Content uploaded by Vicente Alfaro
Author content
All content in this area was uploaded by Vicente Alfaro
Content may be subject to copyright.
Correspondence to V. Alfaro (Tel.: +34 934 021 526;
Fax: +34 934 110 358; e-mail: valfaro@ub.edu).
Role of histamine and platelet-activating
factor in allergic rhinitis
V. Alfaro
Department of Physiology, University of Barcelona
Avda. Diagonal 645, 08028 Barcelona, Spain
(Received on )
V. ALFARO. Role of histamine and platelet-activating factor in allergic rhinitis
(minireview). J. Physiol. Biochem., 60 (2), 101-112, 2004.
This review is focused on the effects of histamine and platelet-activating factor
(PAF) in allergic rhinitis and the plausible implications for therapy. Rhinitis is
defined as a heterogeneous disorder resulting from an IgE-mediated reaction associ-
ated with nasal inflammation of variable intensity. Two phases of response are trig-
gered by an IgE/allergen cross-linking event: the first is the release of preformed
mediators such as histamine or interleukins from mast cells and basophils; the second
begins when cells start producing lipid-derived mediators. One of these mediators is
PAF. Apart from leukotrienes, PAF is perhaps the most potent inflammatory medi-
ator in allergic rhinitis for inducing vascular leakage, a response that may contribute
to the appearance of rhinorrhea and nasal congestion.
Key words: Histamine, PAF, Rhinitis.
J. Physiol. Biochem., 60 (2), 101-112, 2004
Rhinitis is a heterogeneous disorder
characterized by one or more of the fol-
lowing nasal symptoms: sneezing, itching,
rhinorrhea, and/or nasal congestion. It is
often accompanied by symptoms involv-
ing the eyes, ears, and throat, including
postnasal drainage (77). Many causes have
been described that induce rhinitis, but
about 50% of all cases are caused by aller-
gy. Allergic rhinitis results from an IgE-
mediated reaction associated with nasal
inflammation of variable intensity (11).
Potential allergens include pollens, molds,
animal dander, and dust mites.
The immune response to allergens
involves the release of inflammatory
mediators and the activation and recruit-
ment of inflammatory cells to the nasal
mucosa (77). Nasal biopsies conducted in
individuals with active disease revealed an
accumulation of mast cells, eosinophils,
and basophils within the airway epitheli-
um, together with eosinophil accumula-
tion within the deeper lamina propria (13,
14, 26). The accumulated cells have been
activated, and the mediators they release
generate the symptoms of the disease
through stimulation of specific receptors
on the sensory nerves and blood vessels
within the nasal mucosa (Fig. 1) (36, 37).
Allergic rhinitis has a relevant impact
on society because of its high prevalence
(> 10% of whole population), its associa-
tion with an impaired quality of life, and
the presence of comorbidities such as
asthma, sinusitis, and otitis media (12, 29,
80). The management of allergic rhinitis
has several objectives, one of which is to
reduce the symptoms caused by allergen
exposure.
The allergens: perennial and seasonal
allergic rhinitis
The hallmark of allergic rhinitis is the
temporal relationship of symptoms with
the exposure to an allergen. Allergens can
be classified as perennial or seasonal.
Perennial allergens include indoor mold
spores, dust mites, animal dander, and
specific chemicals (cleaning agents or cer-
tain powders). If a patient has allergic
rhinitis symptoms lasting for more than 2
hours per day for more than 9 months,
this would be classified as a perennial
allergic rhinitis, most likely caused by
something in their home or workplace.
Perennial rhinitis is a complex disease that
includes many different categories; the
most common are allergic rhinitis, the
NARES syndrome and vasomotor rhinitis
(11). The major symptom of perennial
allergic rhinitis is nasal obstruction.
Sneezing and rhinorrhea are often present,
but they are less troublesome than in sea-
sonal allergic rhinitis. Unlike perennial
allergic rhinitis, patients with seasonal
allergic rhinitis often present with con-
junctivitis and sometimes asthma. The
symptoms of seasonal allergic rhinitis
appear during a defined season in which
aeroallergens are abundant in the outdoor
air. The pollen from tree, grass, and weed,
together with outdoor mold spores, are
common seasonal allergens. Major symp-
toms include sneezing, rhinorrhea and
nasal blockage, which may not be con-
stant. Additionally, the symptoms of
allergic rhinitis may also be perennial with
seasonal exacerbations, depending on the
spectrum of allergen sensitivities (77).
Epidemiological studies have shown a
prevalence of 10% for seasonal allergic
rhinitis and of 10-20% for perennial aller-
gic rhinitis (52). Based on the concept that
allergic rhinitis is a complex syndrome
involving both the upper and lower air-
ways, as well as on confounding issues
related to the classification of allergic
rhinitis as seasonal, perennial, and occupa-
tional, the ARIA (Allergic Rhinitis and its
Impact on Asthma) panel has proposed
revised classifications for allergic rhinitis
(12).
V. ALFARO
102
J. Physiol. Biochem., 60 (2), 2004
SYMPTOMS
Tissue cell
recruitment and
activation
Structural cell
activation
Immune
activation
Mast cells
Eosinophils
Basophils
Endothelial
cells
Epithelial cells
Mast cells
Lymphocytes T
Lymphocytes B
Disease expression
Cell type involved
Fig. 1. Schematic representation of cellular involvement and sequence underlying allergic rhinitis
(adapted from (6)).
Phases of the allergic response
An allergic reaction can be best thought
of as a cascading set of inflammatory reac-
tions, started by the immune system in
response to environmental antigens (37,
64). Once an allergen is inhaled, it is
processed by the immune cells and stimu-
lates a B-cell mediated IgE response. IgE
is one of 5 types of immunoglobulins pro-
duced by B-cells: IgA, IgD, IgM and IgG
are the others. Each type of antibody can
bind to antigens or allergens, but differ in
the type of responses produced once they
are bound to the antigen. The typical
allergic response is mediated by IgE anti-
bodies when they bind to the allergen
with one end, and to the IgE receptor of
the inflammatory cells with the other end.
This cross-linking on the surface of the
inflammatory cell (e.g., mast cell) triggers
a multi-step process leading to activation
and degranulation of mast cells (typically
located at mucosal surfaces and around
blood vessels) and the release of histamine
and other inflammatory mediators (65).
Once the cascade starts, a whole array of
secondary responses is triggered.
Two phases of responses are triggered
by an IgE/allergen cross-linking event.
The first is the release, in seconds, of pre-
formed mediators such as histamine or
interleukins from mast cells and baso-
phils. These chemical mediators are found
in preformed vesicles and are released by a
calcium-dependent process induced by
the cross-linking of two or more IgE
receptors. Once these products are
released, they are responsible for allergic
(inflammatory) processes like vasodila-
tion, increased vascular permeability, and
increased chemotaxis of other inflamma-
tory cells. The chemotactic factors
released are responsible for recruiting
eosinophils (the major effector inflamma-
tory cells), neutrophils and basophils into
the inflammatory site on the nasal
mucosa. The second phase of the response
begins, in minutes, when cells start pro-
ducing lipid-derived mediators. These
mediators are derived from the conversion
of phospholipids into arachidonic acid via
phospholipase A (PLA
2
), followed by the
subsequent conversion of arachidonic acid
into leukotrienes and prostaglandins (the
so-called eicosanoids). However, another
relevant mediator is the platelet-activating
factor (PAF). Recent studies have shown
that the epithelial/endothelial cells of the
target organs are actively involved in the
recruitment and activation of inflammato-
ry cascades in allergic diseases (50). These
endothelial cells promote the expression
of vascular cell adhesion molecules and E-
selectin, which increase the adhesion of
circulating leukocytes to the endothelial
cells. Chemoattractant cytokines such as
IL-5 promote their infiltration into the
mucosa (60).
The immediate response to the antigen,
which is known as the early-phase allergic
reaction, occurs in more than 90% of
patients with a history of allergic rhinitis
and positive skin tests (38). This early-
phase includes the products of degranula-
tion (preformed mediators such as hista-
mine), and de novo inflammatory media-
tors (e.g., prostaglandin D
2
or LTE
4
). The
late-phase reaction occurs in up to 50% of
patients with allergic rhinitis (38), begins
at two to five hours after allergen chal-
lenge and peaks at six to eight hours after
exposure (77). During the late-phase reac-
tion, an exaggerated non-specific nasal
hyperreactivity occurs simultaneously
with the heightened response to the initial
allergenic stimulus. Therefore, preventing
or suppressing both the early-phase and
late-phase allergen-induced inflammatory
HISTAMINE AND PAF IN ALLERGIC RHINITIS
103
J. Physiol. Biochem., 60 (2), 2004
reactions is crucial for the successful treat-
ment of allergic rhinitis (62).
The role of histamine in allergic rhinitis
Histamine is a biogenic amine synthe-
sized and stored mainly in mast cells and
basophils that was first identified in 1910
thanks to its potent vasoactive properties
and plays a relevant role in the patho-
physiology of allergic diseases (89). Aller-
gen challenge significantly increases the
levels of histamine in nasal secretions of
patients with allergic rhinitis, therefore
suggesting that this mediator is involved
in the pathophysiology of allergic rhinitis
(60, 83). In fact, nasal challenge with hist-
amine induces nasal blockage, sneezing
and rhinorrhea (23). The effects of hista-
mine in allergic disease are derived from
its interaction with the H
1
subclass of his-
tamine G protein-coupled receptors (31).
The interaction of histamine with its H
1
-
receptor mediates several pathophysiolog-
ical effects, including nasal blockage,
sneezing, itching and discharge in rhinitis
(83).
The classical effects of histamine at the
organ level are well documented, but there
is increasing evidence suggesting that
histamine also has direct or indirect
effects on the activity of different inflam-
matory/effector/immunologic cell types
involved in the pathogenesis of allergic
disease (5, 72). Several studies have shown
that histamine receptors are expressed on
the cell surface of basophils, mast cells,
neutrophils, lymphocytes, macrophages,
epithelial cells and endothelial cells, and
therefore is likely to modulate the func-
tion of these cells (5). This finding has led
to the speculation by some investigators
that the antiinflammatory effects reported
for newer second-generation antihista-
mines might derive from their interaction
with the H
1
receptor, rather than with
other non-histamine receptors (66). Due
to their basic structure and their cationic
amphiphilic nature, antihistamines might
also induce non-specific antiinflammato-
ry/antiallergic effects resulting from ionic
association with cell membranes, de-
creased Ca
2+
binding, and inhibition of
membrane-associated enzymes (5). Nev-
ertheless, the antiinflammatory effects of
antihistamines have been found in vitro at
high concentrations and their clinical rele-
vance remains controversial (19).
Antihistamines in the treatment
of allergic rhinitis
Drug therapy for allergic rhinitis is
directed to control symptoms. Antihista-
mines, decongestants, mast cell stabilizers
and corticosteroids are currently used to
provide symptomatic relief of allergic
rhinitis. For many years, antihistamines
were the first-line pharmacological
approach to the management of allergic
rhinitis (71). Acute-phase allergic
responses are mediated primarily by hist-
amine, and the therapeutic effect of anti-
histamines is based on the blockade of H
1
histamine receptors located in the nasal
vasculature and nerve endings. Overall
advantages shown by antihistamine treat-
ment are oral administration, effectiveness
in relieving ocular symptoms, good com-
pliance with the new formulations that
require only one or two administrations
per day, and reduction of sedative and
anticholinergic side effects with the sec-
ond- and third-generation drugs (63).
Nevertheless, most antihistamines are
ineffective in relieving nasal obstruction
and some of them (e.g., astemizole and
terfenadine) were the source of a persis-
V. ALFARO
104
J. Physiol. Biochem., 60 (2), 2004
tent concern for their cardiovascular safe-
ty who led to their market withdrawal.
The relative advantages of antihista-
mines were initially based on their ability
to competitively inhibit the H
1
-receptor
binding of histamine (50). However, at the
appropriate doses many antihistamines
inhibited histamine release from mast cells
and perhaps mast-cell activation itself
(21). In fact, the antiallergic properties of
antihistamines generally refer to their
ability to inhibit mast-cell and basophil
activity (e.g., degranulation), including the
release of preformed mediators such as
histamine, tryptase, leukotrienes, and oth-
ers (7).
More recently, it has been reported that
some antihistamines can also regulate the
expression and/or release of cytokines
(44), chemokines (1), adhesion molecules
(20) and/or inflammatory mediators (33).
Some second-generation antihistamines
inhibit the influx of eosinophils to the site
of allergen challenge in sensitized individ-
uals (93), alter adhesion molecule expres-
sion on epithelium (55) and eosinophils
(20), decrease in vitro cytokine-enhanced
eosinophil survival (73), and alter
eosinophil activation/granule release (24).
Moreover, some antihistamines alter the
production of certain cytokines both in
vitro and in vivo. These include inflamma-
tory cytokines (e.g., TNF-α, IL-1β, and
IL-6) (86) and immunoregulatory
T
H
1/T
H
2 cytokines (e.g., IL-4 and IL-13)
(30) in both basophils and T cells (57).
Second-generation antihistamines are
active in the down-regulation of inflam-
matory mediators such as superoxides,
prostaglandins, PAF and others (85).
The platelet-activating factor
Phospholipids are major components
of cell membranes. They are also known
to be sources of arachidonic acid, which is
metabolized into bioactive eicosanoids
(leukotrienes and prostaglandins), and of
the platelet-activating factor (PAF, Fig. 2).
PAF (1-O-alkyl-2-acetyl-sn-glycero-3-
phosphocholine) is a phospholipid that
exerts bioactive effects via a specific cog-
nate receptor. The term PAF derived from
it being first described in 1972 as the sub-
stance responsible for the aggregation of
platelets that is released from IgE-sensi-
tized rabbit basophils after antigen chal-
lenge (8). The chemical structure of PAF
was later determined in 1979 (9, 22) (Fig.
3). In contrast to unsaturated fatty acid-
derived major autacoid species (e.g.,
prostaglandins and leukotrienes), PAF is
unusual in its intact gylcerophospholipid
structure.
As PAF was the first bioactive phos-
pholipid whose structure had been char-
acterized, this research area was rapidly
developed (17, 32, 70). Besides platelet
activation and hypotensive effects, a wide
variety of PAF bioactions have been eluci-
dated, such as facilitation of hemostasis
and contribution to events associated with
reproduction (49, 92). Nevertheless, PAF
acts as a pathologic mediator in bronchial
asthma and other allergic responses, vas-
cular damage including ischemia-reperfu-
sion injury, several forms of shock (espe-
cially endotoxin shock), acute respiratory
distress syndrome, and inflammatory
bowel disease (18, 32, 34, 70, 92). PAF is
so potent that it can always induce signif-
icant biological responses at nanomolar
concentrations both in vitro and in vivo.
Thus, PAF activates platelets, neutrophils,
monocytes, macrophages, and vascular
smooth muscle cells at concentrations as
low as 10
-12
to 10
-9
mol/L (32, 69, 78, 84).
PAF is not preformed in storage gran-
ules but produced from phospholipids
mobilized from cell membranes by phos-
HISTAMINE AND PAF IN ALLERGIC RHINITIS
105
J. Physiol. Biochem., 60 (2), 2004
pholipase A
2
by many stimulated cell
types (e.g., basophils, neutrophils, mono-
cytes, macrophages or endothelial cells).
PAF produced by monocytes and poly-
morphonuclear leukocytes is secreted (45,
48, 76), whereas PAF synthesized by vas-
cular endothelial cells activated by various
physiologic agonists (e.g., thrombin,
bradykinin, histamine, hydrogen perox-
ide, and leukotrienes C
4
and D
4
) is not
released. In these cells, PAF is expressed
on the cell surface with the polar head
translocated to the outer surface, and
serves as a signal for neutrophils to bind
to the endothelium (68, 91). Leukocyte
adhesion to the endothelium is the first
step in the physiological inflammatory
response and PAF has a homeostatic func-
tion. However, inappropriate or excessive
expression of this adhesion signal and the
subsequent recruitment and activation of
a large number of leukocytes might result
in further vascular damage caused by the
secretion of proteases and oxygen radicals
in these cells (91).
Considerable advances have been made
in understanding the biosynthetic and
catabolic pathways of PAF metabolism
V. ALFARO
106
J. Physiol. Biochem., 60 (2), 2004
LTB
4
Chemotaxis
5-LO
COX 1 (constitutive)
Cytosolic phospholipase A
2
Vasodilatation
Bronchoconstriction
Increased vascular permeability
Platelet aggregation
Chemotaxis
COX 2 (inducible)
5-HPETE
Lyso-PAF
Membrane phospholipids
Arachidonic acid
LTC
4
Vasoconstriction
Bronchospasm
Increased vascular
permeability
LTA
4
PGH
2
PGG
2
PGD
2
PGF
2
α
PGE
2
Vasodilatation
Edema potentiation
PGI
2
Vasodilatation
TXA
2
Vasoconstriction
Platelet - activating factor (PAF)
Fig. 2. Relationship of the platelet-activating factor (PAF) with other metabolites derived from membrane
phospholipids (eicosanoids: leukotrienes and prostaglandins).
Platelet Activating Factor (PAF)
CH
3
-C-O-CH
H
2
C-O-P-O-CH
2
-CH
2
-N-CH
3
O H
2
C-O-(CH
2
)
15-17
-CH
3
O
O
–
CH
3
CH
3
+
Fig. 3. Molecular structure of the platelet-activating
factor (PAF).
HISTAMINE AND PAF IN ALLERGIC RHINITIS
107
J. Physiol. Biochem., 60 (2), 2004
CMP
CDP choline
lysoalkyl GPE
alkylalcyl GPC
acetylCoA
acetyl-
alkylacyl/diacyl
GPE
FA
lyso PAF
Plasmalogens
A
A
P
i
acetylCoA
1-alkyl-2-acetylglycerol
1-alkyl-2-lyso-sn-glycerol-3-phosphate
Choline phosphotransferase
Acetylhydrolase
Acetyltransferase
PLA2
PLA2
Acetyltransferase
Transacylase
Phosphohydrolase
Acetyltransferase
PAF
PAF
A
B
Fig. 4. Synthesis od PAF. A) Platelet-activating factor (PAF) de novo pathway: starting with alkyl acetylglyc-
erol; B) re-modeling pathway: inflammation, cell stimulation and injury activate phospholipase A
2
(PLA
2
),
which converts the membrane lipid alkylacyl GPC (glycero-3-phosphocholine) into arachidonic acid and
lyso-PAF; in the next step, this PAF precursor is converted into active PAF by acetylation.
(35, 79). The synthesis of PAF can occur
through one of two described synthetic
pathways (Fig. 4) (3, 10) and it is tightly
regulated (25, 51, 87, 88). PAF is degraded
by PAF acetylhydrolase, which catalyzes
the hydrolysis of the esterified acetate at
the sn-2 position (82). Three PAF acetyl-
hydrolases have been described: two
intracellular enzymes (tissue types I and
II) and one secreted enzyme (plasma type)
(6). Potential mechanisms that might
explain PAF-induced pathologies could
be the inappropriate activation of PAF
synthesis in PAF-producing cells or the
reduction of PAF acetylhydrolase activity
(90). In both cases, the accumulation of
PAF may provoke a pathological re-
sponse.
Evidence supporting a role for PAF in
pathological processes includes the obser-
vation that several PAF receptor antago-
nists attenuate specific disorders in which
PAF is suspected to act as a mediator (22,
30, 57, 85). The development of PAF
antagonists has contributed both to the
identification of specific PAF receptors
and to the clinical application of PAF.
PAF evokes various intracellular events
though the PAF receptor, a member of the
family of G protein-coupled receptors
that has been linked to inositol phospho-
lipid turnover, changes in intracellular cal-
cium, activation of protein kinase C and
tyrosine kinases, and synthesis of
eicosanoids (75). The human PAF recep-
tor is encoded by a single gene located on
chromosome 1 (75). Two promoters regu-
late the synthesis of two forms of receptor
mRNA, each of which is expressed in dif-
ferent tissues and cells (68, 91).
The platelet-activating factor (PAF)
in allergic rhinitis
Of all the inflammatory mediators
involved in allergic rhinitis, PAF is per-
haps the most potent for inducing vascu-
lar leakage, a response that may contribute
to the appearance of rhinorrhea and nasal
congestion (21, 63). PAF has potent pro-
inflammatory properties and has been
implicated in bronchial asthma (60), but
its role in allergic rhinitis is less well estab-
lished.
Several studies have been performed
with a few PAF receptor antagonists in
animal models of the disease. In guinea
pigs, CV-3988 blocked vascular perme-
ability and increased nasal airway resis-
tance induced by topical application of
PAF, whereas SM-10661 attenuated anti-
gen-induced increase in late-phase nasal
airway resistance (35, 45). Another PAF
antagonist, ABT-491, both inhibited anti-
gen-induced leakage and decreased airway
resistance in rats and guinea pigs (11).
In the clinical setting, instillation of
PAF into the nose induces many of the
symptoms of rhinitis, such as increases in
nasal airway resistance, rhinorrhea, nasal
neutrophil influx, and nasal hyper-
responsiveness to subsequent allergen
challenge (4, 47, 53). Both PAF and its
metabolite (lyso-PAF) have been detected
in the nasal fluids and plasma of patients
with rhinitis (46, 54, 74).
Therefore, a number of experiments
conducted in animal models, and some-
times in humans, have shown that PAF is
involved in many pathophysiological con-
ditions, including allergic rhinitis. This
hypothesis is based on PAF-induced
pathological responses, prevention of the
pathological condition by PAF-r antago-
nists or the presence of PAF-related com-
pounds in the areas affected by the pathol-
ogy. To date, however, few PAF antago-
nists have reached clinical use, whereas
most compounds still in development are
being studied mostly in biological testing
or preclinical phase for the anti-
allergic/antiasthmatic indication. Other
indications often studied include treat-
ment of septic shock, hypertension or
antiplatelet therapy.
In conclusion, PAF and histamine
complement each other in vivo: histamine
is a mediator of early allergic response
released from preformed reservoirs in
mast cells, whereas PAF can be regarded
as a late-response mediator and is mainly
synthesized de novo . Both histamine and
PAF promote the release of each other in
some tissues and cells. Therefore, block-
ing both PAF and histamine might show
greater clinical efficacy than blocking just
one of them. P
IWINSKI et al. (67) reported
that the replacement of the ethoxycar-
V. ALFARO
108
J. Physiol. Biochem., 60 (2), 2004
bonyl group of loratadine, a widely used
H
1
antihistamine, by an acetyl group gave
the resulting compound (SCH-37370) a
dual character, maintaining its antihista-
mine activity and conferring an additional
PAF antagonist activity. A further step
was to increase the potency of compounds
derived from SCH-37370. Two series of
benzocycloheptapyridines (3-pyridy-
lalkyl derivatives and nicotinoyl deriva-
tives) were synthesized and analyzed for
PAF antagonist and H
1
antihistamine
activities. The analysis of different pyri-
dine substitutes led to the discovery of
rupatadine fumarate as a potent dual
antagonist (16). Further clinical studies
have confirmed the usefulness of rupata-
dine as treatment of allergic rhinitis (42).
Epinastine is another antiallergic agent
that has not only antihistaminic properties
but also provides antileukotriene, anti-
PAF and antibradykinin activities, which
are associated with its antiallergic actions
(81).
V. ALFARO. Papel de la histamina y del
factor activador de plaquetas en la rinitis alér-
gica (minirrevisión). J. Physiol. Biochem., 60
(2), 101-112, 2004.
Esta revisión se centra en los efectos de la
histamina y del factor de activación plaquetaria
(PAF) en la rinitis alérgica y sus posibles impli-
caciones en terapia. La rinitis alérgica es un
desorden heterogéneo que resulta de una reac-
ción mediada por IgE asociada con inflamación
nasal de intensidad variable. La reacción cruza-
da IgE/alergeno da lugar a una respuesta que
incluye dos fases: la primera implica la libera-
ción de mediadores formados previamente
tales como la histamina o las interleuquinas por
parte de mastocitos y basófilos; la segunda fase
empieza cuando las células empiezan a produ-
cir mediadores inflamatorios derivados de lípi-
dos. Uno de estos mediadores es el PAF. Apar-
te de los leucotrienos, el PAF es quizás el más
potente mediador inflamatorio en la rinitis
alérgica para inducir infiltración vascular, una
respuesta que puede contribuir a la aparición
de rinorrea y congestión nasal.
Palabras clave: Histamina, PAF, Rinitis.
References
1. Albanesi, C., Pastore, S., Fanales-Belasio, E. and
Girolomoni, G. (1998): Clin. Exp. Allergy, 28,
101-109.
2. Albert, D. H., Malo, P. E., Tapang, P., Shaugh-
nessy, T. K., Morgan, D. W., Wegner, C. D.,
Curtin, M. L., Sheppard, G. S., Xu, L., Davidsen,
S. K., Summers, J. B. and Carter, G. W. (1998): J.
Pharmacol. Exp. Ther., 284, 83-88.
3. Alonso, F., Gil, M. G., Sanchez-Crespo, M. and
Mato, J. M. (1982): J. Biol. Chem., 257, 3376-
3378.
4. Andersson, M. and Pipkorn, U. (1988): Eur. J.
Clin. Pharmacol., 35, 231-235.
5. Bachert, C. (2002): Allergy, 57, 287-296.
6. Bae, K., Longobardi, L., Karasawa, K., Malone,
B., Inoue, T., Aoki, J., Arai, H., Inoue, K. and
Lee, T. (2000): J. Biol. Chem., 275, 26704-26709.
7. Baroody, F. M. and Naclerio, R. M. (2000):
Allergy, 55 (64), 17-27.
8. Benveniste, J., Henson, P. M. and Cochrane, C.
G. (1972): J. Exp. Med., 136, 1356-1377.
9. Benveniste, J., Tence, M., Varenne, P., Bidault, J.,
Boullet, C. and Polonsky, J. (1979): C. R. Seances
Acad. Sci. D., 289, 1037-1040.
10. Blank, M. L., Lee, Y. J., Cress, E. A. and Snyder,
F. (1988): J. Biol. Chem., 263, 5656-5661.
11. Bousquet, J. (1998): Clin. Exp. Allergy, 28(6), 49-
53.
12. Bousquet, J., Van Cauwenberge, P., Khaltaev,
N., Aria Workshop Group and World Health
Organization (2001): 108, 147-334.
13. Bradding, P., Feather, I. H., Wilson, S., Bardin,
P. G., Heusser, C. H., Holgate, S. T. and
Howarth, P. H. (1993): J. Immunol., 151, 3853-
3865.
14. Bradding, P., Feather, I. H., Wilson, S., Holgate,
S. T. and Howarth, P. H. (1995): Am. J. Respir.
Crit. Care Med., 151, 1900-1906.
15. Braquet, P., Touqui, L., Shen, T. Y. and Var-
gaftig, B. B. (1987): Pharmacol. Rev., 39, 97-145.
16. Carceller, E., Merlos, M., Giral, M., Balsa, D.,
Almansa, C., Bartroli, J., Garcia-Rafanell, J. and
Forn, J. (1994): J. Med. Chem., 37, 2697-2703.
17. Chao, W. and Olson, M. S. (1993): Biochem. J.,
292 (3), 617-629.
18. Christie, P. E. and Henderson, W. R., Jr. (2002):
Clin. Allergy Immunol., 16, 233-254.
HISTAMINE AND PAF IN ALLERGIC RHINITIS
109
J. Physiol. Biochem., 60 (2), 2004
19. Church, M. K. (1999): Clin. Exp. Allergy, 29 (3),
39-48.
20. Ciprandi, G., Passalacqua, G. and Canonica, G.
W. (1999): Clin. Exp. Allergy, 29 (3), 49-53.
21. Cuss, F. M. (1999): Clin. Exp. Allergy, 29 (3), 54-
59.
22. Demopoulos, C. A., Pinckard, R. N. and Hana-
han, D. J. (1979): J. Biol. Chem., 254, 9355-9358.
23. Doyle, W. J., Boehm, S. and Skoner, D. P. (1990):
J. Allergy Clin. Immunol., 86, 924-935.
24. Eda, R., Sugiyama, H., Hopp, R. J., Bewtra, A.
K. and Townley, R. G. (1993): Ann. Allergy, 71,
373-378.
25. Elstad, M. R., McIntyre, T. M., Prescott, S. M.
and Zimmerman, G. A. (1991): Am. J. Respir.
Cell. Mol. Biol., 4, 148-155.
26. Enerback, L., Pipkorn, U. and Olofsson, A.
(1986): Int. Arch. Allergy Appl. Immunol., 81,
289-297.
27. Evans, T. W., Rogers, D. F., Aursudkij, B.,
Chung, K. F. and Barnes, P. J. (1988): Am. Rev.
Respir. Dis., 138, 395-399.
28. Evans, T. W., Rogers, D. F., Aursudkij, B.,
Chung, K. F. and Barnes, P. J. (1989): Clin. Sci.
(Lond), 76, 479-485.
29. Fineman, S. M. (2002): Ann. Allergy Asthma
Immunol., 88, 2-7.
30. Gibbs, B. F., Vollrath, I. B., Albrecht, C., Amon,
U., and Wolff, H. H. (1998): Naunyn Schmiede-
bergs Arch. Pharmacol., 357, 573-578.
31. Haaksma, E. E., Leurs, R. and Timmerman, H.
(1990): Pharmacol. Ther., 47, 73-104.
32. Hanahan, D. J. (1986): Annu. Rev. Biochem., 55,
483-509.
33. Hayashi, S. and Hashimoto, S. (1999): Clin. Exp.
Allergy, 29, 1593-1596.
34. Healy, D. P. (2002): Ann. Pharmacother., 36,
648-654.
35. Honda, Z., Ishii, S. and Shimizu, T. (2002): J.
Biochem. (Tokyo), 131, 773-779.
36. Howarth, P. H. (1997): Allergy, 52, 12-18.
37. Howarth, P. H., Salagean, M. and Dokic, D.
(2000): Allergy, 55, 7-16.
38. Iliopoulos, O., Proud, D., Adkinson, N. F., Jr.,
Norman, P. S., Kagey-Sobotka, A., Lichtenstein,
L. M. and Naclerio, R. M. (1990): J. Allergy Clin.
Immunol., 86, 851-861.
39. Imaizumi, T. A., Stafforini, D. M., Yamada, Y.,
McIntyre, T. M., Prescott, S. M. and Zimmer-
man, G. A. (1995): J. Intern. Med., 238, 5-20.
40. Imrie, C. W. and McKay, C. J. (1999): Baillieres
Best. Pract. Res. Clin. Gastroenterol., 13, 357-
364.
41. Ioculano, M., Squadrito, F., Altavilla, D., Canale,
P., Campo, G. M., Bussolino, F., Sardella, A.,
Urna, G. and Caputi, A. P. (1994): J. Cardiovasc.
Pharmacol., 23, 7-12.
42. Izquierdo, I., Merlos, M. and Garcia-Rafanell, J.
(2003): Drugs Today (Barc.), 39, 451-468.
43. Koltai, M., Hosford, D., Guinot, P., Esanu, A.
and Braquet, P. (1991): Drugs, 42, 9-29.
44. Konno, S., Asano, K., Okamoto, K. and Adachi,
M. (1994): Eur. J. Pharmacol., 264, 265-268.
45. Krump, E. and Borgeat, P. (1999): Adv. Exp.
Med. Biol., 447, 107-115.
46. Labrakis-Lazanas, K., Lazanas, M., Koussissis,
S., Tournis, S. and Demopoulos, C. A. (1988):
Haematologica, 73, 379-382.
47. Leggieri, E., Tedeschi, A., Lorini, M., Bianco, A.
and Miadonna, A. (1991): Allergy, 46, 466-471.
48. Leirisalo-Repo, M. (1994): Pharmacol. Toxicol.,
75 (2), 1-3.
49. Levine, A. S., Kort, H. I., Toledo, A. A. and
Roudebush, W. E. (2002): J. Androl., 23, 471-
476.
50. Marshall, G. D., Jr. (2000): J. Allergy Clin.
Immunol., 106, 303-309.
51. McIntyre, T. M., Reinhold, S. L., Prescott, S. M.
and Zimmerman, G. A. (1987): J. Biol. Chem.,
262, 15370-15376.
52. Meltzer, E. O. (1997): J. Allergy Clin. Immunol.,
99, 805-828.
53. Miadonna, A., Milazzo, N., Lorini, M., Sala, A.
and Tedeschi, A. (1996): J. Allergy Clin.
Immunol., 97, 947-954.
54. Miadonna, A., Tedeschi, A., Arnoux, B., Sala, A.,
Zanussi, C. and Benveniste, J. (1989): Am. Rev.
Respir. Dis., 140, 142-147.
55. Mincarini, M., Cagnoni, F., Canonica, G. W.,
Cordone, G., Sismondini, A., Semino, C., Pietra,
G. and Melioli, G. (2000): Allergy, 55, 226-231.
56. Misawa, M. and Iwamura, S. (1990): Jpn. J. Phar-
macol., 54, 217-226.
57. Munakata, Y., Umezawa, Y., Iwata, S., Dong, R.
P., Yoshida, S., Ishii, T. and Morimoto, C.
(1999): Clin. Exp. Allergy, 29, 1281-1286.
58. Mutoh, H., Bito, H., Minami, M., Nakamura,
M., Honda, Z., Izumi, T., Nakata, R., Kurachi,
Y., Terano, A. and Shimizu, T. (1993): FEBS
Lett., 322, 129-134.
59. Mutoh, H., Fukuda, T., Kitamaoto, T.,
Masushige, S., Sasaki, H., Shimizu, T. and Kato,
S. (1996): Proc. Natl. Acad. Sci. USA, 93, 774-779.
60. Naclerio, R. M., Proud, D., Togias, A. G.,
Adkinson, N. F., Jr., Meyers, D. A., Kagey-
Sobotka, A., Plaut, M., Norman, P. S. and Licht-
enstein, L. M. (1985): N. Engl. J. Med., 313, 65-
70.
61. Narita, S. and Asakura, K. (1993): Auris. Nasus.
Larynx., 20, 175-183.
62. Nathan, R. A. (1996): Ann. Allergy Asthma
Immunol., 77, 255-259.
63. Oppenheimer, J. J. and Casale, T. B. (2002):
Expert Opin. Investig. Drugs, 11, 807-817.
V. ALFARO
110
J. Physiol. Biochem., 60 (2), 2004
64. Park, Y. J. and Baraniuk, J. N. (2002): Clin.
Allergy Immunol., 16, 275-293.
65. Pawankar, R., Yamagishi, S. and Yagi, T. (2000):
Am. J. Rhinol., 14, 309-317.
66. Petersen, L. J., Church, M. K., Rihoux, J. P. and
Skov, P. S. (1999): Allergy, 54, 607-611.
67. Piwinski, J. J., Wong, J. K., Green, M. J., Gangu-
ly, A. K., Billah, M. M., West, R. E., Jr. and
Kreutner, W. (1991): J. Med. Chem., 34, 457-461.
68. Prescott, S. M., McIntyre, T. M. and Zimmer-
man, G. A. (1990): Thromb. Haemost., 64, 99-
103.
69. Prescott, S. M., Zimmerman, G. A. and McIn-
tyre, T. M. (1990): J. Biol. Chem., 265, 17381-
17384.
70. Prescott, S. M., Zimmerman, G. A., Stafforini, D.
M. and McIntyre, T. M. (2000): Annu. Rev.
Biochem., 69, 419-445.
71. Rachelefsky, G. S. (1998): J. Allergy Clin.
Immunol., 101, 367-369.
72. Schneider, E., Rolli-Derkinderen, M., Arock, M.
and Dy, M. (2002): Trends Immunol., 23, 255-
263.
73. Sedgwick, J. B. and Busse, W. W. (1997): Ann.
Allergy Asthma Immunol., 78, 581-585.
74. Shirasaki, H. and Asakura, K. (1990): Nippon
Jibiinkoka Gakkai Kaiho, 93, 420-427.
75. Shukla, S. D. (1992): Faseb J., 6, 2296-2301.
76. Sisson, J. H., Prescott, S. M., McIntyre, T. M.
and Zimmerman, G. A. (1987): J. Immunol., 138,
3918-3926.
77. Skoner, D. P. (2001): J. Allergy. Clin. Immunol.,
108, 2-8.
78. Snyder, F. (1990): Am. J. Physiol., 259, 697-708.
79. Snyder, F. (1995): Biochem. J., 305 (3), 689-705.
80. Storms, W.W. (2002): Ann. Allergy Asthma
Immunol., 88, 30-35.
81. Tasaka, K. (2000): Drugs Today (Barc), 36, 735-
757.
82. Tjoelker, L. W., Eberhardt, C., Wilder, C.,
Dietsch, G., Trong, H. L., Cousens, L. S., Zim-
merman, G. A., McIntyre, T. M., Stafforini, D.
M., Prescott, S. M. and Gray, P. W. (1996): Adv.
Exp. Med. Biol., 416, 107-111.
83. Togias, A., Naclerio, R. M., Proud, D., Baum-
garten, C., Peters, S., Creticos, P. S., Warner, J.,
Kagey-Sobotka, A., Adkinson, N. F., Jr., Nor-
man, P. S., et al. (1985): Am. J. Med., 79, 26-33.
84. Venable, M. E., Zimmerman, G. A., McIntyre, T.
M. and Prescott, S. M. (1993): J. Lipid. Res., 34,
691-702.
85. Walsh, G. M., Annunziato, L., Frossard, N.,
Knol, K., Levander, S., Nicolas, J. M.,
Taglialatela, M., Tharp, M. D., Tillement, J. P.
and Timmerman, H. (2001): Drugs, 61, 207-236.
86. Weimer, L. K., Gamache, D. A. and Yanni, J. M.
(1998): Int. Arch. Allergy Immunol., 115, 288-293.
87. Whatley, R. E., Fennell, D. F., Kurrus, J. A.,
Zimmerman, G. A., McIntyre, T. M. and
Prescott, S. M. (1990): J. Biol. Chem., 265, 15550-
15559.
88. Whatley, R. E., Nelson, P., Zimmerman, G. A.,
Stevens, D. L., Parker, C. J., McIntyre, T. M. and
Prescott, S. M. (1989): J. Biol. Chem., 264, 6325-
6333.
89. White, M. V. (1990): J. Allergy Clin. Immunol.,
86, 599-605.
90. Yamada, Y. and Yokota, M. (1998): Jpn. Circ. J.,
62, 328-335.
91. Zimmerman, G. A., McIntyre, T. M., Prescott, S.
M. and Otsuka, K. (1990): J. Lipid. Mediat., 2,
31-43.
92. Zimmerman, G. A., McIntyre, T. M., Prescott, S.
M. and Stafforini, D. M. (2002): Crit. Care Med.,
30, 294-301.
93. Zweiman, B., Atkins, P. C., Moskovitz, A., von
Allmen, C., Ciliberti, M. and Grossman, S.
(1997): J. Allergy Clin. Immunol., 100, 341-347.
HISTAMINE AND PAF IN ALLERGIC RHINITIS
111
J. Physiol. Biochem., 60 (2), 2004
