Eye (1988) 2, 164-171
Eyelid Secretions and the Prevention and Production of Disease
A. J. BRON Oxford
Summary Tears are necessary for the continued health of the ocular surface. Normal con stitutents include water, mucin, and lipids, electrolytes, non-electrolytes, and pro teins. Lacrimal secretion is under cholinergic control and modulated by sympathetic adrenergic, peptidergic (VIP) and humoral influences; the meibomian glands are innervated, but the goblet cells are not. Retinoids are important for ocular health �nd prealbumen may be a carrier for vitamin A in the tears to supply corneal epithelium with its requirements. Changes in tear constituents may cause certain ocular disorders. In dry eyes increased osmolarity is thought to cause surface ocular damage but the presence of granulocytes and inflammatory mediators such as prostaglandins and super-oxide may contribute to inflammatory events in this and other external diseases.
It has long been accepted that tears are neces evaporation and exchange across the ocular sary for the continued health of the ocular surface. surface, maintaining the non-keratinised sur Wolff's basic 3 layer model for the tear film face essential for corneal transparency and still holds today in modified form. The bulk of lubrication required for movement of lid on the tears are water, the surface bears a lipid globe. It is a more recent concept that changes coat and mucin is present in the aqueous in the tear constituents might not only be a phase; however the disposition at the surface reflectionof surface eye disease, but a cause of of the eye is still in question. some of its manifestations. Lacrimal fluid secretion by the lacrimal The normal eye is bathed with tears, com gland is under neural control of the parasym prising lacrimal fluid of lacrimal and accessory pathetic system via cholinergic fibres, which lacrimal origin to which components of con synapse in the pterygopalative ganglion.s junctival and lid origin are added. Tear flow Secretion is modulated by adrenergic sympa has been estimated variously as 0.3 fd/mml or thetic stimulation by its action on the vascular 1.2 f..tllmm.2 Reflex secretion is present at supply. Lacrimal gland cells also secrete in birth, though it is said that emotional tears response to agonists and therefore, presum have their onset at about 3 months of life.3 ably to circulating adrenaline.6•7 The gland Baum has suggested that so-called basal tears also receives peptidergic innervation by vaso are really reflex in nature and that all intestinal peptide (VIP) 8-10 and substance :P measured flow is a response at least to some (SP) immuno-reactive fibres.ll•12 Cholinergic environmental stimulus. In his view basal flow and VIP fibres do not innervate the same is negligible. Tear flow can be amplified over receptors, but cholinergic and, adrenergic one hundred-fold in response to irritation.4 pathways probably converge on the same Tear fluid losses are by bulk lacrimal drainage, second messenger system in the cell, indepen-
Correspondence to: Nuffield Laboratory of Ophthalmology, Walton Street, Oxford OX2 6AW. EYELID SECRETIONS AND THE PREVENTION AND PRODUCTION Of DISEASE 165
dent of that for VIP.9 Humoral factors also delivered to the conjunctiva by the con influence secretion, so that the glandular junctival vessels and there is presumably the secretions in vivo and in vitro are dependent same sequence of retinol carriage by plasma on stimulation by androgens, oestrogens, retinol binding protein (RBP) with delivery to glucagon ACTH and melanocyte stimulating a cellular RBP, that exists for other epithelial 2 hormonesl which influence not only aqueous tissues. For the cornea, which is avascular, and protein production but also glandular another mode of delivery may exist, via the size. The lacrimal gland is generally larger in tears. Vitamin A is present in the tears, the male. In the rat,14 Allansmith and others secreted by the lacrimal gland. 22 Recently, demonstrated an equal rate of development Chao and Butala have suggested that tear up to the age of puberty (2. 5-5. 5 weeks) after specific prealbumen, which is present in sub which area and density of acini increased in stantial quantities in the tears, is a binding males only. Perifused female rat lacrimal protein concerned with retinol carriage in the glands secrete less proteins in response to tears and important for the delivery of vitamin phenylephrine than males, a difference A to the corneal epithelium. 23 This is in keep reduced by oophorectomy. IS Oestradiol ing with the studies of Thoft and his colleagues receptors have been demonstrated on lacri who have demonstrated the transdifferentia mal acini in various species. In rabbit, tion of conjunctival epithelial into corneal oophorectomy is followed by acinar degener epithelial cells, with loss of tear goblet popula ation and massive lymphocyte infiltration.16 In tion, after resurfacing a total corneal defect by the rat, tear volume is increased by orchidec the former cell type. 24.25 Conversely, this tomy, an effect blocked by hypophysectomy, transdifferentiation does not occur if the con but not by thyroidectomy, adrenalectomy or junctival cells re-surface vascularised cornea, oestrogen administration. 17 Interactions are presumably because of the higher levels of evidently complex and probably species retinol delivered to the re-surfacing cells in dependent. This is likely to be of relevance to this situation. 26.27 age related-changes occurring in the lacrimal The table below shows the major categories gland, particularly in the menopause in of tear components. Their role in the preven women. tion and production of disease is now Surface tear oils are derived from the oil discussed. glands of the lids; these are holocrine in nature and secretion onto the lids can be explained as Table. Constituents of the Normal Tears the result of continuous synthesis and release with breakdown of glandular acini. The ana Water lagous sebaceous glands of the skin are Lipids: Meibomian; mucin associated. affected by levels of sex hormones. 18 Mucins: Goblet cell; other? Recently, it has been demonstrated that the Electrolytes meibomian glands receive a rich peptidergic Non-electrolytes: Glucose; lactate; amino-acids; urea innervation (VIP and SP) for which a neu Proteins: (a) Albumin: pre-albumin (b) Enzymes: Lysozyme; peroxidase; roregulatory role must be considered. 19 various glycosidases Mucin is secreted by the goblet cells of the (c) Proteases: plasminogen activators conjunctiva, and mucus glycoprotein has (d) Anti proteases: (XI anti-trypsin; (Xl been immunoidentified in human goblet cells macro globin (e) Immunoglobulins: IgA, G, E; using antibody against purified mucin frac Mediators: Prostaglandins; histamine; complement; tions. These fail to label lacrimal gland. 20'z1 O2 (?) The goblet cells are not innervated, but in Radical Scavengers: Ascorbate; lactoferrin; cerulo other parts of the body respond to humoral plasmin anti-complement stimulation by secretin, serotonin, and prosta Other materials: Catecholamines; endorphins PGD). glandins (PGE2 and Retinol is essen tial to maintain the ocular surface in its non keratinised state and maintain goblet-cell Electrolytes: Tear sodium concentration density within the conjunctiva. Retinol is approximates that of the plasma. This value 166 A. J. BRON
does not represent that of lacrimal fluid as Surprisingly, few reliable studies of tear secreted since sodium is pumped back across sodium concentration have been made in dry the cornea at least, in exchange for chloride eyes. 30 Studies by Mengher in Oxford, have ions, and further modification of con shown a small but significant increase in tear centration arises as a result of evaporation on sodium compared to normal tears. This is in lid opening. The tears are secreted slightly keeping with studies of tear osmolarity since hypotonic and become hypertonic. Potassium electrolytes make the major contribution to levels are about four times those of the the osmolarity of the body fluids. It is puzzling plasma, perhaps, by analogy to the situation that such a rise, attributable to hypercon in the salivary glands, as a result of secretion centration of tears, is not shown by tear of potassium across the lacrimal ductules. It is potassium. of interest that ocular surface cells are able to Gilbard et al demonstrated in a series of tolerate this high external potassium con studies that tear osmolarity is increased in dry centration, which would be lethal to cells eye. 3l This has been reproduced experi exposed to the plasma or extracellular fluid. mentally in the rabbit and rat, with the pro Manganese is also present in tears in a con duction, in some32 but not a1l33 studies, or centration which greatly exceeds plasma surface signs. Gilbard et al have shown that levels; Tapazo originally found levels of one cultured rabbit corneal epithelial cells are thousand fold higher28 while Frey found a 30 damaged by hyperosmolar saline. 34 Their fold difference. 3 Frey has noted the critical studies showed normal tears to have a mean role of the 'salt glands' of the seagull and other osmolarity of 302 mOsm/L while dry eye tears birds as an excretory organ, concerned like showed an average increase of 41 mOsm/L. the kidney in mammals, in electrolyte regu As a diagnostic test, a cut off value of 312 lation. He has proposed a similar, though lim mOsm/L had a sensitivity of 76 per cent and ited, role, for the lacrimal glands in other specificity of 84 per cent. 35 species including man. He has also suggested The tear mucins (mucous glycoproteins) that excretion of manganese in copious emo are responsible for the high relative viscosity tional tears, could influence the emotional of tears (2. 92).36 Their origin from goblet cells state, since this ion has an important function has been proved conclusively in humans, by affecting mood. Similarly, he has proposed immunocyto chemical studies using anti that the secretion of endorphins in tears could bodies against a tear mucous glycoprotein have a similar role. There is not yet strong fraction20 (Moore and Tiffany). This has been evidence for such functions but the idea is confirmed recently by Huang et ai, using anti intriguing. bodies to rabbit ocular mucin. 2l Cross reac Recently, Mills and others demonstrated tivity was demonstrated with antibodies the importance of divalent cation to exotoxin against non-ocular mucins. release by gram positive organisms. 29 They Various authors have identified a glycopro suggest that the fatal toxaemia occurring in tein material in contact with the plasmalem women using certain vaginal tampons could mal surface of the corneal epithelium which is result from adsorption of Magnesium ion in continuity with similar material in epithelial (Mg+ ) by the tampon. Low is a trigger for subsurface vesiclesY The quantity demon release of staphlylococal exotoxin. This mech strable is increased after trigeminal nerve sec anism could be of relevance in the eye and it tion. This appears to be distinct from the would be of interest in relation to contact lens thicker layer of material coating the surface of wear. the cornea and designated ocular mucin, and The tertiary structure of mucous glycopro is most likely to be the cellular glycocalyx, tein, with its highly negative surface charge, is though a mucous glycoprotein role is not influenced by the ambient levels of divalent excluded. cation such as calcium. Fluctuations in cal Many roles for the tear mucous glycopro cium levels, including increases in dry eye teins have been proposed. Their physical could influence mucous glycoprotein rheol behaviour is non-Newtonian, that is, they ogy and hence that of tears. shear-thin at increasing shear rates. This has EYELID SECRETIONS AND THE PREVENTION AND PRODUCTION OF DISEASE 167 been proposed to facilitate lubrication of the Lysozyme makes up about 113 of the tear ocular surface by reducing viscosity during the proteins. In isolation, it has an anti-bacterial blink or saccade. action against a limited number of gram posi Recent studies by Mengher, have demon tive bacteria, by punching holes in the pep strated a low viscosity of tears in dry eyes and tidoglycan cell wall. Action against gram loss of non-Newtonian features, from which negative bacteria occurs in conjunction with would be inferred a denaturation or a fall in complement and specific IgG, which lyses the mucus glycoprotein concentration in the lipopolysaccharide coat of gram negative tears. This would fitin with the lowered goblet organisms and gives access to the pep celp8 density at the corneal surface in this con tidoglycan cell wall. Lysozyme also interacts dition. Further studies have shown a correla with IgA. Its action is facilitated by chelating tion between tear viscosity breakup time and agents, such as lactoferrin, and it is chemosta tear surface tension measured by a micro tic for PMNs, macrophages and monocytes. technique, and NIBUT noninvasive breakup Van der Gaag has spoken of the immune time.39 The NIBUT is a measure of tear stab responses at the ocular surface; (this issue) ility. Since mucous glycoproteins lower the and it may be added that secretory IgA has an surface tension of the tears it is suggested that action similar to that at other mucosal sur a loss of native tear mucous glycoproteins faces, coating bacteria and inhibiting the occurs in dry eye which explains a rise in tear attachment necessary for epithelial invasion. surface tension and a fall in stability. It also renders them mucophilic and encour Holly and Lemp proposed that the normal ages entrapment in tear mucus. Its action too ocular surface is intrinsically hydrophobic and is enhanced by lactoferrin. Other specific rendered wettable by tear mucin. 40 This was immunoglobulins are involved in comp based on studies in which mucin was 'wiped' lement-mediated lysis of micro-organisms. from the ocular surface and then replaced, the All nine components of complement were surface tension of the surface being measured detected in the tears by Yamamoto et al and on each occasion. We have recently shown may be involved in bacterial oponisation, bac that such studies are unphysiological, since terial lysis, chemotaxis and phagocytosis of the wiping process damages the surface epi micro-organisms. 45 This classical pathway is thelial cells. 41 Tiffany has shown for rabbit eye triggered by IgG and IgM complexes, while that the surface tension of cornea washed with the alternative pathway can be initiated by saline or acetyl cysteine is in the region of 70 IgA complexes, endotoxin, and cell wall poly mN/m, and that the removal of surface ocular saccharide (such as that of staphylococci and mucus with acetyl cysteine does not alter this pneumococci). value.42 He has suggested, since this value is Lactoferrin is a potent chelating agent close to that of water, that mucous glycopro found in other external secretions, but also tein is unnecessary to permit wetting of the white cells and other cells. It is secreted by ocular surface, and that it must therefore, per lacrimal glands. Lactoferrin deprives certain form some other function. We think that this bacteria of essential iron (e. g. staphylococci is one of lubrication. and coliforms) and co-operates in other anti Loss of conjunctival goblet cells has been microbial systems (see above). Cerulo documented in a number of non-wetting eye plasmin, is a copper binding enzyme which is conditions and most profoundly in chemical also a ferroxidase. It has free-radical scaveng ing properties, converting superoxide (0 burns of the eye and in xerophthalmia due to 2) to 8 vitamin A deficiency. 3 .43 Vitamin A controls H202, allowing further degradation. Vitamin Ibe state of differentiation of mucosal epi C is also present in tears, at a concentration of thelia; in its absence there is a loss of goblet 20 times that in the plasma. cells, and an increase in keratin content of the With age, lysozyme and lactoferrin levels in oells leading to hyperkeratinisation. the tears fall, while concentrations of cerulo Many proteins in the tears serve a function plasmin and IgG rise.46 The former probably .preventing microbial and oxidative damage reflects a loss of acinar tissue with age, while ttl the surface of the eye. 44 the latter implies an increase in permeability 168 A. 1. BRON of vascular and other barriers between the leucocytesand though their degree of activ& sUbconjunctival compartment and the con tion is not established, it is assumed that they junctival sac. are involved in the release· of mediators int
suggested that in certain situations excessive Measurement of such changes .offers insights protease (plasmin) activity in the tears could into future prevention and treatment. interfere with epithelial healing, by releasing the cell-binding domain a pentapeptide, References GRGDS) from the fibronectin molecule.6l 1 Jordan A and Baum J: Basic tear flow. Does it exist? Ophthalmology 1980.,87: 920-30.. This would have the effect of blocking the 2 Mishima S, Gasset A, Klyce S, Baum J: Determina binding sites of resurfacing epithelium, with tion of tear volume and tear flow. Invest out affording adhesion to the stromal/Bow Ophthalmol1966, 5: 264--76. man's surface. 55 In experimental studies they 3 Frey WH: II. Crying. The mystery of tears. Winston Press. 1985. were able to retard epithelial resurfacing of 4 Maurice DM: Structures and fluids involved in the rabbit cornea using topical, synthetic, cell penetration of topically applied drugs. Int binding domain pentapeptide. The corollary Ophthalmol Clin 1980., 20: 7-20.. of this finding lies in the studies of Tervo et at 5 Ruskell GL: The distribution of autonomic post and Salonen et at in which increased levels of ganglionic nerve fibres to the lacrimal gland in monkeys. J Anat 1971, 109: 229-42. plasmin activity were found in a variety of 6 Botelho SY, Goldstein AM, Martinez EV: Nor resistant ulcers and erosions (0.5-20 epinephrine responsive beta-adrenergic recep mg/ml).64.65 Treatment of affected eyes with tors in rabbit lacrimal gland. AmJ Ph ys iol 1973, Trasylol (aprotinin) (20,000 iu/ml) an 224: 1119-22. 7 Dartt D A: Cellular control of protein electrolyte and inhibitor of plasminogen activator, was fol water secretion by the lacrimal gland. The Pre lowed by healing in many cases, which was ocular Tear Film, Ed. F. J. Holly, Pub. Dry Eye sometimes dramatic. Treatment was associ Institute, 1986,358-70.. ated with a fall in tear plasmin activity. 8 Dartt DA, Baker AK, Vaillant C, Rose PE: Vasoac Although this was an open-ended study, the tive intestinal polypeptide stimulation of protein secretion from rat lacrimal gland acini. Am J rationale and these early results suggest that a Physiol1984, 247: G5D2-9. controlled trial of this and other inhibitors 9 Dartt DA, Gilbard JP, Rossi SR, Gray KL, Shulman would be of great interest. M, Matkin C: Effect of VIP on lacrimal gland and Plaminogen activator is chemotaxic for leu tear secretion in the rabbit. Invest Ophthalmol Vis Sci 1987, 28: (3 Suppl) 156 (Abstracts). cocytes and could therefore play a part in iO Dartt DA and Ronco LV: Comparison of protein calling leucocytes to the ocular surface at kinase C, Cholinergic, alpha adrenergic and VIP injury or in other inflammatory states. It also dependant pathways for lacrimal gland enzyme stimulates the production of latent col secretion. , Invest Ophthalmol Vis Sci27 (No.3) lagenase, for instance in fibroblast cultures suppl 26 Abstr 19. 11 Nikkinen: The lacrimal gland of the rat and the and in organ-cultured alkali-burned corneal guinea pig are innervated by nerve fibres con stroma. It also activates collagenase, which is taining immunoreactives for substance P and vas recognised to have an important role in stro oactive intestinal polypeptide. Histochemistry mal destruction, after alkali burns.66 Plas 198481: 23-7. 12 Rudich L and Butcher FR: Effects of substance P minogen activator is found chiefly in its latent and elodoisin on K+ efflux, amylase release and form in cultured normal corneae, but in its cyclic nucleotide levels in slices of rat parotid activated form in alkali-burned cornea. This gland. Biochem biophys Acta 1976,444: 70.4. correlates with the negligible collagenase 13 Jahn R, Padell U, Porsch P, Soling HD: Adrenocor activity in normal cornea and the presence of a ticotrophic hormone and alpha-melanocyte stim ulating hormone induce secretion and protein high active collagenase in alkali-burned phosphorylation in the rat lacrimal gland by tissue. Once again the possibility of treatment activation of a cAMP-dependant pathway. Eur J with inhibitors of plasminogen activator or Biochem 1982, 126: 623. plasmin arises and offers a fruitful direction 14 Allansmith MR, Hann LE, Sullivan DA: Age and gender-related differences of the lacrimal gland. for clinical research. Invest Ophthalmol Vis Sci1987, 28: 156 (Abstr. The eye is a portal of entry into the body. 1). Many barriers and protective mechanisms 15 Cripps MM, Bromberg BB, Welch MH: Gender exist to prevent damage or infection. They are dependant lacrimal protein secretion. Invest sometimes breached, and the resulting inflam Ophthalmol Vis Sci 1986, 27: No.3. Supp!. 25 (Abstr. 17). matory events are signalled clinically and by 16 Jacobs M, BuxtonD, Kramer P, Lubkin V, Dunn M, chemical and cellular changes in the tears. Herp A, Weinstein B, Southern AL, Perry H: 170 A. J. BRON
Rabbit lacrimal gland shows oestradial receptors. of the rat. Invest Ophthalmol Vis Sci 1987, 28:
Oophorectomised rabbits show lacrimal gland p. 158, (Abstr. 14). cell vacuolisation and acino description at 8/52 3. Gilbard JP, Carter lB, Seng DN et al.: Morphologic and massive Iymphosytic infiltration at20 weeks. effect of hyperosmolarity on rabbit corneal epi InvestOphthalm olVis Sci 1986, 27: No.3 (Suppl. thelium. Ophthalmology 1984, 91: 1205-12. p.25 ) . 35 Gilbard JP and Farris RL: Tear osmolarity and 17 Allansmith MR and Sullivan DA: Hormonal modu ocular surface disease in keratoconjunctivitis lation of tear volume in the rat. Invest sicca. Arch Ophthalmol 1979, 97: 1642-6. Ophthalmol Vis Sci 1986, 27: No. 3 25 (Abstr. 36 Bron AJ: Prospects for the dry eye. Trans 15 ). Ophthalmol Soc UK 1985. 104: 802-26. 18 Schuster S and Thodi AJ: The control and measure 37 Dilley PN and Mackie IA: Surface changes in the ment of sebum secretion. J InvestDermatol 1974, anaesthetic conjunctiva in man, with special 62: 172-90. reference to the production of mucus from a non 19 Hartschuh W, Weihe E, Reinecke M: Peptidergic goblet cell source. Br J Ophthalmol 1981, 65: (neurotensin, VIP, substance P) nerve fibres in 833-42. the skin. Immunohistochemical evidence of an 38 Ralph RA: Conjunctival goblet cell density in involvement of neuropeptides in nociception, normal subjects and in dry eye syndromes. Invest pruritus and inflammation. BrJ Dermatol1983, Ophthalmol1975,14: 299-302. 109: Suppl2, 25: 14-17. 39 Mengher LS: Tear assessment in the dry eye Thesis. 20 Moore JC and Tiffany JM: Human ocular mucus. University of Oxford (Submitted). Origins and preliminary characterization. Exp .0 Holly FJ and Lemp MA: Wettability and wetting of EyeRes 1979, 29: 291-301. corneal epithelium. Exp Eye Res 1971. 11: 239- 21 Huang AJW and Tseng CG: Development of mono 50. clonal antibodies to rabbit ocular mucin. Invest "' Cope C, Dilly PN, Kaura R, Tiffany ]M. Wettability Ophthalmol VisSci 1987, 28: 1483-91. of the corneal surface: a reappraisal. Curr Eye 22 Ubels JL and MacRae SM: Vitamin A is present as Res 1986,5: 777-85. retinol in the tears of rabbits and humans. ., Tiffany ]M: Measurement of wettability of the cor Current EyeRes 1984,3: 815-22. neal surface. Association for Eye Res Meeting. 23 Chao CC and Butala SM: Isolation and preliminary Leuven September 1987. Abstr. 52. characterisation of tear prealbumen from human .3 Sommer A: Nutritional blindness, xerophthalmia ocular mucus. Current EyeRes 1986,5: 895-901. and keratomalacia. Oxford University Press 2" Shapiro MS, Friend J, Thoft RA: Corneal re-epi (1982). thelialization from the conjunctiva. Invest ." Bron A] and Seal DV: Bacterial infection and the Ophthalmol Vis Sci 1981, 21: 135-42. eye. The defences of the ocular surface. Trans 25 Friedenwald ]S: Growth pressure and metaplasia of Ophthalmol Soc UK 1986,105: 18-25. conjunctival and corneal epithelium. Doc ., Yamamoto GK and Allansmith MR: Complement Ophthalmol 1951, 184: 5-6. in tears from normal humans. AmJ Ophthalmol 26 Tseng SCG, Hirst LW, Farazdaghi M, Green 1979, 88: 758-63. WR: Goblet cell density and vascularization .6 Mackie IA and Seal DV: Diagnostic implications of during conjunctival transdifferentiation. Invest tear protein profiles. Br J Ophthalmol 1984. 68: Ophthalmol Vis Sci1984,25: 1168-76. 321-4. "Tseng SCG, Hirst LW, Farazdaghi M, Green WR: H Bron AJ, Mengher LS, Davey CC: The normal con Inhibition of conjunctival transdifferentiation by junctiva and its responses to inflammation. Trans topical retinoids. Invest Ophthalmol VisSci 1987, Ophthalmol Soc UK 1985,104: 424-35. 28: 538-42. ." Kijlstra A and Veerhuis R: The effect of an anti 28 Tapaszto Istvan: Pathophysiology of human tears. complementary factor on normal human tears. Internat Ophthalmol Clin 1973,13: 119-47. AmJ Ophthalmol1981, 92: 24-7. 29 Mills JT, Dode! AW, Kass EH: Regulation of sta .9 Abelson MB and Udell IJ: H, receptors in the
phylococcal toxic shock syndrome. Toxin - 1 and human ocular surface. Arch Ophthalmol 1981, total exoprotein production by magnesium ion. 99: 302-4. Infect Immun 1986,53: 663-70. 511 Weston JH, Udell IJ. Abelson MB: HI receptors in 30 Balik ]: The lacrimal fluid in keratoconjunctivitis the human ocular surface. InvestOphthalmol Vis sicca. AmJ Ophthalmol1952,35: 773-82. Sci 1981, 20(3): (ARVO suppl p. 32). 31 Gilbard JP, Farris RL, Santa Maria J: Osmolarity of 51 Udell IJ, Gleich GJ, Allansmith MR, Ackerman SJ, tear microvolumes in keratoconjunctivitis sicca. Abelson MB: Eosinophil granule major basic Arch Ophthalmol 1978, 96: 677-81. protein and Charcot-Leyden crystal protein in 32 Gilbard J, Huang A, Tseng S, Rossi S. Gray K, human tears. AmJ Ophthalmol1981, 92: 824-8. Hanninen L: A rabbit model for keratocon 52 Storm T: Fibrinolytic activity in human tears. Scand junctivity sicca. Invest Ophthalmol Vis Sci 1985, J Clin Lab Invest 1955,7: 55. 26(3): p. 14 (Abstr. 5) . 53 Prause J: Serum albumin serum antiproteases and 33 Nelson JD, Peterson TA. Wright JC, Anderson p.m.n. leucocyte neutral collagenolytic protease Beckman G: The effects of ligation of the exorbi in the tear fluid of patients with corneal ulcers. tal gland duct on the cornea and exorbital gland Acta Ophthalmol1983, 61: 272-82. EYELID SECRETIONS AND THE PREVENTION AND PRODUCTION OF DISEASE 171
54 Wang HM, Berman M, Law M: Latent and active 61 Berman M, Manseau E, Law M, Aiken D: Ulcera plasminogen activator in corneal ulceration. tion is correlated with degradation of fibrin and Invest Ophthalmol Vis Sci 1985, 26: 511-24. fibrtonectin at the corneal surface. Invest 55 Rijken D, Wyngaards G, Welbergen 1: Immu Ophthalmol Vis Sci 1983, 24: 1358-66. nological characterization of plasminogen activa 62 Lantz E and Anderson A: Release of fibrolyte tor activities in human tissues and body fluids. J activators from the cornea and conjunctival Lab c/in Med 1981, 97: 477-86. Albrecht von GraefesArch Opthalmol }982, 19: 56 Berman M, Barber 1, Langley C: Corneal ulceration 263-7. and the serum antiproteases I, a-antitrypsin. Invest Ophthalmol1973, 12: 759-70. 63 Hayashi K, Berman K, Kenyon K, Pease S: Patho 57 Fujikawa LS, Foster CS, Harrist TJ. Lanigan 1M. genesis of epithelial defects and stromal ulcera Colvin RB: Fibronectin in healing rabbit corneal tion: localization of tissue plasminogen activator wounds. Lab Invest 1981,45: 120-9. and urokinase-like activator in scraped an alkali 58 Phan T-MM, Gipson IK, Foster CS, Zagachin L, burned corneal wound healing models. Invest Colvin RB: Endogenous production of FN in Ophthalmol VisSci 1987,28: Suppl. p. 2,Abstr. corneal stromal wound; An organ culture cross 6. species transplant study. Invest Ophthalmol Vis 64 Tervo T, Salonen EM, Vakeri A: A new therapy to Sci 1986,27: Suppl 3,p. 52 (Abstr. 4). promote corneal healing. Invest Ophthalmol Vis 59 Jensen OL, Glund BS, Eriksen HO: Fibronectin in Sci 1986, 27: Suppl. p. 53, Abstr. 10. tears following surgical trauma to the eye. Acta 65 Salonen E-M, Tervo T, Torma, Tarkkanen A, Ophthalmol1985, 346-50. 63: Vaheri A: Plasmin in tear fluid of patients with 611 Nishida T, Nakagawa S, Watanabe K, Yamada K, corneal ulcers: basis for new therapy. Acta McDonald 1, Otori T, Berman M: Pathobiology Ophthalmol1987, 65: 3-12. of epithelial defects, peptide (GRGDS) of fibro nectin cell binding domain inhibits corneal epi t>6 Berman M: Collagenase and corneal ulceration. In, thelial attachment and spreading on fibronectin. Collagenase in normal and pathological con Invest Ophthalmol Vis Sci 1986, 27: Suppl 3, nective tissues. New York 10hn Wiley and Sons p. 53, Abstr. 7. (1980), pp. 141-74.