LACRIMAL GLAND, TEAR FILM, AND DRY EYE SYNDROMES 2 Basic Science and Clinical Relevance

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

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NATHAN BACK, State University of New York at Buffalo

IRUN R. COHEN, The Weizmann Institute of Science

DAVID KRITCHEVSKY, Wistar Institute

ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research

RODOLFO PAOLETTI, University of Milan

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LACRIMAL GLAND, TEAR FILM, AND DRY EYE SYNDROMES 2 Basic Science and Clinical Relevance

Edited by

David A. Sullivan Darlene A. Dartt The Schepens Eye Research Institute and Harvard Medical School Boston, Massachusetts

and

Michele A. Meneray Louisiana State University Medical Center New Orleans, Louisiana

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

Library of Congress Cataloging-in-Publication Data

Lacrimal gland, tear film, and dry eye syndromes 2 basic science and cllnical relevance / edited by David A. Sullivan, Darlene A. Dartt. and Mlchele A. Meneray.

p. cm. -- (Advances in experimental medicine and biology ; v. 438. J

"Proceedings of the Second International Conference on the Lacrimal Gland. Tear Film. and Dry Eye Syndromes. held November 16-19. 1996. at the Southhampton Princess Resort. 8ermuda"--T.p. verso.

Includes bibliographical references and index. ISBN 978-1-4613-7445-9 ISBN 978-1-4615-5359-5 (eBook) DOI 10.1007/978-1-4615-5359-5 1. Lacrimal apparatus--Physiology--Congresses. 2. Tears-

-Congresses. 3. Dry eye syndromes--Congresses. 1. Sullivan. David D. II. Dartt. Darlene A. III. Meneray. Michele A. IV. International Conference on the Lacrimal Gland. Tear Film. and Dry Eye Syndromes (2nd 1996 Southampton. Bermuda IslandsJ V. Series.

[DNLM, 1. Lacrimal Apparatus--congresses. 2. Tears--physiology­-congresses. 3. Dry Eye Syndromes--congresses. Wl Ad559 v. 438 19981 QP188.T4L332 1998 612.8·47--dc21 DNLM/DLC for Library of Congress 98-17987

CIP

Proceedings ofthe Second International Conference on the Lacrimal Gland, Tear Film, and Dry Eye Syndromes, held November 16 -19, 1996, at the Southampton Princess Resort, Bermuda

ISBN 978- 1-4613-7445-9

© 1998 Springer Science+Business Media New York

Originally published by Plenum Press, New York in 1998

10987654321

AII rights reserved

No part ofthis book may beTeproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written

permission from the Publisher

PREFACE

During the past two decades, a significant international research effort has been di­

rected toward understanding the composition and regulation of the preocular tear film.

This effort has been motivated by the recognition that the tear film plays an essential role

in maintaining corneal and conjunctival integrity, protecting against microbial challenge,

and preserving visual acuity. In addition, research has been stimulated by the knowledge

that alteration or deficiency of the tear film, which occurs in countless individuals

throughout the world, may lead to desiccation of the ocular surface, ulceration and perfo­

ration of the cornea, an increased incidence of infectious disease, and, potentially, pro­

nounced visual disability and blindness. To promote further progress in this field of vision research, the Second International

Conference on the Lacrimal Gland, Tear Film and Dry Eye Syndromes: Basic Science and

Clinical Relevance was held at the Southampton Princess Resort in Bermuda November

16-19, 1996. This conference was organized and directed by David A. Sullivan, Ph.D.,

codirected by Darlene A. Dartt, Ph.D., and Michele A. Meneray, Ph.D., and sponsored by

the Schepens Eye Research Institute (Boston, MA), an affiliate of Harvard Medical

School. The meeting was designed to assess critically the current knowledge and "state of

the art" research on the structure and function of lacrimal tissue, tears, and the ocular sur­

face in both health and disease. The goal of this conference was to promote an interna­

tional exchange of information that would be of value to basic scientists involved in eye

research, to physicians in the ophthalmological community, to pharmaceutical companies

with an interest in the treatment of lacrimal gland, tear film, or ocular surface disorders,

and to representatives of the U.S. Food and Drug Administration and the National Eye In­

stitute. To help achieve this objective, over 230 scientists, physicians, and industry repre­

sentatives from 21 countries, including Australia, Austria, Belgium, Brazil, Canada, Den­

mark, England, Finland, France, Germany, Hungary, India, Italy, Japan, Scotland, Spain,

Sweden, Switzerland, The Netherlands, the United States, and Uruguay, registered as ac­

tive participants in this conference. In addition, this volume, which contains summaries of

the conference's keynote, oral, and poster presentations, was created to provide an educa­

tional foundation and scientific reference for research on the tear film and dry eye syn­

dromes. The editors commend and thank Leona Greenhill for her excellent copy editing, as

well as Benjamin D. Sullivan for his outstanding book indexing and superlative technical

advice. In addition, the editors would like to thank the following individuals for their or-

vi Preface

ganizational, advisory, administrative, technical, and/or editorial help: members of the Or­ganization and Program Committee, including Drs. Anthony J. Bron, Robert I. Fox, Aize Kijlstra, Peter Laibson, Michael A. Lemp, Austin K. Mircheff, J. Daniel Nelson, Stephen C. Pflugfelder, Bernard Rossignol, John M. Tiffany, Kazuo Tsubota, John L. Ubels, Ben­jamin Walcott, and Steven E. Wilson; members of the International Advisory Committee, including Mark Abelson, Roger W. Heuerman, B. Britt Bromberg, Barbara Caffery, P. Noel Dilly, Marshall Doane, Claes H. Dohlman, Peter C. Donshik, Henry F. Edelhauser, R. Linsy Farris, Gary N. Foulks, Philip Fox, Mitchell H. Friedlaender, Roderick J. Fullard, Anne-Marie Gachon, Jeffrey Gilbard, Ilene K. Gipson, Martin J. Gobbels, Jack Greiner, Jean-Pierre Guillon, Brien Holden, Frank J. Holly, Brett Jessee, Renee Kaswan, Donald R. Korb, Gordon W. Laurie, Donald L. MacKeen, Rolf Marquardt, William D. Mathers, Mitchell D. McCartney, James P. McCulley, Charles McMonnies, Paul C. Montgomery, Juan Murube del Castillo, Sudi Patel, Jan Ulrik Prause, AI Reaves, Miguel Refojo, Brenda L. Reis, Maurizio Rolando, Hans-Walter Roth, Robert A. Sack, Ichiro Saito, Elcio H. Sato, Oliver D. Schein, Michael E. Stem, Norman Talal, Alan Tomlinson, O.P. van Bi­jsterveld, N.J. van Haeringen, Dwight Warren, Graeme Wilson, and Koji Yamamoto, and Ms. Sue Dauphin and Jean S. Kahan; and individuals in Acton, MA, Southampton Parish, Bermuda, Boston, MA, Littleton·, MA, Louisville, KY, New York, NY, and Research Tri­angle Park, NC, including Lawrence Bair, Alan Bergl, Tony Best, Gail Burke, Mary Gal­lagher, Marie Groome, Robin Hodges, Marcia M. Jumblatt, PhD, Kevin J. Klein, Kathleen Krenzer, OD, PhD, Margie Leak, Catherine Louis, Karen Madeiros, Margaret Rocco, Eduardo M. Rocha, MD, James W. Putney, PhD, Lilia Aikawa da Silveira, Amy G. Sulli­van, Rose M. Sullivan, and Driss Zoukhri, PhD.

David A. Sullivan

ACKNOWLEDGMENTS

The editors sincerely thank the following companies and foundations, whose gener­ous financial contributions significantly offset the educational expenses and publication costs associated with the Second International Conference on the Lacrimal Gland, Tear Film and Dry Eye Syndromes: Basic Science and Clinical Relevance.

Allergan, Inc. Tear Products Division, Irvine, CA, USA

Allergan, Inc. New Products Marketing Division, Irvine, CA, USA

Alcon Ophthalmic Marketing Division, Alcon Laboratories, Fort Worth, TX, USA

CIBA Vision Ophthalmics Pharmaceutical Research and Development, Duluth, GA, USA

Alcon Ophthalmic Research & Development Division, Alcon Laboratories, Fort Worth, TX, USA

Santen Pharmaceutical Co., Ltd. Research and Development Division, Osaka, Japan

Taisho Pharmaceutical Co., Ltd. Research and Development Division, Tokyo, Japan

Pfizer Inc. Consumer Health Care Division, New York, NY, USA

Vistakon Materials Research & Development Division, Jacksonville, FL, USA

Bausch & Lomb Global Clinical Research Division, Rochester, NY, USA

vii

viii

Bausch & Lomb Pharmaceutical Division, Tampa, FL, USA

Alcon Foundation Fort Worth, TX, USA

Eagle Vision Memphis, TN, USA

Advanced Instruments, Inc. Business Development Division, Norwood, MA, USA

SPECIAL ACKNOWLEDGMENT

Acknowledgments

The editors express their grateful appreciation to L. Alexandra Wickham, whose ex­

ceptional administrative, technical, and editorial assistance wa_s truly invaluable in making

the Second International Conference on the Lacrimal Gland, Tear Film and Dry Eye Syn­

dromes: Basic Science and Clinical Relevance, as well as these proceedings, a reality.

CONTENTS

Conference Address

1. A Clinician Looks at the Tearfilm J. Daniel Nelson

Lacrimal Gland: Cellular and Molecular Biology

2. Influence of Gender, Sex Steroid Hormones, and the Hypothalamic-Pituitary Axis on the Structure and Function of the Lacrimal Gland . . . . . . . . . . . . . 11

David A. Sullivan, L. Alexandra Wickham, Eduardo M. Rocha, Robin S. Kelleher, Lilia Aikawa da Silveira, and Ikuko Toda

3. Androgen-Regulated Transcription in the Epithelium of the Rat Lacrimal Gland 43 F. Claessens, H. Vanaken, I. Vercaeren, G. Verrijdt, A. Haelens,

E. Schoenmakers, P. Alen, A. Devos, B. Peeters, G. Verhoeven, W. Rombauts, and W. Heyns

4. Gene Cloning ofBM180, a Lacrimal Gland Enriched Basement Membrane Protein with a Role in Stimulated Secretion . . . . . . . . . . . . . . . . . . . . . . . . . 49

Anil C. Asrani, Angela J. Lumsden, Rajesh Kumar, and Gordon W. Laurie

5. Sensory Denervation Leads to Deregulated Protein Synthesis in the Lacrimal Gland....................................................... 55

Doan H. Nguyen, Roger W. Beuerman, Michele A. Meneray, and Dmitri Maitchouk

6. Acinar Cell Basal-Lateral Membrane-Endomembrane Traffic May Mediate Interactions with Both T Cells and B Cells . . . . . . . . . . . . . . . . . . . . . . . . . 63

Austin K. Mircheff, Tao Yang, Jian Zhang, Hongtao Zeng, J. Peter Gierow, Dwight W. Warren, and Richard L. Wood

7. Tissue Expression of Tear Lipocalin in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Catherine Ressot, Herve Lassagne, Jean-Louis Kemeny, and

Anne-Marie Francoise Gachon

lx

X Contents

8. The Exorbital Lacrimal Glands of the Rat Are Tensed in Situ . . . . . . . . . . . . . . . . 75 Mortimer Lorber

9. Aberrant Lacrimal Gland Development in an Anophthalmic Mutant Strain of Rat 81 PrabirK. De

10. Hormonal Influences on Syrian Hamster Lacrimal Gland: Marked Repression of a Major 20 kDa Secretory Protein by Estrogens, Androgens, and Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Prabir K. De and Velvizhi Ranganathan

11. Androgen Support of Lacrimal Gland Function in the Female Rabbit Dwight W. Warren, Ana Maria Azzarolo, Zuo Ming Huang,

Barbara W. Platter, Renee L. Kaswan, Elizabeth Gentschein, Frank L. Stanczyk, Laren Becker, and Austin K. Mircheff

89

12. Identification and Hormonal Control of Sex Steroid Receptors in the Eye . . . . . . 95 L. Alexandra Wickham, Eduardo M. Rocha, Jianping Gao,

Kathleen L. Krenzer, Lilia Aikawa da Silveira, Ikuko Toda, and David A. Sullivan

13. Dinucleotide Repeat Polymorphism Near the Tear Lipocalin Gene Eric Lacazette, Gilles Pitiot, Jacques Mallet, and

Anne-Marie Francoise Gachon

101

14. Studies of Ligand Binding and CD Analysis with apo- and bolo-Tear Lipocalins 105 Ben J. Glasgow, Adil R. Abduragimov, Taleh N. Yusifov, and

Oktai K. Gasymov

Lacrimal Gland and Ocular Surface: Signal Transduction, Membrane Traffic, and Fluid and Protein Secretion

15. Signal Transduction Pathways Activated by Cholinergic and a.1-Adrenergic Agonists in the Lacrimal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Darlene A. Dartt, Robin R. Hodges, and Driss Zoukhri

16. Calcium Signalling in Lacrimal Acinar Cells............................. 123 James W. Putney, Jr., Yi Huang, and Gary St. J. Bird

17. Voltage- and Ca2+ -Dependent Chloride Current Activated by Hyposmotic and Hyperosmotic Stress in Rabbit Superior Lacrimal Acinar Cells . . . . . . . . . 129

George H. Herok, Thomas J. Millar, Philip J. Anderton, and Donald K. Martin

18. G Protein Coupling of Receptor Activation to Lacrimal Secretion . . . . . . . . . . . . 133 Michele A. Meneray and Tammy Y. Fields

19. Microtubules and Intracellular Traffic of Secretory Proteins in Rat Extraorbital Lacrimal Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

Philippe Robin, Marie-Noelle Raymond, and Bernard Rossignol

Contents xi

20. Effects ofNeuropeptides on Serotonin Release and Protein and Peroxidase Secretion in the Isolated Rat Lacrimal Gland . . . . . . . . . . . . . . . . . . . . . . . . 145

Jaipaul Singh, Keith A. Sharkey, Robert W. Lea, and Ruth M. Williams

21. Analysis of Phosphodiesterase Isoenzymes in the Ocular Glands of the Rabbit.. 153 Thomas J. Millar and Harry Koutavas

22. Immunohistochemistry and Secretory Effects of Leucine Enkephalin in the Isolated Pig Lacrimal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Jaipaul Singh, Peter K. Djali, and Ernest Adeghate

23. Interaction between Vasoactive Intestinal Polypeptide (VIP) and Neuropeptide Y (NPY) in the Isolated Rat Lacrimal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Jaipaul Singh, Ruth M. Williams, Robert W. Lea, and Ernest Adeghate

24. Identification and Cellular Localization of the Components of the VIP Signaling Pathway in the Lacrimal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Robin R. Hodges, Driss Zoukhri, Jessica P. Lightman, and Darlene A. Dartt

25. Kinesin Activation Drives the Retrieval of Secretory Membranes following Secretion in Rabbit Lacrimal Acinar Cells . . . . . . . . . . . . . . . . . . . . . . . . . . 177

S. F. Hamm-Alvarez, S. R. da Costa, M. Sonee, D. W. Warren, and A. K. Mircheff

26. Protein Kinase C lsoforms Differentially Control Lacrimal Gland Functions 181 Driss Zoukhri, Robin R. Hodges, Christian Sergheraert, and Darlene A. Dartt

27. Role of Protein Kinases in Regulation of Apical Secretion and Basal-Lateral Membrane Recycling Traffic in Reconstituted Rabbit Lacrimal Gland Acini . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

J. Peter Gierow and Austin K. Mircheff

28. Brefeldin A Detoxification in Rat Extraorbital Lacrimal Glands . . . . . . . . . . . . . 191 Philippe Robin, Bernard Rossignol, and Marie-Noelle Raymond

29. Identification and Characterization ofG Proteins in the Mammalian Lacrimal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Michele A. Meneray and D. Jean Bennett

30. Inward-Rectifying Potassium Channels in the Rabbit Superior Lacrimal Gland 205 George H. Herok, Thomas J. Millar, Philip J. Anderton, and Donald K. Martin

31. Electrophysiological Evidence for Reduced Water Flow from Lacrimal Gland Acinar Epithelium ofNZB/NFW F1 Mice . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Peter R. Brink, Elizabeth Peterson, Kathrin Banach, and Benjamin Walcott

Mucins: Origin, Biochemistry, and Regulation

32. Cellular Origin ofMucins of the Ocular Surface Tear Film Ilene K. Gipson and Tsutomu Inatomi

221

xii Contents

33. Soluble Mucin and the Physical Properties of Tears . . . . . . . . . . . . . . . . . . . . . . . 229 John M. Tiffany, Jyotin C. Pandit, and Anthony J. Bron

34. Characterization and Origin of Major High-Molecular-Weight Tear Sialoglycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

Robert A. Sack, Bruce Bogart, Sonal Sathe, Ann Beaton, and George Lew

35. Detection and Quantification of Conjunctival Mucins James E. Jumblatt and Marcia M. Jumblatt

36. Mucous Contribution to Rat Tear-Film Thickness Measured with a

239

Microelectrode Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 7 Philip Anderton and Sophia Tragoulias

3 7. Structural Analysis of Secreted Ocular Mucins in Canine Dry Eye Stephen D. Carrington, Sally J. Hicks, Anthony P. Corfield,

Renee L. Kaswan, Nicki Packer, Shirley Bolis, and Carol A. Morris

253

38. Corneal Epithelial Tight Junctions and the Localization of Surface Mucin 265 Henry F. Edelhauser, David E. Rudnick, and Ramzy G. Azar

39. Breakup and Dewetting of the Corneal Mucus Layer: An Update Ashutosh Sharma

Meibomian Gland and Tear Film Lipids: Structure, Function, and Control

40. The Meibomian Glands and Tear Film Lipids: Structure, Function,

273

and Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Anthony J. Bron and John M. Tiffany

41. Tear Film Interferometry as a Diagnostic Tool for Evaluating Normal and Dry-Eye Tear Film . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Marshall G. Doane and M. Estella Lee

42. Human and Rabbit Lipid Layer and Interference Pattern Observations Donald R. Korb, Jack V. Greiner, Thomas Glonek, Amy Whalen,

Stacey L. Hearn, Jan E. Esway, and Charles D. Leahy

305

43. Abnormal Lipid Layers: Observation, Differential Diagnosis, and Classification 309 Jean-Pierre Guillon

44. Association of Tear Lipid Layer Interference Patterns with Superficial Punctate Keratopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

Aoi Komuro, Norihiko Yokoi, Yoko Takehisa, and Shigeru Kinoshita

45. Meibomian Secretions in Chronic Blepharitis James P. McCulley and Ward E. Shine

319

Contents xfii

46. Androgen Regulation of the Meibomian Gland........................... 327 David A. Sullivan, Eduardo M. Rocha, M. David Ullman,

Kathleen L. Krenzer, Jianping Gao, Ikuko Toda, M. Reza Dana, Dorothy Bazzinotti, Lilia Aikawa da Silveira, and L. Alexandra Wickham

47. Delivery of Meibomian Oil Using the Clinical Meibometer® . . . . . . . . . . . . . . . . 333 John M. Tiffany, Anthony J. Bron, Federico Mossa, and Shabtay Dikstein

48. Volume ofthe Human and Rabbit Meibomian Gland System . . . . . . . . . . . . . . . . 339 Jack V. Greiner, Thomas Glonek, Donald R. Korb, Amy C. Whalen,

Eric Hebert, Stacey L. Hearn, Jan E. Esway, and Charles D. Leahy

49. Effect of Meibomian Gland Occlusion on Tear Film Lipid Layer Thickness . . . . 345 Jack V. Greiner, Thomas Glonek, Donald R. Korb, Stacey L. Hearn,

Amy C. Whalen, Jan E. Esway, and Charles D. Leahy

Tear Film Stability, Evaporation, and Biophysics

50. Meibomian Gland Lipids, Evaporation, and Tear Film Stability . . . . . . . . . . . . . . 349 William D. Mathers and James A. Lane

51. Surface-Chemical Pathways of the Tear Film Breakup: Does Corneal Mucus Have a Role? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Ashutosh Sharma

52. The Biophysical Role in Tear Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Alan Tomlinson, Jennifer P. Craig, and Gerald E. Lowther

53. Longitudinal Analysis ofPrecomeal Tear Film Rupture Patterns Etty Bitton and John V. Lovasik

54. The Role of Tear Proteins in Tear Film Stability in the Dry Eye Patient and in

381

the Rabbit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 Ronald D. Schoenwald, Sangeeta Vidvauns, Dale Eric Wurster, and

Charles F. Barfknecht

55. Relationship between Pre-Ocular Tear Film Structure and Stability . . . . . . . . . . . 401 Michel Guillon, Cecile Maissa, and Elaine Styles

56. Association ofPrecomeal and Preconjunctival Tear Film . . . . . . . . . . . . . . . . . . . 407 Yoko Takehisa, Norihiko Yokoi, Aoi Komuro, and Shigeru Kinoshita

57. Age and.Gender Effects on the Normal Tear Film . . . . . . . . . . . . . . . . . . . . . . . . . 411 Jennifer P. Craig and Alan Tomlinson

58. The Kinetics of Lid Motion and Its Effects on the Tear Film A. Berke and S. Mueller

417

59. Hydrodynamics of Meniscus-Induced Thinning of the Tear Film . . . . . . . . . . . . . 425 Ashutosh Sharma, Sanjay Tiwari, Rajesh Khanna, and John M. Tiffany

xiv

60. Computer-Assisted Calculation of Exposed Area of the Human Eye John M. Tiffany, Bryan S. Todd, and Mark R. Baker

Cytokines, Growth Factors, Proto-Oncogenes, and Apoptosis

Contents

433

61. Cytokines: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 James T. Rosenbaum, Beatriz Brito, Young Boc Han, Jongmoon Park, and

Stephen R. Planck

62. Gender- and Androgen-Related Impact on the Expression of Proto-Oncogenes and Apoptotic Factors in Lacrimal and Salivary Glands of Mouse Models of Sjogren's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447

Ikuko Toda, L. Alexandra Wickham, Eduardo M. Rocha, Lilia Aikawa da Silveira, and David A. Sullivan

63. Apoptosis in the Lacrimal Gland and Conjunctiva of Dry Eye Dogs Jianping Gao, Tammy A. Gelber-Schwalb, John V. Addeo, and

Michael E. Stem

453

64. Cytokines and Tear Function in Ocular Surface Disease . . . . . . . . . . . . . . . . . . . . 461 Keith Barton, Alexandra Nava, Dagoberto C. Monroy, and

Stephen C. Pflugfelder

65. Chemokine Prpduction in Conjunctival Epithelial Cells . . . . . . . . . . . . . . . . . . . . 471 Kazumi Fukagawa, Kazuo Tsubota, Shigeto Simmura, Hirohisa Saito,

Hiroshi Tachimoto, Akira Akasawa, and Yoshihisa Oguchi

66. Molecular Basis and Role of Differential Cytokine Production in T Helper Cell Subsets in Immunologic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479

Andrea Keane-Myers, Vincenzo Casolaro, and Santa Jeremy Ono

67. Presence and Testosterone Influence on the Levels of Anti- and Pro-Inflammatory Cytokines in Lacrimal Tissues of a Mouse Model of Sjogren's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

Eduardo M. Rocha, L. Alexandra Wickham, Zhiyan Huang, Ikuko Toda, Jianping Gao, Lilia Aikawa da Silveira, and David A. Sullivan

68. Infiltrating Lymphocyte Populations and Cytokine Production in the Salivary and Lacrimal Glands of AutoimmUhe NOD Mice . . . . . . . . . . . . . . . . . . . . 493

Christopher P. Robinson, Janet Cornelius, Denise I. Bounous, Hideo Yamamoto, Michael G. Humphreys-Beher, and Ammon B. Peck

69. Do Cytokines Have a Role in the Regulation of Lacrimal Gland Acinar Cell Ion Transport and Protein Secretion? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499

R. William Lambert

70. The Rat Exorbital Lacrimal Gland as a Site of Synthesis ofEGF-like Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505

Herve Marechal, Helene Jammes, Bernard Rossignol, and Philippe Mauduit

Contents xv

71. The Distribution ofFGF-2 and TGF-13 within the Lacrimal Gland of Rabbits . . . 511 Joel Schechter, Dwight W. Warren, and Richard L. Wood

72. Tear Fluid Changes after Photorefractive Keratectomy . . . . . . . . . . . . . . . . . . . . . 515 Minna Vesaluoma and Timo Tervo

73. Time Course of Apoptosis in Lacrimal Gland after Rabbit Ovariectomy . . . . . . . 523 Ana Maria Azzarolo, Richard L. Wood, Austin K. Mircheff, Eric Olsen,

Zuo Ming Huang, Ramin Zolfagari, and Dwight W. Warren

74. Co-Expression ofBCL-2 and CD44S in Basal Layers of Human Ocular Surface Epithelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527

Andrew J. W. Huang, Cheng-Hui Li, You-Wei Chen, and Lilly Y. W. Bourguignon

75. Alterations of Ocular Surface Gene Expression in Sjogren's Syndrome . . . . . . . 533 David T. Jones, Dagoberto Monroy, Zhongua Ji, and Stephen C. Pflugfelder

76. Growth Factor Interaction with Contact Lenses: Evidence for and Possible Effects of Storage of Basic FGF in Contact Lenses: Preliminary Results . . 537

G.-B. van Setten and N. Zengin

Intlammation and Immunity

77. Neural, Endocrine, and Immune System Interactions: Relevance for Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541

Jan A. Moynihan, Barbara Kruszewska, Gary J. Brenner, and Nicholas Cohen

78. Inductive Sites for Rat Tear IgA Antibody Responses . . . . . . . . . . . . . . . . . . . . . . 551 Deanne M. Ridley Lathers, Randall F. Gill, Nancy L O'Sullivan, and

Paul C. Montgomery

79. Anatomy of Mammalian Conjunctival Lymphoepithelium . . . . . . . . . . . . . . . . . . 557 James Chodosh, Robert E. Nordquist, and Ronald C. Kennedy

80. Binding of a Cytopathic or an Invasive Strain of P. aeruginosa to Cytoskeletal, Basement Membrane, or Matrix Proteins of Wounded Cornea Is Similar and Does Not Rely on Interaction with Actin Filaments . . . . . . . . . . . . . . . 567

Linda D. Hazlett and Sharon Masinick

81. Secretory IgAResponses on the Human Ocular Surface . . . . . . . . . . . . . . . . . . . . 575 Aize Kijlstra

82. A Method to Study Induction of Autoimmunity in Vitro: Co-Culture of Lacrimal Cells and Autologous Immune System Cells . . . . . . . . . . . . . . . . . . . . . . . . 583

Harvey R. Kaslow, Zhijun Guo, Dwight W. Warren, Richard L. Wood, and Austin K. Mircheff

83. Rat Lacrimal Glands Contain Activated and Resting Mature T Cells, Recent Thymic Emigrants, and Possibly Extrathymic Populations . . . . . . . . . . . . . 591

Nancy L. O'Sullivan, Cheryl A. Skandera, and Paul C. Montgomery

xvi Contents

84. Immunohistochemical Examination of Lacrimal Gland Tissue from Patients with Ocular Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599

Janine A. Smith, Chi-Chao Chan, Charles E. Egwuagu, and Scott M. Whitcup

85. Immunoglobulin Levels in the Tears of Patients with Corneal Grafts and Transplant Rejection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

Andras Berta and Zsolt Lampe

Tear Film Components and Influence on the Ocular Surface

86. Tear Fluid Influence on the Ocular Surface Stephen C. Pflugfelder

611

87. Effects ofLacrimal Gland Removal on Squirrel Monkey Cornea............. 619 Dmitri Y. Maitchouk, Roger W. Beuerman, Ray J. Varnell, and

Lia Pedroza-Schmidt

88. Lacrimal Gland Growth Factors and Receptors: Lacrimal Fibroblastic Cells Are a Source of Tear HGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625

S. E. Wilson, Q. Li, R. R. Mohan, T. Tervo, M. Vesaluoma, G. L. Bennett, R. Schwall, K. Tabor, J. Kim, S. Hargrave, and K. H. Cuevas

89. Clusterin May Be Essential for Maintaining Ocular Surface Epithelium as a Non-Keratinizing Epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629

Kohji Nishida, Satoshi Kawasaki, and Shigeru Kinoshita

90. Effects of Chronic Hypertonic Stress on Regulatory Volume Increase and Na-K-2Cl Cotransporter Expression in Cultured Corneal Epithelial Cells 637

Victor N. Bildin, Hua Yang, Jorge Fischbarg, and PeterS. Reinach

91. A Unified Theory of the Role of the Ocular Surface in Dry Eye . . . . . . . . . . . . . . 643 Michael E. Stem, Roger W. Beuerman, Robert I. Fox, Jianping Gao,

Austin K. Mircheff, and Stephen C. Pflugfelder

92. Human Tear Film Components Bind Pseudomonas aeruginosa . . . . . . . . . . . . . . 653 Nancy A. McNamara and Suzanne M. J. Fleiszig

93. Small-Volume Analysis ofRabbit Tears and Effects of a Corneal Wound on Tear Protein Spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659

Ray J. Varnell, Dmitri Y. Maitchouk, Roger W. Beuerman, James E. Carlton, and Anthony Haag

94. 31-27 kDa Caseinolytic Protease in Human Tears . . . . . . . . . . . . . . . . . . . . . . . . . 665 Miki Sakata, Ann R. Beaton, Sonal Sathe, and Robert A. Sack

95. Tear Protein Levels following Punctal Plugging . . . . . . . . . . . . . . . . . . . . . . . . . . 669 E. Ian Pearce, Alan Tomlinson, Jennifer P. Craig, and Gerald E. Lowther

96. Characterization of Cells Shed from the Ocular Surface in Normal Eyes . . . . . . . 675 Carolyn G. Begley, Jie Zhou, and Graeme Wilson

Contents xvii

97. Healing Effect ofSodium-Sucrose-Octasulfate and EGF on Epithelial Corneal Abrasions in Rabbits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683

Sven Johansen, Steffen Heegaard, Kirsten Bjerrum, and Jan Ulrik Prause

98. A Novel Approach to Resolve Cellular Volume Responses to an Anisotonic Challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687

Pavel lserovich, Peter S. Reinach, Hua Yang, and Jorge Fischbarg

Artificial Tears and Contact Lenses: Impact on the Tear Film and Ocular Surface

99. Classification of Artificial Tears: 1: Composition and Properties J. Murube, A. Paterson, and E. Murube

693

100. Classification of Artificial Tears: ll: Additives and Commercial Formulas 705 J. Murube, A. Murube, and Chen Zhuo

10 l. The Ocular Surface, the Tear Film, and the Wettability of Contact Lenses . . . . . . 717 Carol A. Morris, Brien A. Holden, Eric Papas, Hans J. Guesser,

Shirley Bolis, Philip Anderton, and Fiona Carney

102. Conjunctival Permeability and Ultrastructure: Effects of Benzalkonium Chloride and Artificial Tears . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723

John L. Ubels, Eric M. Woo, William J. Watts, LisaK. Smith, Uko Zylstra, Jonnell Beaird, and Mitchell D. McCartney

103. Preservative Effect on Epithelial Barrier Function Measured with a Novel Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731

Jerry R. Paugh, Alan Sasai, and Abhay Joshi

104. Video Biomicroscopy of the Tear Film . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 7 P. Noel Dilly, Michel Guillon, and Lucia McGrogan

105. Patient-Dependent and Material-Dependent Factors in Contact Lens Deposition Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745

Brian J. Tighe, Lyndon Jones, Kathryn Evans, and Valerie Franklin

106. Effectiveness ofBion Tears, Cellufresh, Aquasite, and Refresh Plus for Moderate to Severe Dry Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753

Peter C. Donshik, J. Daniel Nelson, Mark Abelson, James P. McCulley, Cliff Beasley, and Robert A. Laibovitz

107. Ocular Residence Time ofCarboxymethylcellulose Solutions Jerry R. Paugh, Ronald C. Chatelier, and Joseph W. Huff

108. Vitronectin Adsorption in Contact Lens Surfaces during Wear: Locus and

761

Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769 Brian J. Tighe, Valerie Franklin, Christopher Graham, Aisling Mann, and

Michel Guillon

xviil Contents

109. Effect of Tears and Tear Residues on Worn Etafilcon and Polymacon Disposable Contact Lenses on the Adhesion of Pseudomonas aernginosa . . . . . . . . . . 775

Miguel F. Refojo, Fee-Lai Leong, and Marta Portoles

110. Hyaluronan in Dry Eye and Contact Lens Wearers . . . . . . . . . . . . . . . . . . . . . . . . 785 Monica Berry, William K. Pastis, Roger B. Ellingham, Louise Frost,

Anthony P. Corfield, and David L. Easty

Classification, Diagnosis, Clinical Features, and Epidemiology of Dry Eye Syndromes

111. Epidemiology and Classification ofDry Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791 Michael A. Lemp

112. CANDEES: The Canadian Dry Eye Epidemiology Study . . . . . . . . . . . . . . . . . . 805 Barbara E. Caffery, Doris Richter, Trefford Simpson, Desmond Fonn,

Michael Doughty, and Keith Gordon

113. Sensitivity and Specificity of a Screening Questionnaire for Dry Eye . . . . . . . . . 807 NealL. Oden, David E. Lilienfeld, Michael A. Lemp, J. Daniel Nelson, and

Fred Ederer

114. Use of a Questionnaire for the Diagnosis of Tear Film-Related Ocular Surface Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821

Maurizio Rolando, Angelo Macri, Trillo Carlandrea, and Giovanni Calabria

115. Importance of Conjunctival Epithelial Evaluation in the Diagnostic Differentiation of Dry Eye from Drug-Induced Epithelial Keratopathy 827

Norihiko Yokoi and Shigeru Kinoshita

116. The Size of Corneal Epithelial Cells Collected by Contact Lens Cytology from Dry Eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831

Graeme Wilson and John Laurent

117. Optimum Dry Eye Classification Using Questionnaire Responses . . . . . . . . . . . . 835 Charles McMonnies, Arthur Ho, and Denis Wakefield

118. Diagnostic Value of Tear Film Abnormalities in a New Syndrome Affecting the Neuroendocrine and Immune Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839

Janos Feher

119. Low-Tech Detection of Tear Film-Related Diseases ofthe Ocular Surface 845 Maurizio Rolando, Salvatore Alongi, Angelo Macri, Marco Schenone, and

Giovanni Calabria

120. Using LIPCOF (Lid-Parallel Conjunctival Fold) for Assessing the Degree of Dry Eye, It Is Essential to Observe the Exact Position of That Specific Fold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853

Frank Schirra, Helmut Hob, Christina Kienecker, and Klaus W. Ruprecht

Contents xix

121. Use of the Tearscope Plus and Attachments in the Routine Examination of the Marginal Dry Eye Contact Lens Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859

Jean-Pierre Guillon

122. Evaluation of Schirmer Tests by Two Types ofTear Clearance Tests . . . . . . . . . . 869 Masafumi Ono, Yukiko Yagi, Eiki Goto, Hao-Yung Yang, and Kazuo Tsubota

123. Fluorescein Dye Concentration as a Factor in Tear Film Fluorescence . . . . . . . . 875 Victor M. Finnemore, Donald R. Korb, Jack V. Greiner, Thomas Glonek, and

John P. Herman

124. A New Method for Measuring Human Basic Tear Fluid Osmolality Pierre L. Emond and Christopher J. Corbett

879

125. Micropachometric Quantification of Tear Assessment Tests . . . . . . . . . . . . . . . . . 883 Hans W. Roth and Rolf Marquardt

126. Use ofCornea1 Thickness Changes to Compare the Efficacy of Conventional Eye Drops with Supracutaneous Treatment of Dry Eye . . . . . . . . . . . . . . . . 887

Hans W. Roth

Pathogenesis of Dry Eye Syndromes

127. Sjogren's Syndrome: Pathogenesis and New Approaches to Therapy Robert I. Fox

128. Reflex Tearing in Dry Eye Not Associated with Sjogren's Syndrome Kazuo Tsubota

129. Cytokine mRNAExpression in Labial Salivary Glands and Cytokine Secretion

891

903

in Parotid Saliva in Sjogren's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 Philip C. Fox, Margaret M. Grisius, Debra K. Bermudez, and Di Sun

130. Age-Related Decrease in Innervation Density of the Lacrimal Gland in Mouse Models of Sjogren's Syndrome................................... 917

Benjamin Walcott, Nidia Claros, Alpa Patel, and Peter R. Brink

131. Aberrant Expression and Potential Function for Parotid Secretory Protein (PSP) in the NOD (Non-Obese Diabetic) Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . 925

Christopher P. Robinson, Denise I. Bounous, Connie E. Alford, Ammon B. Peck, and Michael G. Humphreys-Beher

132. Survey of Canine Tear Deficiency in Veterinary Practice . . . . . . . . . . . . . . . . . . . 931 Renee Kaswan, Christopher Pappas, Jr., Keith Wall, and Susan G. Hirsh

133. Lacrimation and Salivation Are Not Related to Lymphocytic Infiltration in Lacrimal and Salivary Glands in MRL 1pr/lpr Mice . . . . . . . . . . . . . . . . . . 941

Hiromi Fujita, Tsutomu Fujihara, Tsutomu Takeuchi, Ichiro Saito, and Kazuo Tsubota

XX Contents

134. The Sjogren Syndrome and Tear Function Profile . . . . . . . . . . . . . . . . . . . . . . . . . 949 0. Paul van Bijsterveld

Management and Therapy of Dry Eye Syndromes

135. Cytokines May Prove Useful in the Treatment ofSjogrens Syndrome (SS) Dry Eye......................................................... 953

Norman Talal, Toru Nakabayashi, John J. Letterio, Liping Kong, Andrew G. Geiser, and Howard Dang

136. The Now and Future Therapy of the Non-Sjogren's Dry Eye . . . . . . . . . . . . . . . . 959 GaryN. Foulks

13 7. Dry Eye Treatment with Eye Drops that Stimulate Mucin Production . . . . . . . . . 965 Takashi Hamano

138. A Dose-Ranging Clinical Trial to Assess the Safety and Efficacy of Cyclosporine Ophthalmic Emulsion in Patients with Keratoconjunctivitis Sicca . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969

Joseph Tauber, for the Cyclosporine Study Group

139. Oral Pilocarpine for Symptomatic Relief of Dry Mouth and Dry Eyes in Patients with Sjogrens Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973

A. S. Papas, M. M. Fernandez, R. A. Castano, S. C. Gallagher, M. Trivedi, and R. C. Shrotriya

140. Oral Pilocarpine for Symptomatic ReliefofKeratoconjunctivitis Sicca in Patients with Sjogren's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

J.D. Nelson, M. Friedlaender, R. P. Yeatts, R. Yee, M. McDermott, S. Orlin, S. C. Gallagher, R. C. Shrotriya, and the MGI PHARMA Sjogren's Syndrome Study Group

141. Supracutaneous Treatment of Dry Eye Patients with Calcium Carbonate 985 Donald L. MacKeen, Hans Walter Roth, Marshall G. Doane, and

Patricia D. MacKeen

142. Preclinical Safety Studies ofCyclosporine Ophthalmic Emulsion . . . . . . . . . . . . 991 0. Ange1ov, A. Wiese, Y. Yuan, J. Andersen, A. Acheampong, and B. Brar

143. Conjunctival Impression Cytology from Dogs with Keratoconjunctivitis Sicca: Pre- and Post-Treatment with Topical Cyclosporine . . . . . . . . . . . . . . . . . . 997

Denise I. Bounous, Kathleen L. Krenzer, Renee L. Kaswan, and Susan G. Hirsh

144. Cyclosporine Distribution into the Conjunctiva, Cornea, Lacrimal Gland, and Systemic Blood following Topical Dosing of Cyclosporine to Rabbit, Dog, and Human Eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001

Andrew Acheampong, Martha Shackleton, Steve Lam, Patrick Rudewicz, and Diane Tang-Liu

Contents xxi

145. Estrogen Therapy in Keratoconjunctivitis Sicca . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 Jinus Akramian, Andreas Wedrich, Johannes Nepp, and Michael Sator

146. Dry Eye Treatment with Acupuncture: A Prospective, Randomized, Double-Masked Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011

J. Nepp, A. Wedrich, J. Akramian, A. Derbolav, C. Mudrich, E. Ries, and J. Schauersberger

14 7. Puncta! Occlusion for the Treatment of Dry Eye . . . . . . . . . . . . . . . . . . . . . . . . . . 1017 Mitchell H. Friedlaender and Robert I. Fox

148. Keratoprosthesis in Pemphigoid and Stevens-Johnson Syndrome . . . . . . . . . . . . 1021 Claes H. Dohlman and Hisao Terada

149. Portable Device for Programmable, Automatic, or On-Demand Delivery of Artificial Tears . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027

Vo Van Toi and P. A. Grounauer

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033

Index ................................................................. 1037

The editors dedicate this book to Drs. Anthony J. Bron, Claes H. Dohlman, Anne-Marie F. Gachon, Michael A. Lemp, Bernard Rossignol, and John M. Tiffany for their pioneering efforts and outstanding achievements in basic and clinical research on the lacrimal gland, tear film, and/or dry eye syndromes.