Seediscussions,stats,andauthorprofilesforthispublicationat:https://www.researchgate.net/publication/15324220

Isasthmaanepithelialdisease?

ARTICLEinCHEST·APRIL1995

ImpactFactor:7.48·Source:PubMed

CITATIONS

16

READS

12

4AUTHORS,INCLUDING:

StephenIRennard

UniversityofNebraskaatOmaha

687PUBLICATIONS27,785CITATIONS

SEEPROFILE

DebraJRomberger

UniversityofNebraskaMedicalCenter

187PUBLICATIONS3,754CITATIONS

SEEPROFILE

JohnSpurzem

UniversityofMississippiMedicalCenter

101PUBLICATIONS3,069CITATIONS

SEEPROFILE

Availablefrom:DebraJRomberger

Retrievedon:04February2016

DOI 10.1378/chest.107.3_Supplement.127S 1995;107;127S-131SChest

 John R. SpurzemStephen I. Rennard, Debra J. Romberger, Richard A. Robbins and Is Asthma an Epithelial Disease?

  citation

http://chestjournal.chestpubs.org/content/107/3_Supplement/127S.and services can be found online on the World Wide Web at: The online version of this article, along with updated information 

ISSN:0012-3692)http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(

without the prior written permission of the copyright holder.No part of this article or PDF may be reproduced or distributed3300 Dundee Road, Northbrook, IL 60062. All rights reserved. Copyright1995by the American College of Chest Physicians,Physicians. It has been published monthly since 1935.

is the official journal of the American College of ChestChest

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from

SESSION 6

Is Asthma an EpithelialDisease?*Stephen I. Rennard, MD; Debra J. Romberger, MD;Richard A. Robbins, MD; and John R. Spurzem, MD

Asthma has long been known to affect the opithelial sur-

face of the airways.1'2 Histologic alterations of the

airway epithelium in asthma include metaplastic changes.Most often these include goblet cell metaplasia, butsquamous metaplasia can also occur. The lamina reticu-laris, which underlies the true basement membrane of theairway epithelium, is thickened in asthma. An inflamma-tory cell infiltration results in an accumulation of bothsubepithelial and intraepithelial inflammatory cells. Fi-nally, in severe asthma, damage of the airway epithelium,including loss of much of the pseudostratified columnarepithelial cells, can be a prominent feature. When identi-fied in expectorated sputum, these sloughed cells formCreola bodies. Recent evidence, however, suggests that theairway epithelium is involved not only as a target of theinflammatory lesions that characterize asthma, but also canbe an active participant in the pathogenetic processes thatlead to the development and maintenance of asthma.The airway epithelium has been known to produce a

number of factors that can alter smooth muscle function.Epithelial-derived relaxing activities are produced by air-way epithelium3 and may represent heterogeneous factors.Prostaglandin E, for example, is a product of airway epi-thelial cells4 and has been suggested to mediate smoothmuscle relaxation induced by airway epithelium.5-7 Nitricoxide has been suggested as an additional epithelial-derived smooth muscle relaxing factor. In this context,airway epithelial cells have been demonstrated to producenitric oxide.8 These cells express the constitutive form ofnitric oxide synthase and can be induced by cytokines toproduce the inducible form of nitric oxide synthase.9 Inasthma, immunohistochemical studies have demonstratedthe expression of the inducible form of nitric oxidesynthase by airway epithelial cells.'0 It seems reasonable,therefore, to suggest that the production of nitric oxide byairway epithelial cells may play a role in the asthmaticresponse, including not only regulation of airway smoothmuscle tone3 and bronchoconstriction, but also the vascu-

lar responses that characterize asthma."1Airway epithelial cells have also been found to produce

mediators capable of directing the chemotactic recruit-ment of inflammatory cells. Neutrophil chemotactic ac-

tivity is released by airway epithelial cells in response to a

number of stimuli.'126 This activity appears to includeseveral chemotactic factors, including both chemokines17'18and eicosanoids.'9'20 In addition to recruiting neutrophils,airway epithelial cells in vitro can release factors that can

direct the recruitment of monocytes,21 lymphocytes,22 24

eosinophils,25 and basophils. Interestingly, the factorsreleased by airway epithelial cells that recruit lymphocytesappear to show lymphocyte subset specificity. In this

*From the University of Nebraska Medical Center, Omaha.

regard, cultured bovine bronchial epithelial cells havebeen demonstrated to recruit B cells and helper T cells, butnot suppressor T cells. Whether subsets of helper T cells arespecifically recruited by airway epithelial cells under var-ious conditions remains to be determined, but this mech-anism may be important in the control of immuneresponses in the asthmatic airway. Increased chemotacticactivity for T lymphocytes released from epithelial cellsderived from asthmatic patients has been reported.24The list of potential mediators released by airway epi-

thelial cells is rapidly increasing. A variety of differentmethods, cell sources, and species have been utilized in anumber of laboratories to assess mediator production byairway epithelial cells (Table 1). The relevance of theproduction of these mediators in diseases is less clear. Thatthe airway epithelium will be a source of mediators inasthma, however, seems likely. Sousa and colleagues,26 forexample, have used immunohistochemical techniques todemonstrate increased granulocyte monocyte colony stim-ulating factor (GMCSF) production by the asthmatic air-way epithelium. Vittori et a127 and Springall et a128 haveused similar methods to demonstrate increased expressionof endothelin-1 by airway epithelial cells in asthma, andMaestrelli and colleagues29 have demonstrated increasedtumor necrosis factor ca (TNF-a) and interleukin-3 (IL-3).Thus, it seems reasonable that airway epithelial cells willbe able to release mediators driving the recruitment of in-flammatory cells and to release mediators that can regulatethe activity of these cells after their recruitment.An important feature of regulation of inflammatory cell

activity is the ability to bind to specific receptors bothwithin tissues and on cell surfaces. In this context, airwayepithelial cells are capable of expressing antigens of themajor histocompatibility complex (MHC)30-32 and can,therefore, interact with lymphocytes.33 The expression of

Table I-Inflammatory Mediators Released by AirwayEpithelial Cells

MediatorsGranulocyte colony stimulating factor (GCSF)61'62Granulocyte monocyte colony stimulating factor

(GMCSF)61'63-66Interleukin-129,67,68Interleukin-369Interleukin-662,65-67,70,71Interleukin-862 65,66,70,72,73Transforming growth factor-beta (TGF-_)48'74-76Tumor necrosis factor-alpha (TNF-0)'3'29'68

EicosanoidsLeukotriene B4 (LTB4)13'77,78Di-hydroxyeicosotetraenoic acids (di-HETES)13'77'78Prostaglandin E2 (PGE2)77-80Platelet activating factor (PAF)81'82Platelet derived growth factor (PDGF)83Endothelin-184,85Nitric oxide (NO)8'9Substance p86Calcitonin gene reactive protein (CGRP)87Gro-gamma68

CHEST / 107 / 3 / MARCH, 1995 / Supplement 127S

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from

MHC antigens by airway epithelial cells can, in turn, beregulated by components of the inflammatory milieu.3 314Similarly, airway epithelial cells can express the intercel-lular adhesion molecule 1 (ICAM-1) that appears impor-tant in mediating the adhesion of inflammatory cells35 tothe epithelial surface through leukocyte integrin-ICAM-1interactions. The ability of epithelial cells to bind inflam-matory cells through such a mechanism may be animportant pathway mediating airway injury. This inter-action also can be increased by components of the inflam-matory milieu. Substance P, for example, increases neu-trophil adhesion to cultured bovine bronchial epithelialcells through this mechanism.36 Similarly, TNF-a in-creases human bronchial epithelial cell expression ofICAM-1 (I. Striz, personal communication, 1994). Thissuggests that the expression of ICAM-1 by airway epithe-lial cells can be upregulated in inflammatory situations. Insupport of such a mechanism, increased expression of bothICAM-1 and HLA-DR has been reported on epithelial cellsrecovered from the lower respiratory tract of asthmaticscompared with normal individuals.37'38

As noted above, damage of the airway epithelium as partof the inflammatory process of asthma has long been rec-ognized. The mechanisms that lead to repair of the airwayepithelium following injury are, as yet, undefined. It islikely, however, that injury of the airway epithelium maycontribute to some of the features of asthma. For example,the airway epithelium normally provides a barrier be-tween the airway lumen and the airway parenchyma.39 Bydisrupting this barrier, it may be possible for antigens tomore readily reach parenchymal inflammatory cells. Lossof airway epithelial cells may also predispose airway nervesto become activated. Finally, the airway epithelium nor-mally expresses several enzymes, including neutral en-dopeptidase and angiotensin-converting enzyme whichare involved in the metabolism and catabolism of activepeptides. Loss of neutral endopeptidase from a damagedepithelium, for example, has been suggested to contributeto increased airways reactivity in response to substancep.40.41 Thus, loss of normal epithelial function may con-tribute to the increased airways reactivity that may beconsequent to some epithelial damage. Airway epithelialcells may also be targets mediating anti-inflammatory re-sponses. Glucocorticoids, for example, can increase an-giotensin-converting enzyme expression by airway epithe-lial cells.42 Such increased expression may decrease brady-kinin responses43 and, potentially, could contribute to sometherapeutic benefits of glucocorticoids in asthma.The mechanisms that underlie repair of the damaged

airway epithelium are under active investigation. It ap-pears likely that airway epithelial cells can produce medi-ators that recruit not only inflammatory cells, but also pa-renchymal cells of the airway, both epithelial cells44 andfibroblasts.45 Recruitment of neighboring epithelial cellsby basal cells left behind in a damaged airway would beone means of rapidly repairing an epithelial defect. Insupport of this, cultured airway epithelial cells have beendemonstrated to release chemotactic activity for airwayepithelial cells.44 This activity appears to be largely due tofibronectin. Interestingly, fibronectin production by air-way epithelial cells can be stimulated by the cytokine

transforming growth factor beta (TGF-3).46'47 In thisregard, airway epithelial cells are capable of both produc-ing TGF-3 and, importantly, of producing active TGF-3.48Thus, airway epithelial cells at a site of injury may produceincreased amounts of active TGF-3, which, in an autocrineor paracrine manner, could stimulate local fibronectinproduction, which, in turn, could drive the chemotacticrecruitment of neighboring epithelial cells to repair a de-fect. Interestingly, airway epithelial cell-derived fibronec-tin appears to be somewhat more potent than does plasmafibronectin in driving chemotactic responses.45 While themolecular basis for this difference in activity is unknown,regulation of such processes may be an important deter-minant of repair in the damaged asthmatic.

Repair processes of the airway epithelium include notonly the chemotactic recruitment of cells, but also theproliferation of newly recruited cells and their rediffer-entiation.49'50 It is, as yet, unclear what factors regulatethese activities; however, growth stimulating activity forairway epithelial cells has been reported as the product ofmononuclear phagocytes,51 fibroblasts,52 and factors de-rived from serum.53 Thus, it is likely that airway epithe-lial cells will respond to complex growth controls at injurysites.

Factors derived by airway epithelial cells can not onlydrive the participation of neighboring airway epithelialcells in the repair process, but can also drive fibroblast re-sponses. In this regard, airway epithelial cell-derivedfibronectin is chemotactic for fibroblasts.45 In addition,airway epithelial cells release factors capable of stimulat-ing fibroblast proliferation.54'55 Airway epithelial cell-derived factors can also increase the production of extra-cellular matrix components by fibroblasts.56 TGF-3 ap-pears to be an important activity in this regard, and itappears to act by increasing fibroblast mRNA levels forcollagen and fibronectin. Thus, airway epithelial cells maybe important in driving the production of collagen, which,as noted above, forms a prominent feature of the asthmaticairway, the thickened lamina reticularis. Finally, the air-way epithelium may be involved in regulating connectivetissue remodeling. In this regard, airway epithelial cell-conditioned medium has been demonstrated to augmentfibroblast-mediated collagen gel retraction (T. Mio, per-sonal communication, 1994), an experimental system sug-gested to model scar retraction.

Although deposition of connective tissue in the smallairways may lead to fixed airflow obstruction, it is impor-tant to recognize that such lesions are relatively rare. Thefactors that inhibit deposition of abnormal scar tissue in theairway in response to injury are largely undetermined. Theairway epithelium, however, may be important in pro-ducing these factors as well. That is, in addition toproducing factors that can stimulate fibroblast recruit-ment, proliferation, matrix production, and remodeling,airway epithelial cells can also produce inhibitors of theseactivities. Prostaglandin E appears to be particularlyimportant in this regard.57-59 Thus, it seems reasonable tosuggest that the airway epithelium may play a role not onlyin the repair of the airway following injury but also inmaintaining the normal architectural relationships of theairway epithelium.

37th Annual Aspen Lung Conference128S

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from

Mediators released by the airway epithelium may alsoplay a role in regulating smooth muscle activity. As notedabove, airway epithelial cell-derived factors can functionas smooth muscle relaxants. TGF-f, which can be releasedby airway epithelial cells, can also affect smooth muscle3-adrenergic receptor expression. In this context, culturedhuman airway smooth muscle cells have been demon-strated to decrease cyclic adenosine monophosphate re-sponse to d-agonists in the presence of TGF-3, an effectthat appears to be mediated by decreased receptor num-ber with no change in receptor affinity.60 Through such amechanism, the airway epithelium could alter the physi-ologic responses of the airway in a variety of settings.

In summary, the airway epithelium has a large numberof capabilities that can be relevant to asthma. Alterationsof the airway epithelium are well documented in asthma,and it appears that a number of these "capabilities" will berelevant to the pathophysiology of asthma. As the role ofthe airway epithelial cell in asthma is defined, it seemslikely that new opportunities for therapeutic interventionwill be possible.

REFERENCES1 Spencer H. Bronchial asthma. In: Spencer H, ed. Pathology of

the lung. Oxford: Pergamon Press, 1968; 715-202 Jeffery PK. Morphology of the airway wall in asthma and in

chronic obstructive pulmonary disease. Am Rev Respir Dis1991; 143:1152-58

3 Flavahan NA, Aarhus LL, Rimele TJ, et al. Respiratoryepithelium inhibits bronchial smooth muscle tone. J ApplPhysiol 1985; 58:834-38

4 Leikauf GD, Ueki IF, Nadel JA, et al. Bradykinin stimulates CIselection and prostaglandin release by canine tracheal epithe-lium. Am J Physiol 1985; 248:F48-F55

5 Barnett K, Jacoby DB, Nadel JA, et al. The effects of epithelialcell supernatant on contractions of isolated canine trachealsmooth muscle. Am Rev Respir Dis 1988; 138:780-83

6 Tschirhart E, Frossard N, Bertrand C, et al. Arachidonic acidmetabolites and airway epithelium-dependent relaxant factor.J Pharmacol Exp Ther 1987; 243:310-16

7 Brunelleschi S, Haye-Legrand I, Labat C, et al. Platelet-activating factor-acether-induced relaxation of guinea pig air-way muscle: role of prostaglandin E2 and the epithelium. JPharmacol Exp Ther 1987; 243:356-63

8 Robbins RA, Hamel FG, Floreani AA, et al. Bovine bronchialepithelial cells metabolize L-arginine to L-citrulline: possiblerole of nitric oxide synthase. Life Sci 1993; 52:709-16

9 Robbins RA, Springall DR, Warren JB, et al. Inducible nitricoxide synthase is increased in murine lung epithelial cells bycytokine stimulation. Biochem Biophys Res Commun 1994;198:835-43

10 Hamid Q, Springall DR, Riveros-Moreno V, et al. Induction ofnitric oxide synthase in asthma. Lancet 1993; 342:1510-13

11 Ilhan M, Sahin I. Tracheal epithelium releases a vascularsmooth muscle relaxant factor: demonstration by bioassay. EurJ Pharmacol 1986; 131:293-96

12 Shoji S, Ertl R, Rennard SI. Cigarette smoke stimulates releaseof neutrophil chemotactic activity from cultured bronchialepithelial cells. Clin Res 1987; 35:539A

13 Koyama S, Rennard SI, Leikauf G, et al. Endotoxin stimulatesbronchial epithelial cells to release chemotactic factors forneutrophils. J Immunol 1991; 147:4293-4301

14 Koyama S, Rennard SI, Robbins RA. Acetylcholine stimulatesbronchial epithelial cells to release neutrophil and monocyte

chemotactic activity. Am J Physiol 1992; 262:L466-L47115 Raz M, Robbins RA. Viral innoculation of bronchial epithelial

cells induces increased neutrophil chemotactic activity andneutrophil adhesion [abstract]. Am Rev Respir Dis 1992;145:698

16 Von Essen SG, Rennard SI, O'Neill D, et al. Bronchial epithe-lial cells release neutrophil chemotactic activity in response totachykinins. Am J Physiol 1992; 263:L226-L231

17 Kwon OJ, Au TB, Collins PD, et al. Inhibition of interleukin-8expression by dexamethasone in human cultured airway epi-thelial cells. Immunology 1994; 81:389-94

18 Nakamura H, Yoshimura K, Jaffe HA, et al. Interleukin-8 geneexpression in human bronchial epithelial cells. J Biol Chem1991; 266:19611-17

19 Hansbrough JR, Takahashi Y, Ueda N, et al. Identification ofa novel arachidonate 12-lipoxygenase in bovine tracheal epi-thelial cells distinct from leukocyte and platelet forms of theenzyme. J Biol Chem 1990; 265:1771-76

20 Holtzman MJ, Aizawa H, Nadel JA, et al. Selective generationof leukotriene B4 by tracheal epithelial cells from dogs.Biochem Biophys Res Commun 1983; 114:1071-76

21 Koyama S, Rennard SI, Leikauf GD, et al. Bronchial epithelialcells release monocyte chemotactic activity in response tosmoke and endotoxin. J Immunol 1991; 147:972-79

22 Robbins RA, Shoji S, Linder J, et al. Bronchial epithelial cellsrelease chemotactic activity for lymphocytes. Am J Physiol1989; 257:L109-L115

23 Von Essen SG, O'Neill D, Wisecarver J, et al. Grain sorghumdust extract causes lymphocyte chemotaxis directly and bystimulating bronchial epithelial cells to secrete chemotacticactivity. Am Rev Respir Dis 1991; 143:A47

24 Bellini A, Yoshimura H, Vittori E, et al. Bronchial epithelialcells of patients with asthma release chemoattractant factors forT lymphocytes. J Allergy Clin Immunol 1993; 92:412-24

25 Koyama S, Fujimoto K, Sato E, et al. Bradykinin stimulatesbronchial epithelial cells to release eosinophil chemotactic ac-tivity. Am Rev Respir Dis 1993; 147:A241

26 Sousa AR, Poston RN, Lane SJ, et al. Detection of GM-CSF inasthmatic bronchial epithelium and decrease by inhaled corti-costeroids. Am Rev Respir Dis 1993; 147:1557-61

27 Vittori E, Marini M, Fasoli A, et al. Increased expression ofendothelin in bronchial epithelial cells of asthmatic patients andeffect of corticosteroids. Am Rev Respir Dis 1992; 146:1320-25

28 Springall DR, Djukanovic R, Howarth PH, et al. Endothelinimmunoreactivity of airway epithelium in asthmatic patients.Lancet 1991; 337:697-701

29 Maestrelli P, DiStefano A, Turato G, et al. TNF alpha and IL-1beta immunoreactivity in the bronchial mucosa of subjects withoccupational asthma induced by toluene diisocyanate (TDI).Am J Respir Crit Care Med 1994; 149:A952

30 Glanville AR, Tazelaar HD, Theodore J, et al. The distributionof MHC class I and II antigens on bronchial epithelium. Am RevRespir Dis 1989; 139:330-34

31 Rossi GA, Sacco 0, Balbi B, et al. Human ciliated bronchialepithelial cells: expression of the HLA-DR antigens and of theHLA-DR alpha gene, modulation of the HLA-DR antigens bygamma-interferon and antigen-presenting function in themixed leukocyte reaction. Am J Respir Cell Mol Biol 1990;3:431-39

32 Taylor PM, Rose ML, Yacoub MH. Expression of MHC anti-gens in normal human lungs and transplanted lungs withobliterative bronchiolitis. Transplantation 1989; 48:506-10

33 Kalb TH, Chuang MT, Marom Z, et al. Evidence for accessorycell function by class II MHC antigen-expressing airwayepithelial cells. Am J Respir Cell Mol Biol 1991; 4:320-29

34 Spurzem JR, Sacco 0, Rossi GA, et al. MHC class II expressionby bronchial epithelial cells is modulated by lymphokines and

CHEST / 107 / 3 /MARCH, 1995 / Supplement 129S

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from

corticosteroids. Am Rev Respir Dis 1990; 141:A68135 Robbins RA, Koyama S, Spurzem JR, et al. Modulation of neu-

trophil and mononuclear cell adherence to bronchial epithelialcells. Am J Respir Cell Mol Biol 1992; 7:19-29

36 De Rose V, Robbins RA, Snider RM, et al. Substance P increasesneutrophil adhesion to bronchial epithelial cells. J Immunol1994; 152:1339-46

37 Vignola AM, Chanez P, Campbell AM, et al. Quantification andlocalization of HLA-DR and intercellular adhesion molecule-i(ICAM-1) molecules on bronchial epithelial cells of asthmaticsusing confocal microscopy. Clin Exp Immunol 1994; 96:104-09

38 Vignola AM, Campbell AM, Chanez P, et al. HLA-DR andICAM-1 expression on bronchial epithelial cells in asthma andchronic bronchitis. Am Rev Respir Dis 1993; 148:689-94

39 Schneeberger EE. Airway and alveolar epithelial cell junctions.In: Crystal RG, West JB, eds. The lung: Scientific foundations,Vol. 1 New York: Raven Press, 1991; 205-14

40 Sekizawa K, Tamaoiki J, Nadel JA, et al. Enkephalinase inhib-itor potentiates substance P- and electrically induced contrac-tion in ferret trachea. J Appl Physiol 1987; 63:1401-05

41 Borson DB, Brokaw JJ, Sekizawa K, et al. Neutral endopepti-dase and neurogenic inflammation in rats with respiratory in-fections. J Appl Physiol 1989; 66:2653-58

42 Muns G, Vishwanatha JK, Rubinstein I. Regulation of angioten-sin I-converting enzyme in cultured bovine bronchial epithelialcells. J Cell Biochem 1993; 53:352-59

43 Ichinose M, Barnes PJ. The effect of peptidase inhibitorson bradykinin-induced bronchoconstriction in guinea-pigs invivo. Br J Pharmacol 1990; 101:77-80

44 Shoji S, Ertl RF, Linder J, et al. Bronchial epithelial cells pro-duce chemotactic activity for bronchial epithelial cells: possiblerole for fibronectin in airway repair. Am Rev Respir Dis 1990;141:218-25

45 Shoji S, Rickard KA, Ertl RF, et al. Bronchial epithelial cellsproduce lung fibroblast chemotactic factor: fibronectin. Am JRespir Cell Mol Biol 1989; 1:13-20

46 Romberger DJ, Beckmann JD, Claassen L, et al. Modulation offibronectin production of bovine bronchial epithelial cells bytransforming growth factor-beta. Am J Respir Cell Mol Biol1992; 7:149-55

47 Wang A, Cohen DS, Palmer E, et al. Polarized regulation offibronectin secretion and alternative splicing by transforminggrowth factor. J Biol Chem 1991; 266:15598-601

48 Sacco 0, Romberger D, Rizzino A, et al. Spontaneous produc-tion of transforming growth factor beta 2 by primary culturesof bronchial epithelial cells: effects on cell behavior in vitro. JClin Invest 1992; 90:1379-85

49 Keenan KP, Combs JW, McDowell EM. Regeneration ofhamster tracheal epithelium after mechanical injury. VirchowsArch 1982; 41:193-214

50 Lane BP, Gordon R. Regeneration of rat tracheal epitheliumafter mechanical injury: I. The relationship between mitoticactivity and cellular differentiation. Proc Soc Exp Biol Med1974; 145:1139-44

51 Takizawa H, Beckmann J, Shoji S, et al. Pulmonary macro-phages can stimulate cell growth of bovine bronchial epithelialcells. Am J Respir Cell Mol Biol 1990; 2:245-55

52 Shoji S, Rickard KA, Takizawa H, et al. Lung fibroblasts pro-duce growth stimulatory activity for bronchial epithelial cells.Am Rev Respir Dis 1990; 141:433-39

53 Takizawa H, Beckmann JD, Hoshida M, et al. Regulation ofbovine bronchial epithelial cell proliferation and proto-onco-gene expression by growth factors. Am J Respir Cell Mol Biol1991; 5:548-55

54 Koizumi S, Ertl R, Rennard S. Bronchial epithelial cells stimu-late fibroblast proliferation. Am Rev Respir Dis 1991; 143:A526

55 Nakamura Y, Tate L, Ertl R, et al. Bovine bronchial epithelial

cells stimulate fibroblast DNA synthesis. Am Rev Respir Dis1993; 147:A278

56 Kavamoto M, Nakamura Y, Tate L, et al. Modulation offibroblast type I collagen and fibronectin production by bron-chial epithelial cells. Am Rev Respir Dis 1992; 145:A842

57 Nakamura Y, Ertl RF, Kawamoto M, et al. Bronchial epithelialcells modulate fibroblast proliferation: role of prostaglandin E2.Am Rev Respir Dis 1992; 145:A827

58 Ertl RF, Valenti V, Spurzem JR, et al. Prostaglandin E inhibitsfibroblast recruitment [abstract]. Am Rev Respir Dis 1992;145:19

59 Bitterman PB, Wewers MD, Rennard SI, et al. Modulation ofalveolar macrophage-driven fibroblast proliferation by alter-native macrophage mediators. J Clin Invest 1986; 77:700-08

60 Nogami M, Romberger DJ, Rennard SI, et al. TGF-beta mod-ulates beta-adrenergic receptor number and function in cul-tured human tracheal smooth muscle cells. Am J Physiol 1994;266:L187-L191

61 Ohtoshi T, Vancheri C, Cox G, et al. Monocyte-macrophagedifferentiation induced by human upper airway epithelial cells.Am J Respir Cell Mol Biol 1991; 4:255-63

62 Levine SJ, Larivee P, Logun C, et al. Corticosteroids differen-tially regulate secretion of IL-6, IL-8 and C-GSF by a humanbronchial epithelial cell line. Am J Physiol 1993; 265:L360-L368

63 Ohtoshi T, Tsuda T, Vancheri C, et al. Human upper airwayepithelial cell-derived granulocyte-macrophage colony-stimu-lating factor induces histamine-containing cell differentiationof human progenitor cells. Int Arch Allergy Appl Immunol1991; 95:376-84

64 Marini M, Soloperto M, Mezzetti M, et al. Interleukin-1 bindsto specific receptors on human bronchial epithelial cells andupregulates granulocyte/macrophage colony-stimulating fac-tor synthesis and release. Am J Respir Cell Mol Biol 1991;4:519-24

65 Mattoli S, Marini M, Fasoli A. Expression of the potentinflammatory cytokines, GM-CSF, IL6 and IL8, in bronchialepithelial cells of asthmatic patients. Chest 1992; 101:27S-29S

66 Cromwell 0, Hamid Q, Corrigan CJ, et al. Expression andgeneration of interleukin-8, IL-6 and granulocyte-macrophagecolony-stimulating factor by bronchial epithelial cells and en-hancement by IL-1 beta and tumour necrosis factor-alpha.Immunology 1992; 77:330-37

67 Mattoli S, Miante S, Calabro F, et al. Bronchial epithelial cellsexposed to isocyanates potentiate activation and proliferation ofT-cells. Am J Physiol 1990; 259:L320-327

68 Carter JD, Reed W, McKinnon KP, et al. Oxidant stress alterssteady-state concentrations of inflammatory mediator mRNAsin an airway epithelial cell line [abstract]. Am J Respir CritCare Med 1994; 149:319

69 Von Essen SG, O'Neill DP, Mio T, et al. IL-8 release by bron-chial epithelial cells and macrophages after grain dust extractchallenge, a response modulated by a beta 1,3 glucan [abstract].Am J Respir Crit Care Med 1994; 149:517

70 Ruef C, Jefferson DM, Schlegel-Haueter SE, et al. Regulationof cytokine secretion by cystic fibrosis airway epithelial cells.Eur Respir J 1993; 6:1429-36

71 Noah IL, Paradiso AM, Madden MC, et al. The response of ahuman bronchial epithelial cell line to histamine: intracellularcalcium changes and extracellular release of inflammatorymediators. Am J Respir Cell Mol Biol 1991; 5:484-92

72 Standiford TJ, Kunkel SL, Basha MA, et al. Interleukin-8 geneexpression by a pulmonary epithelial cell line: a model for cy-tokine networks in the lung. J Clin Invest 1990; 86:1945-53

73 Nakamura H, Yoshimura K, McElvaney NG, et al. Neutrophilelastase in respiratory epithelial lining fluid of individuals withcystic fibrosis induces interleukin-8 gene expression in a human

37th Annual Aspen Lung Conference1 30S

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from

bronchial epithelial cell line. J Clin Invest 1992; 89:1478-8474 Steigerwalt RW, Rundhaug JE, Nettesheim P. Transformed rat

tracheal epithelial cells exhibit alterations in transforminggrowth factor-beta secretion and responsiveness. Mol Carcinog1992; 5:32-40

75 Pelton RW, Johnson MD, Perkett EA, et al. Expression oftransforming growth factor-beta 1, -beta 2 and -beta 3 mRNAand protein in the murine lung. Am J Respir Cell Mol Biol 1991;5:522-30

76 Thompson NIL, Flanders KC, Smith JM, et al. Expression oftransforming growth factor-beta 1 in specific cells and tissues ofadult and neonatal mice. J Cell Biol 1989; 108:661-69

77 Holtzman MJ, Hansbrough JR, Rosen GD, et al. Uptake, releaseand novel species-dependent oxygenation of arachidonic acidin human and animal airway epithelial cells. Biochim BiophysActa 1988; 963:401-13

78 Holtzman MJ. Epithelial cell regulation of arachidonic acidoxygenation. In: Lenfant C, ed. Lung biology in health anddisease. News York: Marcel Dekker, 1991; 65-115

79 Churchill L, Chilton FH, Resau JH, et al. Cyclooxygenase me-tabolism of endogenous arachidonic acid by cultured humantracheal epithelial cells. Am Rev Respir Dis 1989; 140:449-59

80 Leikauf GD, Driscoll KE, Wey HE. Ozone-induced augmen-tation of eicosanoid metabolism in epithelial cells from bovinetrachea. Am Rev Respir Dis 1988; 137:435-42

81 Samet JM, Noah TL, Devlin RB, et al. Effect of ozone onplatelet-activating factor production in phorbol-differentiatedHL60 cells, a human bronchial epithelial cell line (BEAS S6),and primary human bronchial epithelial cells. Am J Respir CellMol Biol 1992; 7:514-22

82 Holtzman MJ, Ferdman B, Bohrer A, et al. Synthesis of the1-0-hexadecyl molecular species of platelet-activating factor byairway epithelial and vascular endothelial cells. Biochem Bio-phys Res Commun 1991; 177:357-64

83 Michelson PH, McKinnon KP, Reed W, et al. Growth factorproduction in human airway epithelial cells exposed to ozonein vitro. Am J Respir Crit Care Med 1994; 149:A316

84 Endo T, Uchida Y, Matsumoto H, et al. Regulation of endo-thelin-1 synthesis in cultured guinea pig airway epithelial cellsby various cytokines. Biochem Biophys Res Commun 1992;14:1594-99

85 Marciniak SJ, Plumpton C, Barker PJ, et al. Localization ofimmunoreactive endothelin and proendothelin in the humanlung. Pulm Pharmacol 1992; 5:175-82

86 Gallego R, Garci-Caballero T, Roson E, et al. Neuroendocrinecells of the human lung express substance-P-like immunoreac-tivity. Acta Anat Basel 1990; 139:278-82

87 Baluk P, Nadel JA, McDonald DM. Calcitonin gene-relatedpeptide in secretory granules of serous cells in the rat trachealepithelium. Am J Respir Cell Mol Biol 1993; 8:446-53

Expression of Interleukin-6 byAirway Epithelial Cells*

Effects on Airway Inflammation andHyperreactivity in Transgenic Mice

Bruno DiCosmo, MD; Greg Geba, MD;Dominic Picarella, PhD; Jack A. Elias, MD;John A. Rankin, MD; Barry Stripp, MD;Jeffrey A. Whitsett, MD; and Richard A. Flavell, PhD

thma is a chronic inflammatory disorder characterized,in part, by dysregulated cytokine production. Abnor-

malities of interleukin (IL)-6 are well documented in thisdisorder. However, the exact role that IL-6 plays in thepathogenesis of the inflammation and hyperresponsivenessthat characterize the asthmatic diathesis has not been es-tablished.To understand the role that IL-6 plays in asthma, we

produced transgenic mice in which the synthesis of humanIL-6 was directed by the rat CC10 promoter, whichexpresses in epithelial cells of the conducting airways.Three lines of transgenic mice were created. These micewere examined morphologically and physiologically. Mea-surement of human IL-6 in the bronchoalveolar lavage(BAL) fluid of transgenic mice revealed marked levels ofhuman IL-6 (10.1 + 3.6 ng/mL) while none (<3 pg/mL)was detected in nontransgenic animals (p<0.025). IL-6 wasalso detected in the serum of transgenic animals at farlower concentrations (245 ± 10 pg/mL) but not in the se-rum of nontransgenics (<3 pg/mL) (p<0.0005). Histolog-ically, the expression of IL-6 resulted in a mononuclear cellinfiltrate adjacent to large and midsized airways. Immu-nohistochemistry revealed these cells to be predominantlyCD4+ cells, MHC class II+, and B220+ cells. Additionalmice were anesthetized subsequently with pentobarbital,tracheostomized, and respiratory system resistance (Rrs)was determined via body plethysmography. Airway re-sponsiveness was assessed by determining the concentra-tion of nebulized inhaled methacholine that produced a100% increase in Rrs (PCI00).

These studies demonstrated that both transgenic andnontransgenic mice had similar baseline Rrs (0.45 ± .07 vs0.43 ± .09 cm H20/mL/s, p>0.05). However, in compar-ison to nontransgenic mice, transgenic mice had a signif-icantly higher log PC100 (1.34 + .24 vs 0.34 ± .05 mg/mL,p<0.01), thus less reactivity to methacholine. We concludethat overexpression of IL-6 in the airway of transgenicmice results in a CD4+, MHC class II+, and B220+ lym-phocytic infiltration of the airway; no change in basal res-piratory resistance; and diminished reactivity to meth-acholine. These findings demonstrate an uncoupling ofairway lymphocytic inflammation and airway responsive-ness leading us to hypothesize that some forms of airwayinflammation may serve to restore airway physiology andthus may be beneficial.*From the Pulmonary and Critical Care Section and Departmentof Immunobiology, Yale University School of Medicine, NewHaven, Conn; and the Children's Hospital Medical Center,Cincinnati, Ohio. Dr. DiCosmo is under grant support from theAmerican College of Chest Physicians.

CHEST / 107 / 3 I MARCH, 1995 / Supplement 131S

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from

DOI 10.1378/chest.107.3_Supplement.127S 1995;107; 127S-131SChest

R. SpurzemStephen I. Rennard, Debra J. Romberger, Richard A. Robbins and John

Is Asthma an Epithelial Disease?

 July 13, 2011This information is current as of

 

http://chestjournal.chestpubs.org/content/107/3_Supplement/127S.citationUpdated Information and services can be found at:

Updated Information & Services

http://chestjournal.chestpubs.org/content/107/3_Supplement/127S.citation#related-urlsThis article has been cited by 5 HighWire-hosted articles:

Cited Bys

http://www.chestpubs.org/site/misc/reprints.xhtmlbe found online at: Information about reproducing this article in parts (figures, tables) or in its entirety canPermissions & Licensing

http://www.chestpubs.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

Reprints

"Services" link to the right of the online article.Receive free e-mail alerts when new articles cite this article. To sign up, select the

Citation Alerts

PowerPoint slide format. See any online figure for directions. articles can be downloaded for teaching purposes inCHESTFigures that appear in Images in PowerPoint format

 1995 by the American College of Chest Physicians by guest on July 13, 2011chestjournal.chestpubs.orgDownloaded from