e of increased airway and microvascular permeability

REVIEW
e of increased airway microvascular permeability and
plasma exudation in asthma
K.F. Chung, D.F. Rogers, P.J. Barnes, T.W. Evans
airway microvascultu permeability and plasma exudaJion
D.F. Rogers, P J . Barnes, T.W. Evans.
oedema and Inflammation are recognized as cardinal
resulting from Increase microvascular permeability or
circulation wltb the exudation or pla.<~ma and innammatory
eJrway lumen. Resistance to airflow Is increased and the
nu..ruu' ""• eltber directly or by cytotoxic proteins derived
Jofiammatory cells. Such mediators Include bradykinin,
factor (PAF), leukotrlenes and histamine. Antigen·
nl'!~trol!enllc tnnammatlon, generated by Immunoglobulin E
respectively, may also contribute to oedema
~:.U~e~Sme1n1 of increased bronchial vascular permeabtllty In
Involved measurement or the extravasation or radlolaproteln-bound dyes. Non-Invasive techniques are less
but measurement or the rate of clearance or Inhaled
isotope may prove successful. Airway oedema appears
feature of asthma and future research may be aimed
drugs that specifically prevent airway microvascular
is a prominent feature of patients who
asthmaticus [1, 2]. An accompanying
presence of exudatcd plasma in the interairway wall as well as in the lumen, both
be responsible for the shedding of ciliated
which is histologically characteristic of
mcreasea microvascular permeability is one
signs of the inflammatory process [3] and
in ihe pathophysiology of asthma has
ngly apparent with the accumulation of
un the physiological and phannacologiairway mic.rovasculature (4, 5]. Although
circulation receives only 1- 2% of total
recent studies of the anatomical distribuial microcirculation in casts of human
the presence of abundant capillary¥"''"...,'"~ in the submucosal layer [6]. These
studies indicate the potential importance of
network in the airways. Whether or not the
junctions in the airways of asthmatic
abnonnally leaky is unknown. However, they
to ':llany of the inflammatory mediators that
m .the pathogenesis of asthma [7] . In this
potenual mechanisms and effects of increased
ular permeability will be considered and
re 0 ~ ph:tn11ncological agents discussed, parliculation to the treatment of asthma.
Dept of Thoracic Medicine, National Heart and Lung
Institute, Dovehouse Street, London, UK.
Correspondence: Dr T.W. Evans, Brompton
Hospital, Fulham Road, London SW3 6HP, UK.
Keywords: Asthma; plasma leakage; airway fluid
Received: July 1988; accepted after revision
September 11, 1989.
Effects of plasma exudation
Airway mechanics
In humans, local instillation of antigen onto the bronchial mucosa of asthmatic subjects causes acute swelling
and narrowing of the airways which can be directly
visualized through a bronchoscope [8, 9]. The response
is rapid in onset, resolves slowly and could represent
airway mucosal oedema secondary to increased
microvascular leakage. The duration of swelling is
possibly dependent on the removal of exuded fluid by
bronchiallymphatics, or its passage into the airway lumen.
Very little information is available on the role of airway
lymphatics in such circumstances due to the technical
difficulties in studying their physiology. Secondly,
re-entry of exuded fluid into the vascular compartment
may occur, although there is no evidence for this. The
precise degree to which measurements of airway resistance reflect smooth muscle contraction or acute inflammation after inhalation of a mediator is not known,
although there is indirect evidence to suggest that
oedema contributes significantly to increased resistance.
For example, platelet-activating factor (PAF) causes
airway narrowing that is only partly inhibited by a dose
of beta-agonist which completely prevents methacholineinduced bronchoconstriction (10]. Because PAF has little
330
K.P. CHUNO, D.P. ROOERS, P.J. BARNES, T.W.EVANS
direct contractile effect on airway smooth muscle in vitro,
but has been shown 10 increase plasma exudation from
bronchial vessels [I J, 121. the partial inhibition may be
due to airway oedema which is unaffected by betaagonists. ln addition to basement membrane thickening,
smooth muscle hypertrophy and intraluminal mucus
airway oedema is one of the features of asthma which
may underlie the enhanced airway responsiveness to
endogenous and exogenous bronchoconstrictor mediators
[13]. Small increases in wall tltickness due to oedema
which do not lead to changes in baseline lung function
may, theoretically, significantly increase airflow
resistance (14, 15].
Epithelial changes
The epitltelium is being increasingly recognized as
playing an important role in the maintcnance of airway
homeostasis [161. In asthma, the epil.hclium is damaged
( I, 171. although the mechanisms by which tltis occurs
remain unclear. Plasma exuded into tlte airway interstitium may increase hydrostatic pressure and physically
disrupt the epithelium. Cytotoxic proteins derived from
migrating eosinophils ( 18) may also damage epithelial
~ells d!r~y. The significance of transudation of plasma,
10 addaoon to Inflammatory celJs, into the airway lumen
through t1te damaged epithelium is becoming increasingly apparent
Proteina.ceous mucou~ plugs are found in the airways
of asthmat.tcs [1] and thetr sputum contains elevated levels
of plasma proteins when compared to control subjects,
even when the disease is relatively mild (9, 19, 20j.
Plasma proteins may increase tlte viscosity and quantity
(2 1, 22] of airway mucus leading to decreased mucociliary clearance (23]. Indeed, increased airway microvascular permeability by agents such as PAF administered
vi~ the trachea or intravenously [24, 25], capsaicin (which
st.tmulates the release of tachykinins such as substance
P) and antigen in sensitized animals (25, 26] have been
as~iat~ ~i~ an. incrcas~ in luminal protein recovery,
wh1ch IS and1catave of mcrcased airway epithelia!
permeability.
The mechanism underlying this coincidence of
increased airway epithelial and venular endothelial
penneabilities is unclear. It is possible that mediators
affect both barriers simultaneously and comparisons of
results following tlteir administration via the intravenous
? r endOtracheal routes might resolve this point Secondly,
mcreased epithelial permeability may result from the
extravasation of plasma into the bronchial interstitium
a~ter an incr~se .in endothelial permeability. The mcchanasms of eptthehal permeability changes have not been
establish~, but it seems clear that increased epithelial
permeab1hty to molecules such as albumin is not invariably accompanied by epithelial damage.
Generation of mediators
Increased k~llikrein activity, possibly secondary to
plasma exudauon, has been found in bronchoalvcolar
lavoge nujd from asthmatics and may res •
bradykinin genermion [27). Bradykinin j1 1t tn
to stimulate bronchial C-fibre sensory nc03
dogs (281. Damage to the airway cpithcJ!"C
may result in exposure of these nerve •urn
wo~ld '!'en be stimulated by bradykinin [29).
aellvall~>n or local axon renexes, With
conductJon down tlte collatcrol nerve lib 0...
proposed~ a m~hanism for development ~r
mflammauon wath plasma exudation (30]
~ors may also be generated from exuded
annammatory cells. Although complement
not been detected in the circulation of a~u, m...t.
acute attacks or after allergen chaUenge
occur _tocal.ly in airway tissue following
bronchtal m1crovascular permeability leading
~tion of airway inflammatory responses.
IS a Jack of data as to whether significt~nl
both complement fragments and kinins are
t1te inflammed airways of asthmatics.
°
Measurement of airway mlcro
permeability
Animals
Methods for measuring airway microvascular
bility are usually invasive and rely on the
of intravascular albumin. In animals, SARJA o.nd
[32, 33) made use of Evans blue dye., used
skin [33]. to assess the extravasation of m"''""'""
in the airways quantitatively. Evans blue binds
albumin when injected intravenously and SllCIOtrc:JD
elric measurement of the quantity of dye P.s: r,mcte
airway tissue has been used as an index or
microvascular permeability. In skin, this index
well with extravasation of radio-labelled ul
cutaneous microvascular permeability is in
histamine [34]. A similar correlation is
airways (Rogers et al. J. Pharmacal. Methods,
309-315). One advantage of the method is that
ment of regional changes in microvascular
at different anatomical levels of the
in addition to localization of the tissue ttt~llllllllll
dye using fluorescence light microscopy [331.
with this metltod the site of dye extravasation
determined precisely because Evans blue is
diffusible molecule and once in the intc
dissociate from albumin and diffuse back in10 the
Jar space. In addition, the role of other f:~c tors
lymphatic clearance and reabsorption into the
space is unknown. Monastral blue, a copper
anine pigment with a particle size of approx
nm, also crosses areas of increased
meability and is subsequently trapped in the
f35]. Because of its electron density, Monas
be used to localize the site of increased m
permeability. Indian ink particles share simil~
and have been used to examine airway m
leakage in guinea-pigs ( 11 ]. There arc
331
MICROVASCULAR PERMEABILITY IN ASTHMA
data between the Evans blue and Monastral
but the former suffers from the disadIOI'r"'""·" '" ly showing high baseline values,
Lhe effects of surgical procedures (such
vean in the neck) on permeability.
of Lhe macromolecular tracer fluorescein
dextran (FITC-dextran) which has a
L similar to that of albumin, but a larger
can be visualized directly under fluoresand the nwnber of leakage sites counted
et al. [37] have quantified the content of
FITC-dcxuan in excised airway tissue in
as a measure of vascular leakage and also
the blood pool content using technetiumMlll!OC;yte:s. This technique required no surgiguinea-pig had to be intubated to
lnh"''"~~ncm administration of test agents. The
~Eileat'C~O to be sensitive, as surgical procedures
,_,.,.,;,,n of the neck to expose the vagi caused
va,... u'"' of FITC-dextran. In addition,
of albumin in the airway secretions
the endotracheal tube provides a measepitbcliaJ permeability. The method theresimultaneous assessment of endothelial and
permeability and the time-course of events.
et al. l381 examined the extravasation of
bovine serum albumin in guinea-pig
vo and measured blood volume using
erythrocytes and expressed their results as
albumin per g dry weight of trachea.
IIISI~ncr1t of airway oedema is more difficult.
dehydration affect the degree of oedema.
techniques have been used to demonstrate
"cuffs" of fluid in pulmonary oedema
not been applied to the airways. Measureto dry weight ratios is possible, but may be
{40, 26). Direct visualization of airway
.endoscopy following local instillation of
subjects has been reported [8, 9],
NU'"'"''v" of the response is difficult. In an open
:.pnlp8J11li,Or in the dog, rapid changes in mucosal
been recorded using a probe to touch the
after administration of vasoactive agents
i: VlliChc:a I circulation [41). The changes were of
and probably reflect changes in bronchial
rather than the accumulation of extravascular
i'.m1eas:urcment of airway microvascular penncadlfficuiL and information about mechanisms and
~the bronchial microvasculature has been
g~ly _from animal experiments. Methods that
an mtact man are clearly required for the
Plasma exudation in the lower airways. Recent
examined the rate of transfer of inhaled
diet.hylenetriamine pente-acetate (DTPA),
le of 492 daltons, into blood as a measure
•• pcnncability".
Thus, bronchial clearance of
DTPA has been found to be increased in smokers but not
in aslhmatic subjects [42, 431 . However, Lhc site of
"permeability" measured by Lhis mclhod is unclear amJ
may be the vascular or mucosal epithelium [441. 1l1e
reported increase in DTPA clearance in asthmatics afler
histamine inhalation [45, 46] may, therefore, not reflect
increased airway microvascular permeability. The penetration of inhaled solutes such as DTPA into the vascular
compartment may involve mechanisms that are distinct
from those underlying the exudation ·of plasma from the
microvasculature into the bronchial interstitium and
lumen. Thus, DTPA clearance cannot be used as an index
of microvascular leakage in the airways. Measurement
of proteins in bronchoalveolar lavage fluid is a feasible
means of assessing plasma exudation into the airways.
Recovery from small volume (20-30 ml) lavage may
represent fluid sampled from the large airways and
assays of specific proteins can provide an indicallon of
the selectivity of the increase in plasma e xudation. Thus,
FICK et al. [91 reported that immediately after the local
instillation of alle rgen, the concentrations o f small
molecular weight proteins in lavage flu id (e.g. albumin,
transferrin and caeruloplasmin) increase, but the proteins
with molecular weights greater than 345,000 daJtons (e.g.
alph~ g lobulin and fibrinogen) rise to a lesser extent. An
increase in the recovery of labelled albumin in lavage
fluid was reported by the same group followi ng allergen
challenge in man. Such studies are unfortunately limiled
in their application because of their invasive nalure. The
measurement o f plasma exudation into the nasal
passages has recenlly been attempted through the quantification of albumin levels in nasal lavage and may
provide a model for the evaluation of the mechanisms
controlling permeability changes in the distal airways.
Mechanisms
Many of the mediators implicated in asthma are capable
of increasing airway microvascular leakage [7]. Ultrastructural studies of systemic microvascular beds support
the view that the inflammatory leakage of protein-rich
plasma does not occur in capillaries, but via widened
gaps between the endothelial cells of postcapillary
venules (47, 48]. Various inflammatory mediators are
known to cause venular endothelial cells to contract
aclively, thus causing cellular separation, followed by
movement of plasma proteins through the endothelial
gaps, across the basement membranes of the endothelium and epithelium, with subsequent leakage into the
airway lumen.
Blood flow
Protein extravasation is partially dependent on blood
flow, although mediators such as PAF, which induces
arteriolar constriction, are also extremely potent in increasing airway microvascular leakage [11, 12). Furthermore. synergism between mediators which principally
increase blood now, such as PGE2 , vasoactive intestinal
332
K.P. CHUNG ET AL
peptide (VIP), calcitonin gene-related peptide (CGRP),
and those which induce protein extravasation, such as
the leukotrienes and bradykinin, has been demonstrated
in the skin [49, 50].
Such interaction may not be relevant in the airways;
thus, CGRP which is a potent vasodilator does not
potentiate the airway response to substance P, which
increases vascular permeability in guinea-pigs [51).
However, decreasing blood flow by alpha-adrenoceptor
mediated vasconstriction does inhibit PAF-induced
airway microvascular leakage whilst betaz-adrenoceptor
agonists such as salbutamol, which are vasodilators, have
no enhancing effect [52] . One explanation for the lack of
potentiation may be due to the relatively greater blood
flow in airways compared to skin: potentiation is not
possible where flow is adequate and may only be
demonstrable where flow is reduced.
Mediators of inflammation
Most studies concerning the effects of inflammatory
mediators on airway microvascular leakage have reported
results following their intravenous administration to
experimental animals. This systemic approach may
influence the bronchial microcirculation by changing the
perfusion pressure or via central reflex mechanisms. Few
investigators have examined the effects of mediators
administered by aerosol, or injected directly into the
bronchial arteries. In asthma, mediators may be released
locally within the airway lumen or interstitium, such that
high local concentrations can be achieved without spillover into the systemic circulation. Thus, the relevance of
studying the effects of intravenously administered
mediators may be questioned.
Histamine. In animals, intravenous histamine increased
the permeability of bronchial venules of both submucosal and peribronchial plexuses to colloidal carbon via
the transient formation of large endothelial animals
[53, 54]. In the respiratory tract of the guinea-pig histamine is most active in the proximal large airways [55],
with a prolonged effect lasting up to 30 min. Local
instillation of histamine on to human nasal mucosa leads
to increased recovery of albumin in nasal lavage fluid,
suggesting transient increases in both epithelial and
endothelial penneabilities (56].
P/atelet-aclivating factor. PAF is one of the most potent
inducers of microvascular leakage throughout the
guinea-pig respiratory tract when administered intravenously [11, 12], being approximately 10,000 fold more
potent than histamine, although its duration of action is
shorter. The effect of i.v. PAF is not mediated via the
secondary release of histamine, prostaglandins or sulphidopeptide leukotrienes, but is inhibited by the PAF
receptor antagonists BN 52063 and WEB 2086 [12, 57).
PAF directly causes the contraction of human endothelial cells in culture [58], which permits the opening of
endothelial gap junctions. Local perfusion of PAF in
guine~-pig airw~y.s induces ~n increa80 in
secretions suggesting exttavasauon of al bumin
vascular compartment through the end
epithelial barriers [25] . In addition, inudllraQh.IOii
induces the delayed leakage of plasma
airway lumen of guinea-pigs [59).
52021 also inhibits endotoxin-induced
cular leakage in guinea-pigs, indicating a
[60]. It has been suggested that oedema
increased airway permeability may be
airway narrowing in human subjects after
of PAF, as PAF does not contract human"'"'"'"'muscle in vitro [61, 62).
Leulcotrienes. The sulphidopeptide leukotricne o
is slightly less potent than PAP in 1 •
microvascular permeability in the
administered intravenously, although both
throughout the respiratory tract (11, 55].
0 4 directly increases gap formation at the
venular endothelium as assessed b y e
microscopy [63]. LTC4 and LTD, both produce
and flare responses in human skin at low cortcelriM
in a similar manner to PAF, although their
human airway vascular permeability are not
[64, 65].
Bradykinin. Intravenous bradykinin induces
microvascular leakage (66], an effect that may
mediated through P AF release, possibly from
lar endothelial cell (67] and partly via the
prostaglandins [68). Instillation of bradykinin to
nasal mucosa results in an increase in nl
TAME-esterase activity, reflecting increases in
and epilhelial permeability [69). The n h <:Prvllt
tissue kallikrein is present in the airways
asthmatic subjects [27] suggests that local Jo:CIII1flll"!!
bradykinin may be responsible for airway
asthma [27].
or
lgE-mediated responses. During IgE-induced
using intravenous antigen in sensitized
i
plasma extravasation is mediated partly by hi<:l.nmllll
leukotrienes, depending upon airway level [70].
mine release also contributes to leakage
in the central intrapulmonary airways, but PAF
appear to be involved in this response [57, 70].
results are consistent wilh the preferential site of
of these mediators in increasing micr
permeability when applied exogenously [55j . .
interactions between mediators released. dunnndg
mediated anaphylax.is remain to be exammed .a
be significant in asthma. Local instillation of ~ugen
the respiratory mucosa of allergic asthmatiC
causes an increase in the total protein conccn
lung lavage fluid. In addition, an immediate .i
labelled serum albumin from the circulation mto
fluid is observed [9]. Similar results have been
following the instillation of allergen onto the nasal
of allergic subjects [71].
MICROVASCULAR PERMEABILIT Y IN ASTHMA
may play a significant role in lhe increase
perrneability induced by several inflamsuch as LTB 4 [72, 73}, complement
ludlng C5a [74], and synthetic chemotac·
for example F-met-leu-phe [72-74}.
of neutrophil migration, increases in
- n~w.:r•mlity to C52-des-arg are observed
of LTB-4-induccd microvascular
hamster cheek-pouch has shown lhat it
of ncutropbH adherence in post-capiHary
T-fl"'"""', more recent work suggests that
A"'~'""'"''~" and diapedesis in response to LTB 4
occur without protein lcalcage [75). 'These
DOl been performed in l.he airways and it is
the passage of inDammatory cells through
into Lhe airway lumen does not inOucooe
MmPJ~hility to plasma proteins.
_,.,u.....~'" of neutrophils to endothelial cells
on both the endothelial and leucocyte
there is evidence to suggest that a
membrane complex on the leucocyte, the
complex, is recjuired for neutrophil
On the endothelial cell surface a
such as bacteriallipopolysaccharides
I, cause increased adhesiveness to
[77]. The exact nature of the interaction
endothelial cells and circulating neutroremains to be established. Neutrophils
nu .. vc:~ :.c; vascular endothelium in the presence
otnctic stimuli [78]. Ultrastructural
that migration occurs via intercellu·
wilhout apparent injury to endothelial cells
·H nwl'.•vt•r, under certain conditions, neutrophils
endothelial cell junctions via the action of
-em:vm;P.'! and reactive oxygen species [81].
permeability cannot be induced by
ueo,lete:dof circulating neutrOphils, although
ne and bradykinin are unchanged [731.
the increase in tracheal vascular permeaby toluene di-isocynate (TDI) requires the
neutrophils [82]. Bacterial endotoxin increases
ility of the pulmonary circulation to
dye, an effect dependent on the presence of
[83]; it also increases bronchial vascular
. with a slow onset of action, which may
time required for leucocyte recruitment [60].
in microvascular leakage
""'Ulal'ion. Electrical stimulation of the distal end
~liiO!l<~d cervical vagus nerve evokes an increase
vascular permeability in the trachea and main
the rat [32] und guinea-pig [84]. Efferent vagal
do not seem to be involved because the
not blocked by either ganglionic blockade or
of muscarinic reccptors (32]. Capsaicin, which
~ry ne.rve.s .or neuropeptidcs such as sub( ) IR5), mh1b1ts the vagally-induccd increase
333
in microvascular leakage suggesting that release of sensory neuropcptides is involved in neurogenic plasma
extravasation [32]. Furthermore, SP anwgonist drugs
partially inhibit vagally-induccd increases in airway
oedema [841. The increased airway vascular permeability attributable to histamine, brady!Unin and acutelyadministered capsaicin is inhibited by capsaicin
pretreatment, suggesting thnt sensory nerves arc involved
in mediating these responses [86). lnOammatory stimuli,
such as cigarette smoke, induce plasma leakage into the
airways, an effect which has been shown to be mediated
by capsaicin-sensitive vagal afferents (87j. However,
capsaicin pretreatment does not inhibit TDI-inducod
tracheal plasma extravasation [88], which seems to be
neutrophil-dependent [82].
Neuropeptides. In addition to SP, two other structurally-
related pcptidcs (tachykinins), neurokinin (NK) A and B,
have recently been identified and neurokinin-like
immunoreactivity has been observed in the lung. SP,
NKA and NKB induce plasma exudation [5 1] and are all
possible mediators of neurally-induced microvascular
leakage. Whether they act directly on venules or
stimulate the production of other mediators, which in
turn increase vascular permeability, is not known. SPinduced plasma exudation is not mediated by neutrophils
[89}, although SP may cause adherence of leucocytes to
venular walls [90). lt is possible that the dense SPimmunorcactive nerves in the airway epithelium release
neuropeptides, which then diffuse to affect venular
endothelium, since there are few nerves localized near
vcnules [9 1].
Sensory nerve stimulation may cause other cells within
the airway epithelium to release other mediators known
to increase plasma exudation, including lcukotriencs C
and n. [92). In the rat, vagal nerve stimulation cause,;
goblet cell discharge as well us increasing epithelial
permcabi lity [9 1]. Opioid pcpudes prevent plasma exudation, during vagal nerve stimulation in tbc guinea-pig
by a pre-synaptic mechanism involving inhibition of
release of neuropcptides from sensory nerve endings in
the airways [93]. Clearly, such neural control mechanisms have been carried out mainly in rodents. rnformation concerning higher species or man is unavailable.
although preliminary data suggest that local application
of substance P and capsaicin to the human nasal mucosa
does not result io plasma exud:uion (94]. Whether the
distal airways will behave similarly remains speculative.
Therapeutic aspects of airway
microvascular leakage
Despite the importance of airway plasma exudation in
asthma, relatively little is known about the influence of
currcmly available anti-asthma drugs on this process.
Adrenergic drugs
Beta-adrenergic agonists have been shown either to
have no therapeutic action or to exhibit inhibitory effects
334
K.P. CHUNO ET AL
o n plasma leakage in several microvascular beds
(95, 96), despite the fact that they cause vasodilatation
which, in skin, potentiates microvascular leakage [74].
This suggests that beta-agonists may have a direct
eUcct in preventing venular endotheHal contraction.
Terbutaline, for example, attenuate·S histamine and
lcukotriene-induced microvascular leakage in the trachea
of cats and guinea-pigs [97, 98}.
In a superfused tracheal preparation of the intact guineapig, small dose s of intratracheally administered
terbutaline inhibit capsaicin-induced leakage o f FITCdextran into the trachea and main bronchi, although
terbutaline has no effect on neurally-induced tracheal
microvascular leakage of Evans blue dye in the rat [99].
Similarly, salbutamol does not influence PAP-induced
microvascular leakage in guinea-pig airways [52}. The
reasons underlying these conflicting observations are not
clear although the different results indicate that tissue
oedema and plasma leakage into the airway lumen may
not necessarily be linked. Nevertheless, adrenaline is
hig hly effective in pre venting leakage, per haps by
limiting blood flow to the sites of leakage via its
vasoconstrictor properties [52]. The effects of adrenaline
are probably mediated via alpha-receptors localized to
precapillary arterioles.
microvascular permeability, PAP anUJgont~til.l
inhibit ovalbumin-induced leakage in
pigs [57, 71) although FPL 55712, a
antagonist, has a partial inhibitory effect [70],
Other drugs
Calcium antagonists such as verapamil inhiblt
cular leakage in the hamster cheek pouch
preventing contraction of the intracellular
elements responsible for gap-fo rmation
endothelial cells [104]. In guinea-pig
has an inhibitory effect on leakage at
although higher and lower doses are without
Potassium channel activators are currently
gation as therapy for a number of diseases
[1 05]. However, their vasodilatory effects are
preclude them from use in inhibition of
leakage and we have found that the polassium
blocker cromakalim had no inbitory effect
induced leakage in guinea-pig airways
Boschetto, unpublished observations).
Conclusion
Alethy~nthines
Methylxanthines inhibit histamine-induced microvascular leakage in hamster cheek pouch [100]. and
capsaicin-induced leakage in guinea-pig airways [59] but
do not inhibit PAP-induced microvascular leakage in the
airways of guinea-pigs [52]. However, it remains an
intriguing possibility that the partial protection afforded
by theophylline and enprofylline against the laLe phase
response to antigen [ 10 l) may be via alterations in airway oedema fonnation. Theophylline also inhibits the
delayed leakage of plasma proteins into the airways
induced by intratracheally-administe red PAF in the
guinea-pig [59}.
Corticosteroids
High doses of glucocorticosLeroids prevent the increase
in microvascular penneability induced by histamine and
bradykinin via mecha nisms that are independent of
changes in blood Oo w, microvascular pressure, pcrfused
surface area or specific mediator receptor blockade [102].
Dexamethasone inhibits plasma leakage induced by both
PAP and antigen in rat aiJways [103].
Mediator antagonists
Since many different mediators with the potential to
increase airway microvascular leakage may be released
during the asthmatic inflammatory proce ss [7]. it
is unlikely that a single antagonist will prove useful.
Despite the potent effect of PAF in increasing
Plasma exudation into the aiJways appears
significant role in the pathogenesis of asthma.
further work is needed to evaluate its precise
tion, but is impeded by lack of sa tis n1ctCl1rv~'
invasive methods for measurement of
in the aiJways. Because airway oedema is I
important feature in asthma, future research
aimed at developing anti-asthma drugs which
cally prevent airway microvascular leakage.
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Le role de /'augmentation de permiabiliJe micro-vasculaire
des vole.r aeriennes et de I' exsudation pla.rmatiques da.n s
l'astlvne. K.F. ChUIIg, D.F. Rogers, P.J. Barnes, T.W. £vans.
Ri!SUM~: L'oc&me des voics aeriennes et !'inflammation sont
consideres comme des caracteristiques cssentiellcs de l'asthme:
elles resultent d'une permeabilit6 micro-vasculaire accrue dans
la circulation bronchique, avec e:uu.d ation de plasma et de
cellules inflarnmatoires das la lumicre des voies a&iennes. La
resista.ncc aux courants a.t!ricns est accrue et I 'epithelium est
lest!. soit directemcnt, soil par les prot61nes cytotoxiq ues
provenant des cellules inn an1matoi~ migratrices. Lcs mediateurs en cause sont la bradykinine, le PAP, Ios leu.lcotrienes et
I 'histamine. L' infiammation induitc par les anti gene.~ et
J'inrtammation neurogene produitc pnr lcs lg E el lc:s
neuropeptides, respcctivemcnt, pcuvcnt t!galcmenl contribucr l
la production d'oed~cs. L'appr~iation do !'augmentation de
la pennenbil it~ vasculaire bronch.iquc cbez lcs nnimaux a
repos6 largcmcnt sur la mcsure de l'extratva.sa.tion d'albumine
radio-marquee ou de colorants lies aux protcines. Les
techniques non invusives sont moins valables che7.les hommcs,
mais la mcsurc du taux de clc8111Jlce des panicules inhalccs,
marquees par un isotope, pcut etrc couronncc de succes.
L'oedeme des voics acriennes est unc caractcristique
importante de l'asthme. etlcs rcchcrches futures devraient avoir
pour objct le developpcment de medicaments qui prcviennent
sp6ciliqucmcnt la fuite micro-vascu lairc au nivcau des voies
aeriennes.
Eur Respir J., /990, 3, 329-337.