Leukocyte rolling and firm adhesion in the microcirculation

GASTROENTEROLOGY

1993;104:310-323

EDITORIALS Leukocyte Rolling and Firm Adhesion in the Microcirculation

A tion

central

event in inflammation

is the activation

circulating leukocytes, leading of these cells in the inflamed

their

extravasation,

with

the vascular

steps, a process recent

leukocytes

endothelium

mediating

need

to interact

in several

that has gained

years with the discovery

receptors actions

the

increased

sequential attention

of specific

Commonly

inter-

used experimental

sys-

tems to study these interactions include various in vitro assays for leukocyte adhesion as well as different indirect kocyte

in vivo methods accumulation

such as measurement

in inflamed

tissues.

with these techniques

it is not possible

spatial

and temporal

details

matory

events.

is intravital observation changes. suring

and With

nature

permits

localization

techniques, and

which

of

direct

visual

microcirculatory

this methodology

sequence

of choice

of quantitative

our knowledge

the

inflam-

the method

the development

useful in improving

However,

of microvascular

For this purpose,

microscopy,

of leu-

to elucidate

very

about the dynamic

of microvascular

uninflamed

tion with

venular

adhesion

and

endothelium

rolling

inflammatory

interac-

and precedes diapedesis

of

agents.

to leukocyte

extravasation

leading studies

leukocytes

easy to quantitate by direct (rolling

adherent

and the number area ?-6,9,10

This sequence

involve

leukocyte

a reference

interactions.“-l4 tein complex

per unit

of emigrated

cells

vessel per

For example, family,

the leukocyte belonging

has been shown

ments,

functional

antibodies

blocking

completely

of CD18

inhibited

cells capable

of interacting

with

For example,

in vitro studies

have shown

used

are the hamster rabbit,

preparations cheek pouch

in inflammation

research

and the mesentery

rat, and mouse. ‘r2 In tissues prepared

of cat,

for intra-

vital microscopy, 30%50% of the total number of leukocytes passing through a vessel (total leukocyte flux) can be seen rolling along the endothelium of small venules at a considerably lower velocity than freeflowing

blood

components.3-7

The rolling

is initiated

after displacement of the leukocytes from the axial stream (margination) when they enter postcapillary venules.

However,

whether

rolling

is a normal

physio-

logical phenomenon or if it reflects a state of activation of leukocytes is a matter of debate. Thus, leukocyte rolling appears to be augmented by mild injury,3 and it has been suggested that rolling may be a consequence of the exteriorization of tissues required for intravital microscopy. 8 However, very recently it was shown that leukocyte rolling is a prominent feature of venules in the intact ear of mice,’ strongly indicating that the rolling mechanism is indeed operative under

in several

by monoclonal

exteriorized quently

glycopro-

the leukocyte

sion

fre-

and

intravital microscopic studies to be vitally important for the process of firm adhesion. 10,15-17In these experi-

tants.

the most

tissue

to the p2 sub-

Tissues suitable for intravital microscopy are selected mainly on the condition that they can be easily and

length,

unit

receptor-ligand

phenomena.

and transilluminated,

of

point

of rolling

cell surface

CDll/CD18,

1) mi-

flux), the number

leukocytes

specific

(Figure

of the number

passing

It is now clear that the phenomena adhesion

the firm leukocytes

in intravital

counting

per minute

in the microvessel of firmly

leuko-

established

by chemotactic

has been relatively croscopic

Nevertheless,

the earliest

subsequent

activation

of events

conditions.

represents

group of the integrin

mea-

has proven

resting

cyte rolling

upon in

cell surface

the leukocyte-endothelium

(see below).

of

to local accumulatissue area. Before

induced

by a number

In addition

cules, there are also adhesive

tion

of cultured

of different

to the leukocytic

endothelium

may result in a slowly developing

chemoattrac-

cell adhesion

receptors

mole-

on endothelial

passing

with

adhe-

leukocytes. that stimula-

certain

increased

cytokines expression

of the immunoglobulin-related intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-l), which recognize leukocytic integrins as their ligands. “*‘s Much less is known about the functional significance of VCAM-1 and ICAMin vivo; however, monoclonal antibodies against ICAM1 have been found to block the rapid leukocyte adhesion induced by the complement factor C5a in the rabbit mesentery” as well as eosinophil accumulation in the asthmatic lung of monkeys.” In contrast to chemoattractant-induced firm adhesion of leukocytes to the venular endothelium, leukocyte rolling is unaffected by treatment with monoclonal antibodies against the common /3 subunit of the CD1 l/CD18 complex, suggesting that rolling is independent of p2 integrins.15,16 In fact, recent intravital microscopic studies have shown that leukocyte rolling

EDITORIALS

January 1993

Maraination

via selectins

Rolling

Adhesion

Diapedesis

is necessary

to allow firm integrin-me-

diated binding to develop at physiological

Migration

blood flow

rates. This is also in line with the observation adherent

cells are recruited

exclusively

ling cell population. 6 Moreover, between

rolling and adhesion

neutrophil

Venule

extravasation

311

that the

from the rol-

such a relationship

may help explain why

into inflamed tissue sites can

be inhibited either by interference

with the L-selectin-

receptor function31-33 or by treatment with anti-CD18 Figure 1. Schematic

illustration of the sequential steps involved in inflammatory leukocyte recruitment. Margination (i.e., displacement from the axial stream) and rolling along the endothelium in small venules precede firm adhesion to the vessel wall. These events are followed by diapedesis (extravasation, emigration) and further migration in the extravascular tissue.

antibodies.‘5T’6,34 Following the initial interactions

lial lining, the leukocytes extravasate through interendothelial junctions35 and migrate further in the perivascular tissue against a chemotactic molecular mechanisms

family;

by cell surface molecules

i.e., leukocyte

interference 1, LAM-l,

rolling

tin)

and

with the leukocytic

two

GMP-140, Whether

is largely inhibited

gp90MEL) function.‘*”

tins have been identified:

L-selectin

on

endothelial E-selectin

by

(LECAM-

To date, three selec-

one on leukocytes

CD62; endothelial

of the selectin

cells or

(L-selec-

(P-selectin

or

ELAM-1).‘3~21~22

P- and E-selectins

also mediate

gradient.36*37 The

behind leukocyte tissue migra-

tion have not been characterized is mediated

with the endothe-

in vivo. However,

seems likely that specific receptor-mediated interactions

with different

extravascular

i’

adhesive

matrix corn.

ponents (e.g., collagen, hyaluronic acid, fibronectin and laminin) form the basis for this type of leukocyte movement. A number

of inflammatory

shown to be chemotactic microscopic

mediators

have beer

for leukocytes, and intravita

studies have contributed

significantly

t(

leukocyte rolling in vivo is not known. However, leu-

reveal details of their mode of action in the microcir

kocytes have been shown to roll on artificial lipid bilayers containing purified P-selectin.23 Furthermore,

culation.

all three known selectins, which have a sugar-binding

tide

lectin domain,

can bind to the same or very similar

have all been shown to stimulate leukocytes to adher

ligands,2”27 and there may even exist a the

in postcapillary and small venules in a rather stereo typical manner. 38 Another group o f chemical factor

on

released during inflammatory reactions may be termel “modulators” of inflammation because they can en

carbohydrate reciprocal

receptor-l&and

leukocytic

and endothelial

A dependency shear-related rolling)

relationship selections.28*29

of firm adhesion

leukocyte endothelium

was indicated

between

of leukocytes interactions

(i.e.,

in vitro by Ley et ales” Subse-

quently, it was shown in a laminar flow chamber that selectin-mediated leukocyte rolling was a prerequisite

(PAF),

For example, leukotriene

C5a, platelet-activating

B, (LTB,),

facto

and the bacterial

formyl-methionyl-leucyl-phenylalanine

pep

(fMLP

hance and/or suppress the actions of chemotactic

me

diators. Among these modulators, adenosine, hista mine, prostaglandin E,, and calcitonin gene-relate peptide (CGRP)

all have the capacity to both enhanc

for evoked firm adhesion through integrins,23 and, by qualitative observations in vivo, that inhibition of Lselectin-mediated rolling reduced spontaneous leuko-

and suppress leukocyte function in rather comple manner.39* Taken together, quantitative intravital microscopj

cyte adhesion.5 More recently, it was shown that graded selective reduction of the rolling leukocyte flux

studies using modern optoelectronic and biochemic; developments have played an important role in ac

before chemotactic

vancing our understanding of inflammatory processe In particular, the sequence of leukocyte marginatio’

stimulation

was paralleled

over a

wide range by a proportional decrease in chemoattractant-induced leukocyte adhesion.6 The latter finding thus strongly supports a close relationship between the extent of leukocyte rolling and the magnitude of the subsequent firm adhesion response, and that an initial rolling interaction is indeed a precondition for firm adhesion to occur in small venules in vivo. In other words, retardation of circulating leukocytes by reversible binding to the venular endothelium (i.e., rolling)

rolling, adhesion, diapedesis, and oriented tissue m gration, which is a delicate and dynamic event requi ing intact microenvironmental structures only achie7 able in vivo, is more or less impossible to stuc accurately and reliably with other techniques. Furthe more, this methodology is well suited for detailed stuc ies of mechanisms of action by anti-inflammato compounds.

3 12

GASTROENTEROLOGY

EDITORIALS

In this issue of GASTROENTEROLOGY, have

taken

technique effects

advantage

of the

to examine

in vivo

of adenosine

cyte rolling

and adhesion

they elegantly

stein

in the rat mesentery.

Thus,

is mediated

in vitro

studies

adherence

suggest

is operative

vivo.

et al. used the “AZ-receptor

in postcapillary

sonable

to

should

Although

suggest

an

the notion

this approach AZ-receptor

be remembered

that DMPX

the cells

that

this

venules

in the

of A,-recepmakes it rea-

involvement, is far from

it selec-

tive and not very potent at A, receptors.47 Unfortunately, AZ-receptor antagonists with appreciable potency

and

thereby

selectivity

making

for this receptor Interestingly, MTX inhibited

have

it difficult

not

yet been

to define

PAF but not by LTB,. One explanation ing observation may be, as the authors gest, that rat leukocytes challenge

are relatively

(for references,

see Asako

developed,

the specific

subtype. Asako et al. found that the leukocyte responses

role

dogenous leukocyte

for this intriguthemselves sugresistant

to LTB,

et a1.45). Yet, this

was greater than that induced by 100 Moreover, recent experiments in anmicroscopic model indicate that en-

ADO may indeed inhibit LTB,-induced responses in the microcirculation. Appar-

ently, further studies stimulus specificities

of rolling

are necessary to clarify potential regarding the anti-inflammatory

effects of ADO, for example by comparisons in vitro of leukocyte adhesion induced by PAF, LTB,, and other chemoattractants, or by additional intravital microscopic studies in species other than the rat. Knowing that leukocyte rolling and firm adhesion are mediated by distinct molecular mechanisms, it would be of interest to know if ADO suppresses both or only one of these two different types of leukocyteendothelium interactions. In their study, Asako et al. choose to present the effects of ADO and MTX on changes in leukocyte rolling velocity (which was in-

and MTX during leukocyte

difficult

PAF challenge)

flux,

a fact that

to determine

No. 1

whether

in-

makes

ADO

it

inhib-

ited leukocyte adhesion directly or as a result of reducing the number of rolling leukocytes. Namely, an increased

rolling

necessarily,

velocity

associated

rolling

leukocytes.

diated

slow

rolling-type

of the flowing leukocytes quently,

may with

words,

increase

to adhere.

an increase

in blood

flow velocity

of the

weakening

of rolling

velocity.6,23

leukocytes

without

leuko-

the drag force

fewer

response

of

between

chemotactic

ume flow (the usual

not

the number

rolling

above,

but

number

if the selectin-me-

interaction

will reduce

as described

will cause

be,

cells is weakened,

blood

and/or

well

a reduced

In other

cytes and endothelial

Conse-

stimulation On the other and/or

to vasodilating selectin-mediated

volagents) rolling

may increase both the velocity23,49 and the number of rolling leukocytes, and it is well established in vivo that

the extravascular

sponse greatly Thus,

leukocyte

to chemoattractants enhanced values

when

manner.

accumulation

in re-

such as PAF and LTB, local blood

on changes

alone are not sufficient not a compound affects antiadhesive

ADO and elicited by

argument does not seem to be in harmony with the finding that the leukocyte adherence evoked by 20 nmol/L LTB, nmol/L PAF. other intravital

by ADO

somewhat

hand,

antagonist”

(DMPX) and Scyclopentyl-1,3-dipropyl-

“A,-receptor antagonist” xanthine (DPCPX) to support tor involvement.

that

also in line with

et a1.,44 and

mechanism Asako

by Cron-

to endothelial

via A, receptors,

by Cronstein

3,7-dimethyl-l-propargylxanthine

as a inhiinter-

in vitro

the authors

of leukocyte

by ADO

of ADO

(MTX)-induced

been shown

et a1.46 Moreover,

to

leuko-

leukocyte-endothelium

as has recently

inhibition

related

creased stead

microscopic

on inflammatory

of methotrexate

of inflammatory

actions,

intravital mechanisms

show the in vivo relevance

likely mediator bition

(ADO)

Asako et a1.45

Vol. 104.

is

flow is increased.!j’

in leukocyte

rolling

velocity

for determining whether or the rolling interaction in an

However,

the primary

aim of

the paper by Asako et al. is not to specifically settle these issues but to confirm and extend the role of ADO as an endogenous tion

of firm

the results late further with

actions

mediator

leukocyte

of MTX-induced

adhesion.

are clear and convincing efforts to develop related

and should

anti-inflammatory

to the purine

inhibi-

In this perspective, stimudrugs

system.

JOHAN RAUD, M.D.,PH.D. LENNART LINDBOM, M.B.,PH.D. Department of PhysiologyI Karolinska Institutet S- 104 0 I Stockbo/m,Sweden

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January1993

EDITORIALS

interaction

in inflammation.

leukocyte

p2 integrins

Comparison of L-selectin and E-selectin ligand specificities: thl L-selectin can bind E-selectin ligands sialyl Le” and sialyl La” Biochem Biophys Res Commun 1992; 184: 1048- 1055.

Distinct roles for LECAM-1 and the

in vivo.

Proc

Nat1 Acad

Sci

USA

1991;88:7538-7542. 6. Lindbom L, Xie X, Raud J, Hedqvist P. Chemoattractant-induced leukocyte adhesion to vascular endothelium in vivo is critically dependent on initial leukocyte rolling. Acta Physiol Stand

26.

Foxall C, Warson SR, Dowbenko D, Fennie C, Lasky LA, Kiso N Hasegawa A, Asa D, Brandley BK. The three members of th selectin receptor family recognize a common carbohydrate ep tope, the sialyl LewisX oligosaccharide. J Cell Biol 199; 117:895-902.

27.

Larsen GR, Sako D, Ahern TJ, Shaffer M, Erban J, Sajer SA, Git son RM, Wagner DD, Furie BC, Furie B. P-selectin and E-selectir Distinct but overlapping leukocyte ligand specificities. J Bit Chem 1992;267:11104-11110.

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Kishimoto TK, Warnock RA, Jutila MA, Butcher EC, Lane C, Ar derson DC, Smith CW. Antibodies against human neutrophil LE CAM- 1 (LAM- l/Leu-g/DREG-56 antigen) and endothelial ce ELAM- 1 inhibit a common CD18-independent adhesion pat1 way. Blood 199 1;78:805-8 11.

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Picker I-J, Warnock RA, Burns AR, Doerschuk CM, Berg El Butcher EC. The neutrophil selectin LECAM- 1 presents carboh] drate ligands to the vascular selectins ELAM-1 and GMP-14( Cell 199 1;66:92 l-933.

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Ley K, Lundgren E, Berger E, Arfors K-E. Shear-dependent inhibi tion of granulocyte adhesion to cultured endothelium by dextrar sulfate. Blood 1989;73: 1324- 1330.

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Lewinsohn DM, Bargatze RF, Butcher EC. Leukocyte-endotheliz cell recognition: Evidence of a common molecular mechanisn shared by neutrophils, lymphocytes, and other leukocytes. J Im munol 1987;138:4313-4321.

1992;146:415-421. 7. Mayrovitz HN. Leukocyte rolling: a prominent feature of venules in intact skin of anesthetized mice. Am J Physiol 1992; 262:H157-H161. 8. Fiebig E, Ley K, Arfors K-E. Rapid leukocyte accumulation by “spontaneous” rolling and adhesion in the exteriorized rabbit mesentery. Int J Microcirc Clin Exp 1991:10:127-144. 9. Raud J. Dahlen S-E, Sydbom A, Lindbom L, Hedqvist P. Enhancement of acute allergic inflammation by indomethacin is reversed by prostaglandin E,: apparent correlation with in vivo modulation of mediator release. Proc Natl Acad Sci USA 1988;85:2315-

2319. 10. Perry MA, Granger DN. Role of CD1 l/CD 18 in shear rate-dependent leukocyte-endothelial cell interactions in cat mesenteric venules. J Clin Invest 199 1;87: 1798- 1804. 11. Carlos TM, Harlan JM. Membrane proteins involved in phagocyte adherence to endothelium. lmmupol Rev 1990; 114:5-28. 12. Springer TA. Adhesion receptors of the immune system. Nature 1990;346:425-434. cell recognition: three (or 13. Butcher EC. Leukocyte-endothelial more) steps to specificity and diversity. Cell 1991;67: 1033-

1036. 14. Zimmerman GA, Prescott SM, McIntyre TM. Endothelial cell interactions with granulocytes: tethering and signaling molecules. Immunol Today 1992; 13:93- 100. 15. Arfors K-E, Lundberg C, Lindbom L, Lundberg K, Beatty PG, Harlan JM. A monoclonal antibody to the membrane glycoprotein complex CD 18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood 1987;69:338-340. 16. Lindbom L, Lundberg C, Prieto J, Raud J, Nortamo P. Gahmberg CG. Patarroyo M. Rabbit leukocyte adhesion molecules CD1 l/ CD 18 and their participation in acute and delayed inflammatory responses and leukocyte distribution in vivo. Clin lmmunol Immunopathol 1990;57:105-119. 17. Argenbright LW, Letts LG, Rothlein R. Monoclonal antibodies to the leukocyte membrane CD18 glycoprotein complex and to intercellular adhesion molecule- 1 inhibit leukocyte-endothelial adhesion in rabbits. J Leukocyte Biol 199 1; 19:253-257.

31

32. Jutila MA, Rott L, Berg EL, Butcher EC. Function and regulation c the neutrophil MEL-14 antigen in vivo: Comparison with LFAand MAC- 1. J lmmunol 1989; 143:3318-3324. 33. Watson SR, Fennie C, Lasky LA. Neutrophil influx into an inflarr matory site inhibited by a soluble homing receptor-IgG Nature 199 1;349: 164- 167.

chimaerr

34. Price TH, Beatty PG, Corpuz SR. In vivo inhibition of neutroph function in the rabbit using monoclonal antibody to CD 18. J In munol 1987;139:4174-4177. 35. Thureson-Klein A, Hedqvist P, Ohlen A, Raud J, Lindbom L. Let kotriene B,, platelet-activating factor and substance P as medir tors of acute inflammation. Pathol lmmunopathol Res 198i 6: 190-206. 36. Zigmond SH. Mechanisms of sensing chemical gradients by pal! morphonuclear leukocytes. Nature 1974;249:450-452.

18. Pober JS, Cotran RS. What can be learned from the expression of endothelial adhesion molecules in tissues? Lab Invest 1991; 64:301-305. 19. Wegner CD, Gundel RH, Reilly P, Haynes N, Letts LG, Rothlein R.

37.

Raud J, Lindbom L, Dahlen S-E, Hedqvist P. Periarteriolar localizi tion of mast cells promotes oriented interstitial migration of ler kocytes in the hamster cheek pouch. Am J Pathol 198s

Intercellular adhesion molecule- 1 (ICAM- 1) in the pathogenesis of asthma. Science 1990;247:456-459. Ley K, Gaehtgens P, Fennie C, Singer MS, Lasky LA, Rosen SD. LEG-CAM 1 mediates leukocyte rolling in mesenteric venules in vivo. Blood 1991;77:2553-2555. McEver RP. Selectins: Novel receptors that mediate leukocyte adhesion during inflammation. Thromb Haemost 199 1;65:223228. Springer TA, Lasky LA. Cell adhesion. Sticky sugars for selectins. Nature 1991;349:196-197. Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiologic flow rates. Distinction from and prerequisite for adhesion through integrins. Cell 199 1;65:859-873. Polley JM, Phillips ML, Wayner E, Nudelman E, Singhal AK, Hakomori S-l, Paulson JC. CD62 and endothelial cell-leukocyte adhesion molecule 1 (ELAM-I) recognize the same carbohydrate ligand. sialyl-Lewis”. Proc Natl Acad Sci USA 1991;88: 6224-6228. Berg EL, Magnani J, Warnock RA, Robinson MK, Butcher EC.

38.

Smedeg;lrd G. Mediators of vascular permeability tion. Prog Appl Microcirc 1985;7:96- 1 12.

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134:161-169. rn inflamm;

Brain SD, Williams TJ. Inflammatory oedema induced by syne gism between calcitonin gene-related peptide (CGRP) and medi; tors of increased vascular permeability. Br J Pharmacol 198! 86:855-860. 40. Mannaioni PF, Fantozzi R. Giannella E, Masini E. Pathophysiolog cal significance of the distribution of histamine receptor sut types: a proposed dual role for histamine in inflammation an type I hypersensitivity reactions. Agents Actions 1988;24:26 34. 41. Kaminski PM, Proctor KG. Attenuation of no-reflow phenomenon neutrophil activation, and perfusion injury in intestinal microcircr lation by topical adenosine. Circ Res 1989;65:426-435. 39.

Raud J. lntravital microscopic studies on acute mast cell-deper dent inflammation. Acta Physiol Stand 1989; 135(Suppl578): 1 58. 43. Raud J, Lundeberg T, Brodda-Jansen G, Theodorsson E, Hedc vist P. Potent anti-inflammatory action of calcitonin gene-relate

42.

3 14

44.

45.

46.

47.

48.

EDITORIALS

GASTROENTEROLOGY Vol. 104, No. 1

peptide. Biochem Biophys Res Commun 1991; 180: 14291435. Cronstein BN, Levin RI, Philips M, Hirschorn R, Abramson SB, Weissmann G. Neutrophil adherence to endothelium is enhanced via adenosine A, receptors and inhibited via adenosine A, receptors. J lmmunol 1992; 148:220 l-2206. Asako H, Wolf RE, Granger DN. Leukocyte adherence in rat mesenteric venules: effects of adenosine and methotrexate. Gastroenterology 1993; 104:31-37. Cronstein BN, Eberle MA, Gruber HE, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA 199 1;88:244 l2445. Jacobson KA, van Galen PJM, Williams M. Adenosine receptors: pharmacology, structure-activity relationships, and therapeutic potential. Med Chem 1992;35:407-422. Rosengren S, Arfors KE, Proctor KG. Potentiation of leukotriene

tkm

by

0

C

Iblast

the pharmacological prostaglandins

of

profile of the naturally occurring

and their synthetic analogues. Much of

this work was directed toward elucidating nisms underlying

the property

?

uting factors.4 More recently,

ne of the major growth areas of gastroenterological research in the 1980s was the investigation

Address requests for reprints to: JohanRaud, M.D., Ph.D., Department of PhysiologyI, Karollnska Instltutet, S-104 01 Stockholm, Sweden. Supportedby the SwedishMedical ResearchCouncil(14X-4342, 04P-8865) and the SwedishSocietyfor Madical Research. 0 1993 by the American GastroenterologlcalAssociation

the

of

twsFrom

B,-mediated inflammatory response by the adenosine antagonist, 8-phenyl theophylline. Int J Microcirc Clin Exp 1991; 10:345-357. 49. Atherton A, Born GVR. Relationship between the velocity of rolling granulocytes and that of the blood flow in venules. J Physiol (Lond) 1973;233: 157- 165. 50. Williams TJ. Interactions between prostaglandins, leukotrienes and other mediators of inflammation. Br Med Bull 1983;39:239242.

the mecha-

of these fatty acids

an involvement

of sen-

sory neurons, probably reflecting the local release of the neuropeptide calcitonin gene-related peptide, in the

acute

(PGE,)

protective

actions

of

and its 16,16-dimethyl

prostaglandin analogue

identified.’ In the current issue of GASTROENTEROLOGY, Hoshow the potent ability of

known as gastric cytoprotection, a concept pioneered and developed by the late Andre Robert.‘p2 Early stud-

gaboam et al. convincingly

ies had revealed that many endogenous prostaglandins

prostanoids

and their analogues,

tory mediators histamine and platelet-activating

independently

of any antisecre-

E,

has been

to inhibit the release of the proinflammafactor

tory actions, had the ability to prevent acute deep ne-

(PAF)

crotic injury to the gastric mucosa induced by a num-

(TNFa)

ber of directly

cells.” Early studies with PGE,“,” as well as with PGE, and 16,16-dimethyl PGE2i2 had shown inhibi-

applied chemical

irritants

including

acid and ethanol.lm5 Although they had limited pathophysiological of peptic

or clinical relevance to the development

ulceration,

these models

used to explore the phenomenon

were extensively

of cytoprotection

in-

and the cytokine from

both

centrations

ies would identify the underlying processes and hence

lease of histamine,

lead to pharmacological

16,16-dimethyl

to provide

a clinically

useful antiulcer

agent with a

factor

and peritoneal

a

mast

were required to elicit this action. In the

current

of this property

intestinal

necrosis

tion of histamine release from rat peritoneal mast cells induced by compound 48/80 or antigen, but high con-

duced by prostanoids. It was anticipated that such studexploitation

tumour

study,” inhibition PAF,

analogue,

of ionophore-induced

re-

and TNFcY by PGE,,,

its

and misoprostil

occurred

rapidly and at much lower concentrations,

although

actions of prostanoids can be shown in humans, such actions do not appear to contribute significantly to their clinical antiulcer actions, therapeutic efficacy being consistently found only in acid-inhibitory doses.6p7

the potency of each prostanoid appeared to differ between the type of mast cell and the mediator studied. The authors thus suggested that this mast cell-directed action may contribute to the overall cytoprotective actions of such prostaglandins.

The mechanisms underlying the protective properties of prostanoids still, however, remain of interest because such effects may have physiological relevance in the maintenance of tissue integrity. Stimulation of luminal processes, including mucus and bicarbonate secretion as well as the prevention of microvascular . , .a 1 121 1 .I

There is considerable circumstantial evidence linking mast cell degranulation and secretion to mucosal injury,‘3,‘6 yet the potential involvement of inhibition of mast cell mediator release in the acute protective actions of prostanoids is far from obvious. Thus, whereas PAF can cause extensive acute gastric mucosal . . 1’1. . -1 r._v. .I .I ,.

novel mechanism

of action.

Although

the protective