DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

954 Physiological and Pathological Functions of PAF. PAF
generally is viewed as a mediator of pathological events
and has been implicated in allergic asthma, endotoxic
shock, acute pancreatitis, certain cancers, dermal inflammation,
and inflammatory cardiovascular diseases such
as atherosclerosis. Dysregulation of PAF signaling or
degradation has been associated with some human diseases,
aided by data from genetically modified animals.
Reproduction and Parturition. A role for PAF in ovulation, implantation,
and parturition has been suggested by numerous studies.
However, PAF receptor–deficient mice are normal reproductively,
indicating that PAF may not be essential for reproduction.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Inflammatory and Allergic Responses. The pro-inflammatory actions
of PAF, and its elaboration by endothelial cells, leukocytes, and mast
cells under inflammatory conditions, are well characterized. The
plasma concentration of PAF is increased in experimental anaphylactic
shock, and the administration of PAF reproduces many of its signs
and symptoms, suggesting a role for the autacoid in anaphylactic
shock. Indeed, studies with PAF receptor–deficient mice confirm the
actions of PAF, and PAF-like molecules, as dominant anaphylactic
mediators. In addition, mice overexpressing the PAF receptor exhibit
bronchial hyperreactivity and increased lethality when treated with
endotoxin (Ishii et al., 2002). PAF-receptor knockout mice display
milder anaphylactic responses to exogenous antigen challenge,
including less cardiac instability, airway constriction, and alveolar
edema; they are, however, still susceptible to endotoxic shock.
Deletion of the PAF receptor augments the lethality of infection with
gram-negative bacteria while improving host defense against grampositive
pneumococcal pneumonia. PAF receptor-overexpressing
mice show increased airway responsiveness when challenged, an
effect likely mediated through generation of TxA 2
and CysLTs (Ishii
and Shimizu, 2000). PAF-AH deficiency is associated with asthma
in some populations (Stafforini, 2009).
Despite the broad implications of these observations, the
effects of PAF antagonists in the treatment of inflammatory and
allergic disorders have been disappointing. Although PAF antagonists
reverse the bronchoconstriction of anaphylactic shock and
improve survival in animal models, the impact of these agents on
animal models of asthma and inflammation is marginal. Similarly, in
patients with asthma, PAF antagonists partially inhibit the bronchoconstriction
induced by antigen challenge but not by challenges
by methacholine, exercise, or inhalation of cold air. These results
may reflect the complexity of these pathological conditions and the
likelihood that other mediators contribute to the inflammation associated
with these disorders.
Cardiovascular System. PAF is a potent vasodilator in most vascular
beds; when administered intravenously, it causes hypotension in all
species studied. PAF-induced vasodilation is independent of effects
on sympathetic innervation, the renin–angiotensin system, or
arachidonate metabolism and likely results from a combination of
direct and indirect actions. PAF may, alternatively, induce vasoconstriction
depending on the concentration, vascular bed, and involvement
of platelets or leukocytes. For example, the intracoronary
administration of very low concentrations of PAF increases coronary
blood flow by a mechanism that involves the release of a
platelet-derived vasodilator. Coronary blood flow is decreased at
higher doses by the formation of intravascular aggregates of platelets
and/or the formation of TxA 2
. The pulmonary vasculature also is constricted
by PAF, and a similar mechanism is thought to be involved.
Intradermal injection of PAF causes an initial vasoconstriction
followed by a typical wheal and flare. PAF increases vascular
permeability and edema in the same manner as histamine and
bradykinin. The increase in permeability is due to contraction of
venular endothelial cells, but PAF is more potent than histamine or
bradykinin by three orders of magnitude.
Platelets. The PAF receptor is constitutively expressed on the surface
of platelets. PAF potently stimulates platelet aggregation in vitro and
in vivo. Although this is accompanied by the release of TxA 2
and the
granular contents of the platelet, PAF does not require the presence
of TxA 2
or other aggregating agents to produce this effect. The intravenous
injection of PAF causes formation of intravascular platelet
aggregates and thrombocytopenia.
Because PAF is synthesized by platelets and promotes aggregation,
it was proposed as the mediator of COX-inhibitor-resistant,
thrombin-induced aggregation. However, no bleeding or thrombotic
phenotypes have been associated with deletion of the PAF receptor.
In addition, PAF antagonists fail to block thrombin-induced aggregation,
even though they prolong bleeding time and prevent thrombus
formation in some experimental models. Thus, PAF may
contribute to thrombus formation, but it does not function as an independent
mediator of platelet aggregation.
Leukocytes. PAF is a potent and common activator of inflammatory
cells, providing a point of convergence between the hemostatic
and innate immune systems (Zimmerman et al., 2002). PAF
stimulates a variety of responses in polymorphonuclear leukocytes
(eosinophils, neutrophils, and basophils) when it is generated in
both physiological and pathological situations. PAF stimulates
PMNs to aggregate, degranulate, and generate free radicals and
LTs. Because LTB 4
is more potent in inducing leukocyte aggregation,
it may mediate the aggregatory effects of PAF. PAF is a potent
chemotactic for eosinophils, neutrophils, and monocytes and promotes
PMN-endothelial adhesion contributing, along with other
adhesion molecular systems, to leukocyte rolling, tight adhesion,
and migration through the endothelial monolayer. PAF also stimulates
basophils to release histamine, activates mast cells, and
induces cytokine release from monocytes. In addition, PAF promotes
aggregation of monocytes and degranulation of eosinophils.
When given systemically, PAF causes leukocytopenia, with neutrophils
showing the greatest decline. Intradermal injection causes
the accumulation of neutrophils and mononuclear cells at the site
of injection. Inhaled PAF increases the infiltration of eosinophils
into the airways.
Smooth Muscle. PAF generally contracts GI, uterine, and pulmonary
smooth muscle. PAF enhances the amplitude of spontaneous uterine
contractions; quiescent muscle contracts rapidly in a phasic fashion.
These contractions are inhibited by inhibitors of PG synthesis. PAF
does not affect tracheal smooth muscle but contracts airway smooth
muscle. Most evidence suggests that another autacoid (e.g., LTC 4
or
TxA 2
) mediates this effect of PAF. When given by aerosol, PAF
increases airway resistance as well as the responsiveness to other bronchoconstrictors.
PAF also increases mucus secretion and the permeability
of pulmonary microvessels; this results in fluid accumulation
in the mucosal and submucosal regions of the bronchi and trachea.