evaporative DED also has various causes, including meibomian gland disease, eyelid aperture disorders or lid/globe incongruity, blink disorders, and ocular surface disorders. […] The most common cause is meibomian gland dysfunction (MGD; also called posterior blepharitis), a condition of meibomian gland obstruction. […] First, any form of dry eye may be associated with any other form. […] Second, because of the interaction between the 2 global DED mechanisms, tear hyperosmolarity and tear film instability, the differentiation between aqueous-deficient and evaporative DED is often unclear. […] Certain DED etiologies involve multiple mechanisms.

• #2 The Role of Neuropeptides in Pathogenesis of Dry Eye

  https://www.mdpi.com/2077-0383/10/18/4248

  Dry eye induction increases the expression of factors that promote lymphangiogenesis, including VEGF-C and VEGF-D and the related receptors VEGFR-2 and VEGFR-3. […] Neuropeptides lead to leukocyte influx and chemotaxis of immune cells to the inflammation site by inducing vasodilation/plasma extravasation and edema and stimulating the release of chemotactic chemokines. […] Neuropeptides are known as important mediators between the nervous and immune systems.

• #2 TRPV1 in Dry Eye Disease

  https://www.imrpress.com/journal/FBL/29/5/10.31083/j.fbl2905175/htm

  Research has demonstrated that TRPV1 functions as a hypertonic osmotic sensor. Therefore, inhibition of TRPV1 could provide osmotic protection and minimize ocular surface damage caused by hyperosmolality. […] TRPV1 perceives a range of environmental stimuli and is triggered by these to stimulate cellular Ca2+ influx, which in turn induces the activation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB, leading to increased production of pro-inflammatory cytokines. […] Neurogenic inflammation is a particularly important mechanism by which TRPV1 causes inflammation of the ocular surface in DED. […] The corneal epithelium is most susceptible to damage during dry eye conditions. It serves as a protective shield against damaging stimuli, and epithelial cells are maintained by the migration of basal cells to the upper layers of the tissue to replace terminally differentiated cells at the surface. […] The loss or blocking of TRPV1 expression in mice with alkali burns inhibits the production of TGFβ and other proinflammatory factors, resulting in severe and long-lasting corneal inflammation and scarring.

• #2 The Pathophysiology, Diagnosis, and Treatment of Dry Eye Disease (30.01.2015)

  https://di.aerzteblatt.de/int/archive/article/167472

  Dry eye disease (DED) is common; its prevalence around the world varies from 5% to 34%. Its putative pathogenetic mechanisms include hyperosmolarity of the tear film and inflammation of the ocular surface and lacrimal gland. […] Recent studies have shown that dry eye is an inflammatory disease that has many features in common with autoimmune disease. Stress to the ocular surface (environmental factors, infection, endogenous stress, antigens, genetic factors) is postulated as the pathogenetic triggering mechanism. Proinflammatory cytokines, chemokines, and matrix metalloproteinases lead to the expansion of autoreactive T helper cells which infiltrate the ocular surface and lacrimal gland. The result is a vicious circle of damage to the ocular surface and inflammation. […] Dry eye disease is defined as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and subacute inflammation of the ocular surface.

• #2 What is the impact of microbiota on dry eye: a literature review of the gut-eye axis | BMC Ophthalmology | Full Text

  https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-024-03526-2

  Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. […] However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease. […] Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects.

• #2 What is the impact of microbiota on dry eye: a literature review of the gut-eye axis | BMC Ophthalmology | Full Text

  https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-024-03526-2

  By summarizing the changes in the ocular surface and intestinal microbiota when dry eye occurs, it is speculated and concluded that the intestine may affect the occurrence of eye diseases such as dry eye through several pathways and mechanisms, such as the occurrence of abnormal immune responses, microbiota metabolites- intervention of short-chain fatty acids, imbalance of pro-inflammatory and anti-inflammatory factors, and release of neurotransmitters, etc. […] The inflammatory nature of dry eye is linked to changes in microbiomics, emphasizing the importance of altered ocular surface microbiota in dry eye development. […] The imbalance of the ocular surface microenvironment, inflammation, imbalance of the Th17/Treg, abnormal activation of the immune system are key factors in the development of dry eye. […] Considering immune balance and metabolite production induced by gut microbiota, it is reasonable to suggest that gut microbiota may influence eyes by affecting host immunity, creating a potential gut-eye axis.

• #2

  https://visivite.com/blogs/dry-eye/mechanisms-of-dry-eye?srsltid=AfmBOopTg-bTLl_SP5YISG–s11EsyH3esrNwEtR17KrSdHX_HfYpMvS

  Dry Eye Syndrome is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort. […] Examples of Dry Eye Syndrome due to excessive tear evaporation include blepharitis, lid abnormalities and contact lens use. […] Low bioavailability of androgens is a common feature of Primary Lacrimal Gland Deficiency. Androgens increase secretory factor and IgA secretion by the lacrimal gland. […] Sjogren’s Syndrome is associated with extensive lacrimal gland inflammation. This inflammation may then cause loss of neuronal innervation. […] It is the composition of tears, more than the actual quantity of tears, that is of greater importance in the comfort and health of the ocular surface.

• #2

  https://journals.lww.com/jomh/fulltext/2017/08020/dry_eye_syndrome_in_menopause_and_perimenopausal.1.aspx

  Both androgens and estrogen have known effects on the synthesis and components of the tear film. […] Increased levels of estradiol are believed to be a risk factor for dry eye. […] Alteration of sex hormones plays an important role in the pathophysiology of DED in perimenopausal and menopausal age group.

• #2

  https://visivite.com/blogs/dry-eye/mechanisms-of-dry-eye?srsltid=AfmBOopTg-bTLl_SP5YISG–s11EsyH3esrNwEtR17KrSdHX_HfYpMvS

  Mucin has historically been underestimated in importance in the ocular tear film. This glycoprotein is manufactured by the entire ocular surface, including the squamous epithelial cells of the cornea and conjunctiva. […] Therefore, the tear film appears to be dominated by a hydrated mucin gel, with overlying aqueous and lipid layers.

• #2 Research progress on the immune mechanism of thyroid-related eye disease combined with dry eye | Journal of Ophthalmic Inflammation and Infection | Full Text

  https://joii-journal.springeropen.com/articles/10.1186/s12348-025-00477-7

  The lacrimal gland of TAO patients become the target of autoantibody attack, resulting in lacrimal gland damage and reduced tear production. […] During the course of TAO, ocular surface damage is the main cause of dry eye symptoms in patients, and the cornea is the most direct and sensitive effector organ of ocular surface damage. […] Current studies have found that corneal changes are mainly reflected in corneal inflammation and decreased nerve sensitivity. […] The immune inflammatory edema of the extraocular muscles and orbital fat in TAO causes increased orbital pressure. […] The cornea is rich in nerve endings, which not only maintain the sensation of the cornea, but also play an important role in ion transport between corneal layers, cell division, wound healing, and maintaining the stability of the ocular surface microenvironment.

• #2 Chapman University Digital Commons

  https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/9/

  Conjunctival fibrosis may underlie the noted decrease in goblet cells and ocular surface mucins, thus contributing to GVHD-associated dry eye. […] Our results demonstrated that ocular GVHD causes a significant increase in expression of -smooth muscle actin (SMA), a marker of myofibroblasts, in the conjunctiva. […] An increase in the components of renin-angiotensin system component (RAS), angiotensinogen and angiotensin converting enzyme, was also noted in the conjunctiva suggesting that ocular GVHD causes conjunctival fibrosis by myofibroblast formation and activation of conjunctival RAS.

• #2 Lacrimal Hypofunction as a New Mechanism of Dry Eye in Visual Display Terminal Users | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011119

  These findings suggest the presence of damage in tear secretion function in our model. […] Our study supports the concept that a proper number of blinks are required in order for healthy LG function to occur. […] It is our belief that the current study findings will pave the way for further research or discoveries, including nutraceuticals or pharmacological treatment modalities that will be enable the restoration of LG function.

• #2 Pathophysiology of dry eye disease and novel therapeutic agents

  https://scielo.org.za/scielo.php?script=sci_arttext&pid=S2410-15162024000100021&lang=es

  Dry eye disease (DED) is one of the most common ocular surface diseases, which is caused by decreased tear production or increased evaporation. […] All reviewed papers showed that DED is characterised by the loss of homeostasis, resulting in tear film instability, hyperosmolarity and inflammation of the ocular surface. […] The causes of DED are complicated and multifactorial but currently, inflammation of the ocular surface is believed to be the main cause. […] Dysfunction of more than one tear producing cells and/or glands leads to unstable tear film. Increased tear osmolarity (hyperosmolarity) is the hallmark or core mechanism of DED that activates stress signalling pathways in the ocular surface epithelium and triggers production of innate inflammatory molecules that initiate a vicious cycle that leads to decline in tear function and worse symptoms.

• #2 The Role of Neuropeptides in Pathogenesis of Dry Eye

  https://www.mdpi.com/2077-0383/10/18/4248

  Neuropeptides are thought to be important factors in the pathogenesis of dry eye disease, as suggested by the well-known role between the nervous and immune systems, and several recently published studies have elucidated the previously unknown pathogenic mechanisms involved in the role of the neuropeptides secreted from the corneal nerves in dry eye disease. […] The current concept of immunopathogenesis of DED is summarized as follows. Hyperosmolar stress caused by desiccating stress (DS) can hijack the physical barrier system through the activation of intracellular signaling pathways, mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) stress signaling pathways and can initiate proinflammatory cytokine production. […] In DED-induced corneas, decreased density and altered morphologic structure of the subbasal nerves have been reported.

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