lnflammation and dry eye disease—where are we?

INTRODUCTION

The Dry Eye Workshop (DEWS) II defines dry eye disease(DED) as a multifactorial disorder of the tears and ocular surface, associated with symptoms of discomfort,visual disturbance, and tear film instability, accompanied by increased osmolarity of the tear film and inflammation of the ocular surface

. The tear film is part of a larger ocular surface ecosystem, that also comprises the lids and their adnexa, the blink reflex and lacrimal drainage system, the lacrimal and accessory glands, and the epithelia of the cornea and conjunctiva. These structures function in an integrated manner to provide ocular comfort, clear vision, and maintain the structural integrity of the ocular surface. The co-ordination of these activities is brought about by a complex interplay of various neural, humoral, endocrine, vascular, and immune system inputs, which are also influenced by the environment,the systemic health of the individual and various dietary,social factors and medications

. A disturbance of this delicate homeostasis results in dysregulation of the balance and disease of the ocular surface, and inflammation plays a major role in this process.

The burden of DED is steadily increasing and it is believed to be one of three rapidly growing eye-problems in the aged, and results in one out of 4 visits to the ophthalmologist

. There is increasing prevalence worldwide

especially in the Asian population, with a greater occurrence of meibomian gland dysfunction (MGD), in the elderly

. However, with changing lifestyles and increasing use of video display terminals(VDT) in low humidity environments, the prevalence of tear dysfunction and ocular surface symptomatology is now steadily increasing in younger patients as well, and they form a significant proportion of those affected

. The management of this condition has evolved beyond the use of tear substitutes,with the increased understanding of the role of inflammation in ocular surface changes.

Inflammation in general pathology is typified by the four key symptoms described by Celsus-redness, swelling, heat and pain. Virchow critically analyzed these symptoms in inflammation and added loss of function of the inflamed tissues in 1871

.

These tenets apply to the ocular surface as well,and inflammation produces a red eye, often with conjunctival edema, and significant discomfort. If inflammation is left untreated, progression of changes can result in transient visual fluctuations in the early stages and corneal damage and permanent loss of vision in the later stages. Interestingly,inflammation is a defense mechanism that is triggered by damage to living tissues and is intended to protect them from infection and injury. The acute response by the innate immune system, is short-lived, helps to eliminate the noxious agent,and restore the integrity of damaged tissues through repair processes

.

In the presence of a persistent stimulus however,the adaptive immune response is activated, resulting in chronic inflammation. This triggers a self-perpetuating vicious cycle which makes multiple abortive attempts at healing, resulting in scarring and damage of the ocular surface

.

Although the association between DED and inflammation has been known for the past 40y

, the exact role of the latter in the disease process, its temporal evolution and the processes involved at the cellular and molecular levels are still being elucidated.It is now understood that inflammation is both a cause and a consequence of DED. This article explores current knowledge in this area and attempts to answer the following issues related to ocular surface inflammation in DED.

DYSREGULATION OF THE OCULAR SURFACE AND INFLAMMATION

Hyperosmolarity and tear film instability are considered as primary events that initiate the various changes seen in the ocular surface in DED

.

These result from a decrease in production of aqueous tears or an increase in evaporative loss of the tear film. The hyperosmotic tear film activates stressassociated mitogen-activated protein kinases in the ocular surface epithelial cells, such as c-Jun N-terminal kinase,and p38

.

The mitogen-activated protein kinase signaling pathway then initiates a sequence of events that result in the accumulation of various mediators, and inflammation of the ocular surface. The various mechanisms by which such changes occur include 1) A decrease in tear secretion-occurs in diseases that cause lacrimal gland inflammation and destruction such as Sj?gren’s syndrome, other autoimmune conditions, graft versus host disease (GVHD), and Stevens-Johnson syndrome(SJS). Factors such as chronic contact lens wear, topical medications containing preservatives, and surgical procedures or other causes of neurotrophy can affect the afferent arm of the feedback system on the ocular surface. 2) Altered tear distribution and turnover-occur in lid margin irregularities, lax lids, or abnormalities in lid position, and conjunctivochalasis.Alterations in the regularity of the ocular surface like pterygia or pinguecula, or post-surgical alterations can result in reduced wettability of portions of the ocular surface, with desiccation and epithelial stress. 3) Increased evaporative loss of the tear film. Dysfunction of the meibomian glands can result in reduced or excessive lipid secretion onto the surface, or an alteration in the quality of meibum can be caused by eye surgery, hormonal disturbances, floppy eyelid syndrome,giant papillary conjunctivitis, rosacea, and the presence of

or

blepharitis. A poor blink rate can be related to prolonged use of VDTs or from conditions such as Parkinsonism or thyroid eye disease that can reduce the blink rate. Environmental conditions that result in increased temperature, low humidity and or excess air flow across the ocular surface can also result in increased tear evaporation.

根據(jù)自研處方比例，按處方量80%、100%、120%精密稱取富馬酸喹硫平20、25、30 mg對照品及輔料各4份，置于量瓶中，分別用“2.2”項下4種不同溶出介質(zhì)900 mL稀釋成供試品溶液，按“2.2”項下條件測定含量并計算回收率，結(jié)果表明，4種溶出介質(zhì)配制的低、中、高3種濃度供試品溶液的平均回收率在99.8%～101.7%（RSD為0.23%～0.42%，n＝3），表明在所選擇的溶出條件及測定條件下，方法準(zhǔn)確度良好。

I N F L A M M AT I O N A S A P R O T E C T I V E O R DESTRUCTIVE RESPONSE

Many of the initiating conditions occur in an acute manner and the resulting acute inflammatory response is a short-lived process that is orchestrated by the innate immune defense.Satisfactory resolution of the condition occurs when the noxious stimulus or offending condition is removed,

, when a toxic topical medication is stopped. In DED, however, the persistence of hyperosmolarity and frictional trauma to the ocular surface caused by insufficient lubrication, continue to act as drivers of inflammation

. With the persistence of the insult, the adaptive immune system is activated and chronic inflammation results. The perpetuation of inflammation results in damage to the ocular surface, further dysregulation of the immune system and an amplification of the inflammatory response. A vicious cycle of inflammation is then formed,which perpetuates itself independent of the initial insult.

根據(jù)監(jiān)控系統(tǒng)的檢測結(jié)果和派出人員的工作情況進行定點觀察，確定擁堵時段，制定車輛擁堵時段的限行政策。對于存在違章停車的車輛，需要實行勸阻、拖離和加入黑名單等政策。同時，還需要在學(xué)校內(nèi)開展相關(guān)的宣傳活動，比如會議和考試等，為校園交通安全管理提供更良好的實施環(huán)境。

INFLAMMATION

Tear film hyperosmolarity, instability and inflammation tend to co-exist. As discussed in the first section, the tear film disturbance affects epithelial cells and triggers the inflammatory cascade. As the DED progresses, so does the inflammation, and damages the surface epithelium,nerves, and goblet cells, worsening the DED. Inflammation also results in changes in the meibomian glands (MGs) and MGD further perpetuates the cycle of DED. Eventually, DED becomes an irreversible chronic inflammatory condition that is self-perpetuating, concurrent with a similar self-perpetuating vicious cycle of inflammation. In these conditions, DED is the initiating event and triggers inflammation.

In other systemic immune-mediated conditions like Sj?gren’s syndrome, lymphocyte infiltration in the lacrimal glands can result in damage and fibrosis

.

This results in reduced tear secretion and inflammatory cytokines in the tears from the affected gland. In GVHD an increased density of dendritic cells(DC) has been reported in the cornea

.

In the same condition,infiltration of inflammatory cells in the MGs has been noted and postulated to cause excessive fibrosis and atrophy of these glands

. Similarly, in otherwise normal eyes, the occurrence of SJS results in a pro-inflammatory cytokine storm in the tears of patients, causing ocular surface damage. In systemic inflammatory conditions, inflammation acts as the trigger that damages the ocular surface and DED then ensues.

近年來，諸多學(xué)者通過應(yīng)用CFD技術(shù)對離心泵的汽蝕性能進行了大量的研究，也取得了一定的研究成果[2-7]，但對離心泵產(chǎn)生汽蝕的機理以及內(nèi)部流場仍需要進一步研究。為此，本文應(yīng)用ANSYS-CFX軟件對1臺比轉(zhuǎn)數(shù)為132的離心泵進行了汽蝕性能的數(shù)值模擬，分析研究了泵汽蝕時葉片上的壓力及氣泡相的分布規(guī)律。

Recently, the Asia Dry Eye Society (ADES) defined dry eye as “a multifactorial disease characterized by an unstable tear film causing a variety of symptoms and/or visual impairment potentially accompanied by ocular surface damage”

.They emphasize the importance of the unstable tear film,and described an entity termed short tear film break-up time(TFBUT) dry eye, seen in VDT workers. They created a rat model to mimic these changes and were able to show that there was lacrimal gland dysfunction, as evidenced by a decrease in tear secretion, which resolved when the desiccating stimulus was removed

.

In another report, infiltration of immune cells was not noted in the lacrimal glands of VDT workers, unlike that seen in the glands of patients with Sj?gren’s syndrome.From these findings, they proposed a non-inflammatory mechanism for VDT work-related dry eye, in which the tear secretion disorder is probably related to a poor blink rate

.However,

in this condition if the stimulus persists long enough it is likely that both DED and inflammation can occur, and it is unclear as to which of these could be the initial event.

McMonnies

has suggested that risk factors for DED should be classified as modifiable and non-modifiable. An example of the former would be environmental conditions like exposure to low humidity environments, while the latter would be ageand sex-related changes in aqueous and lipid production.Identifying these risk factors would help address the specific mechanisms driving DED and inflammation in an individual patient. He suggests that inflammation can be categorized as that occurring on the ocular surface, in the lacrimal gland and in the MGs. The first is easily accessed by topical medications and hence may respond quickly. However, in the latter two conditions, the inflammation is harder to manage and may require increased frequency, dosage, and duration of topical treatment, with possible supplementation using oral medications as well.

Apart from these clinical signs, the use of point-of-care tests like the tear lab analysis device (TearLab Corp, Escondido,CA, USA) to measure tear osmolarity, or the Inflamma Dry(Quindel Inc, San Diego, CA, USA) to detect the presence of MMP-9 at levels greater than 40 ng/mL can be used as objective markers of inflammation on the ocular surface. There are tests being developed for other biomarkers of inflammation as well. Confocal microscopy can be used to look for the presence of inflammatory cells, epithelial changes, and the nerve plexus in such eyes

. Although these tests provide objective measures, the cost of the device and the per test cost are deterrents for their routine clinical use, apart from issues with the collection of tear samples without reflex tearing, and the variability in the osmolarity values with diurnal changes and also with repeat testing. MMP-9 is one of the markers for inflammation, and since the test only detect values higher than 40 ng/mL (normal values are 10 ng/mL), early inflammation may be missed. There is also the possibility that in some eyes the inflammation may produce markers other than MMP-9, while is some eyes MMP-9 can be produced in conditions other than DED. One of the ways that these tests can be useful however,is when the osmolarity is normal in an eye with elevated MMP-9 and this may suggest that the inflammation is due to causes other than DED.

All immune processes share certain common characteristics.They are triggered by stimuli and recognition of the noxious agent is facilitated by cells which can present the antigen to immune cells in the appropriate lymphatic processing center.In the center, there is activation of the effector immune cells,which travel back to the target tissue

lymphatics to initiate the inflammatory response and eliminate the offending agent.In an uninflamed ocular surface, the presence of an antigen which is considered harmless, results in the production of a tolerogenic antigen presenting cell (APC) by the epithelial cell,by as yet unrecognized mechanisms. These APCs are able to produce T helper cell subsets in the lymph nodes, which then travel back to the ocular surface

lymphatics. On subsequent exposure to the antigen, these T helper cells are activated and immune system activity is regulated to result in a quiet ocular surface. When the epithelial cells are damaged in DED however, the protective mechanism is lost, and the APCs now produce effector T cells in the lymph nodes, which are able to provide an escalation of the immune response on the ocular surface and increased inflammation.

The cells involved in this process include the APCs, effector T cells, regulatory T cells and natural killer (NK) cells. The effector T cells produce inflammation, while the regulatory T cells suppress the immune response. The presence of effector cells in the ocular surface initiates a cascade of events that requires the presence of multiple agents.

In the ocular surface, a stressful stimulus, which can be environmental, microbial, endogenous, hormonal, or genetic,results in activation of APCs and DCs. These travel to the regional lymph nodes through afferent lymphatic vessels,where they prime naive T cells. These transform into CD4+T-helper cell subsets T

1 and T

17 and migrate through the efferent vasculature back to the ocular surface, where they induce epithelial damage and cytokine release

.

本次研究數(shù)據(jù)整理后用SPSS22.0軟件進行統(tǒng)計學(xué)處理,計數(shù)資料以(n%)進行表示,計量資料經(jīng)(±s)進行表示,檢驗水準(zhǔn)經(jīng)P<0.05對結(jié)果的論述,并證實結(jié)果具有統(tǒng)計學(xué)意義。

1) Cytokines are signaling molecules that mediate intercellular communication. 2) Interleukins are cytokines that aid signalling between lymphocytes. 3) Chemokines are cytokines that are responsible for targeted migration of immune cells, a process termed chemotaxis. 4) Matrix metalloproteinases (MMP) are endopeptidases involved in tissue remodeling. 5) HLA-DR,fas and fas ligand are involved in antigen presentation and apoptosis. 6) Cell adhesion molecules are surface molecules that enhance cell migration by binding to extracellular matrix.The affected epithelial cells in DED stimulate the inflammatory cascade involving mitogen-activated protein kinases and nuclear factor κ-light-chain-enhancer of activated B cell singling pathways, cytokines [interleukin (IL)-1α, IL-1β,tumor necrosis factor (TNF)-α, and MMP-9]

.

T

1 and T

17 can initiate the release of additional inflammatory mediators like interferon γ, TNF-α, IL-2 and IL-17. These results in goblet cell dysfunction and death and disruption of corneal barrier function, and this is further aided by the presence of MMP-9. These changes result in deterioration of tear function and epithelial cell damage, which promotes more inflammation. IL-17 also promotes corneal lymphangiogenesis in DED, and these vessels provide a potential route by which APCs can travel to the lymph nodes, and activated T cells back to the ocular surface. IL-17 can also upregulate the expression of MMP-9

. The presence of IL-6 has been reported to correlate with the severity of irritation symptoms.

端午節(jié) 農(nóng)歷五月初五為端午節(jié)，這天也是達斡爾族傳統(tǒng)的節(jié)日。天沒亮，一家人或親朋好友三五成群到郊外踏青、采艾蒿，把艾蒿插在頭上，把艾蒿葉塞進耳朵里。回家后將艾蒿插在門框上或房屋不同的位置。也有些人把艾蒿采回家后，用水煮沸艾蒿，然后用艾蒿水洗臉、洗澡，認為這樣做能夠防病治病。……