Cooperative modulation of gastrointestinal mucosal defence
by prostaglandins and nitric oxide
John L. Wallace, PhD
Clin Invest Med 1996; 19 (5): 346-51.
[résumé]
Dr. Wallace is director of the Intestinal Disease Research Unit,
University of Calgary, Calgary, Alta.
Reprint requests to: Dr. John L. Wallace, Department of Pharmacology
and Therapeutics, University of Calgary, 3330 Hospital Dr. NW,
Calgary AB T2N 4N1; fax 403 270-3353; wallacej@acs.ucalgary.ca
Abstract
The role of prostaglandins as mediators of gastrointestinal mucosal
defence has been recognized for more than two decades. However,
there is renewed interest in the potent actions of this group
of fatty acids in modulating the mucosal immune system and inflammatory
responses. Moreover, there is a rapidly growing body of evidence
that nitric oxide is another important mediator of mucosal defence
and the mucosal immune system. In this review, the effects of
prostaglandins and nitric oxide on specific aspects of mucosal
immunocyte function (e.g., mast cell reactivity) are reviewed,
as is the evidence that these two groups of endogenous mediators
cooperate in the modulation of mucosal defence.
Depuis plus de deux décennies, le rôle des prostaglandines
en tant que médiatrices de la protection muqueuse gastro-intestinale
a été reconnu. Par contre, on note un intérêt
accru au sujet des actions puissantes de ce groupe d'acides gras
dans la modulation du système immunitaire muqueux et des
réponses inflammatoires. De plus, il apparaît de
plus en plus clairement que l'oxide nitreux est un autre médiateur
important du système immunitaire muqueux et de la protection
muqueuse gastro-intestinale. Dans cet article, nous revisons les
effets des prostaglandines et de l'oxide nitreux sur certains
aspects fonctionnels des immunocytes muqueux (par exemple, la
réactivité des mastocytes) de même que les
données suggérant que ces deux groupes de médiateurs
endogènes collaborent à la modulation de la défense
muqueuse.
[Table of contents]
The gastrointestinal tract is exposed daily to a variety of noxious
substances, ranging from digestive juices (acid, enzymes and bile)
to bacterial toxins. The ability of the mucosa to withstand damage
is attributable to a complex mucosal defence system, which includes
epithelial secretions (mucus and bicarbonate), rapid epithelial
turnover, mucosal microcirculation and the mucosal immune system.
It has been suggested that the mucosa of the intestine is in a
state of "controlled inflammation," continuously defending
against breaches of the epithelium by microbes or microbial products.
Loss of control of the inflammatory response can lead to an inappropriate
recruitment of phagocytes into the mucosa and, in turn, to mucosal
injury. Prostaglandins and nitric oxide, along with several cytokines
(e.g., interleukin-10), appear to play crucial roles in regulating
the immune response to injury in the gastrointestinal tract as
well as in modulating several of the other components of mucosal
defence.
[Table of contents]
Even in the absence of overt inflammation, the mucosa of the gastrointestinal
tract contains a substantial number of immunocytes, including
neutrophils, eosinophils, mast cells and macrophages. The number
of these cells varies considerably along the length of the digestive
tract. To some extent, this variation reflects the number of luminal
microbes in each region. As they do on other external surfaces
(e.g., skin, lungs and the urogenital tract), some of these immunocytes,
particularly mast cells and macrophages, play an important role
as "alarm cells." These cells sense the entry of foreign
matter or antigen into the lamina propria and respond by releasing
soluble mediators and cytokines that initiate a defensive inflammatory
response to prevent the foreign matter from gaining access to
the systemic circulation. Many of the inflammatory mediators and
cytokines that are released exert chemotactic effects on leukocytes,
resulting in their recruitment into the region where the immunocytes
have been activated. For example, mast cell activation, which
occurs when the cells are exposed to antigen to which the organism
has previously been sensitized, leads to the release of mediators
such as platelet-activating factor, histamine and leukotrienes.
These mediators alter mucosal blood flow and vascular permeability.
In the cases of platelet-activating factor and leukotriene B4,
eosinophils and neutrophils respectively are recruited from the
vasculature into the tissue. Although migration of leukocytes
into the tissue is primarily a defensive response, it can result
in substantial injury. The alterations in mucosal blood flow stimulated
by these mediators may also adversely affect the resistance of
the mucosa to injury induced by luminal irritants. This has been
demonstrated in experimental models of the following mast cell-derived
mediators: histamine, platelet-activating factor, peptido-leukotrienes,
tumour necrosis factor (TNF) and endothelin.[1-6] Macrophages
can also produce many of these inflammatory mediators and, therefore,
can influence mucosal integrity. Moreover, both mast cells and
macrophages can act as cytotoxic cells, using nitric oxide or
TNF to kill other cells. Although the primary targets of these
cytotoxic cells would ordinarily be microbes, these cells can
also damage the tissue of the host in some circumstances.
[Table of contents]
Prostaglandins can modulate the activity of many immunocytes,
including macrophages and mast cells. The effects of prostaglandins
or prostaglandin synthesis inhibitors on TNF release from macrophages
have been extensively studied, primarily by Kunkel and colleagues.[7,8]
Prostaglandin E2 is a potent inhibitor of TNF release and gene
expression in macrophages. On the other hand, inhibitors of endogenous
prostaglandin synthesis can increase the release of TNF.[5,9,10]
For example, administration of ulcerogenic doses of indomethacin
results in a significant increase in serum TNF levels in rats.[5,11]
It has been suggested that TNF is responsible for producing at
least a portion of the tissue injury observed after administration
of nonsteroidal anti-inflammatory drugs (NSAIDs).[5,11] Prostaglandins
can also regulate the release of other cytokines, including interleukin-1
and interleukin-8, from macrophages.[12,13]
The inhibitory effects of prostaglandins on cytokine and mediator
release are also evident when mast cells are considered. For example,
Raud[14] demonstrated that prostaglandins could partially suppress
acute mast cell-dependent inflammation. With the use of isolated
mast cells from the peritoneum and the intestinal mucosa, Hogaboam
and associates[15] demonstrated that several prostaglandins dose-dependently
inhibited the release of mediators such as histamine, platelet-activating
factor and TNF. The prostaglandins were found to be extremely
potent modulators of mast cell reactivity. Inhibitory effects
were observed at concentrations as low as 10-11 mol/L. The suppression
of mast cell reactivity by prostaglandins may contribute to the
well-documented cytoprotective effects of these agents.[16]
[Table of contents]
Neutrophil infiltration into a tissue is a hallmark of inflammation.
Although migration of neutrophils from the vasculature into the
mucosa is primarily aimed at preventing entry of foreign material
into the systemic circulation, neutrophils can also produce considerable
injury to the host tissue. Indeed, neutrophils have been implicated
in the damage associated with various disorders of the gastrointestinal
tract, including gastropathy due to NSAIDs,[17] ischemia-reperfusion
injury[18] and colitis.[19,20] These cells can further cause mucosal
injury by amplifying the inflammatory response through the release
of several chemotaxins (e.g., leukotriene B4) and reactive oxygen
metabolites. Once again, prostaglandins serve an important modulatory
role by down-regulating several neutrophil functions that contribute
to inflammation and injury. For example, prostaglandins can inhibit
neutrophil adherence to the vascular endothelium, thereby preventing
the emigration of neutrophils from the vascular space.[2123]
Prostaglandins also suppress the generation of superoxide anion
and the release of proinflammatory mediators (e.g., leukotriene
B4 and interleukin-8).[2429] The hypothesis that prostaglandins
are important physiological regulators of neutrophil adherence
is supported by the observation that NSAIDs caused an increase
in the number of neutrophils adhering to the vascular endothelium
and that this increase could be prevented by administering exogenous
prostaglandins.[22,23,30]
[Table of contents]
Studies conducted during the past few years have pointed to a
very important role played by nitric oxide as a modulator of mast
cell reactivity, yet another function in which there is an overlap
with the prostaglandins. By modulating mast cell reactivity, nitric
oxide may influence several other gastrointestinal functions,
including acid secretion and the barrier properties of the epithelium.
Kubes, Suzuki and Granger[31] first described neutrophil adherence
to the vascular endothelium after blockade of nitric oxide synthesis.
Initially, the interpretation of this observation was that removal
of a tonically produced mediator (nitric oxide) that can inhibit
neutrophil function leads to neutrophil adherence. However, careful
examination of their mesenteric venule preparations in rats led
Kubes and colleagues to another conclusion. They noted the presence
of mast cells in close apposition to the mesenteric venules. When
inhibitors of nitric oxide synthase were administered, the mast
cells appeared to degranulate.[32] This process was then proven
through measurement of serum levels of a protease specific to
mucosal mast cells in rats.[33] Inhibition of nitric oxide synthase
resulted in more than a doubling of the serum levels of this protease,
and the release could be prevented by pretreating the rats with
mast cell stabilizers.[33] The effect of blockade of nitric oxide
synthase on leukocyte adherence could be mimicked by inducing
mast cell degranulation with compound 48/80.[34] Interestingly,
blockade of nitric oxide synthesis resulted in significant changes
in intestinal epithelial barrier function.[33,35] Kanwar and associates[33]
demonstrated that permeability of the intestinal epithelium increased
markedly after blockade of nitric oxide synthase, and that this
could be reversed by pretreating the rats with mast cell stabilizers
or receptor antagonists for histamine (H1) and platelet-activating
factor, both of which could be released by mast cells. Kubes[35]
also demonstrated that exogenous nitric oxide administration (i.e.,
provision of a nitric oxide donor) prevented the epithelial barrier
dysfunction induced by blockade of endogenous nitric oxide synthesis.
Taken together, these studies suggest a role for nitric oxide
as a modulator of mast cell reactivity, which in turn can influence
both the vascular endothelium and the intestinal epithelium. The
role of nitric oxide as a modulator of mast cell reactivity was
further examined by Hogaboam and associates.[15] The release of
platelet-activating factor and nitric oxide from peritoneal mast
cells was examined with the use of an in vitro system in which
aggregation of rabbit platelets was used as a bioassay for both
mediators. The investigators found that mast cells spontaneously
released nitric oxide under these conditions. Moreover, exposure
of the mast cells to the cytokine interleukin-1 led to a rapid
and profound increase in nitric oxide release. This release appeared
to exert feedback inhibition of the release of platelet-activating
factor from the mast cell, which is consistent with the findings
of Kanwar and associates[33] that blockade of nitric oxide synthesis
led to release of platelet-activating factor. Others have demonstrated
that exposure of mast cells to exogenous nitric oxide diminishes
histamine release.[36] It has also been suggested that nitric
oxide plays a role in the regulation of gastric acid secretion.[37]
This raises the possibility that nitric oxide-induced modulation
of histamine release from mast cells has physiological relevance
to the regulation of acid secretion. It is noteworthy in this
regard that interleukin-1, which Hogaboam and associates[15] demonstrated
to be a potent stimulus of nitric oxide release from mast cells,
has been shown to inhibit gastric-acid secretion through a nitric
oxide-dependent pathway.[37]
[Table of contents]
During the past few years, researchers have generated a considerable
body of evidence that nitric oxide is an important mediator of
mucosal defence, performing many of the same functions as the
prostaglandins but also acting in a cooperative manner with prostaglandins
to increase the resistance of the mucosa to injury. Indeed, recent
evidence suggests that in circumstances in which the production
of one of these mediators is suppressed there are compensatory
increases in the production of the other. Furthermore, there is
evidence that nitric oxide and prostaglandins can modulate the
expression of enzymes responsible for the synthesis of one another.[38,39]
Both nitric oxide and prostaglandins exert cytoprotective effects
in experimental models of ulcer.[16,40,41] Nitric oxide may exert
these effects through mechanisms similar to those of the prostaglandins
(i.e., stimulation of mucus and bicarbonate secretion, maintenance
of mucosal blood flow, etc.). Suppression of nitric oxide synthesis
greatly increases the susceptibility of the gastrointestinal mucosa
to injury.[41] On the other hand, administration of nitric oxide
or nitric oxide donors reduces the severity of experimental gastric
damage[4044] and the severity of intestinal damage associated
with endotoxic shock.[45] Elevation of mucosal nitric oxide synthesis
through administration of low doses of endotoxin has recently
been shown to increase the resistance of the mucosa to injury
induced by an irritant.[46]
As mentioned earlier, there appears to be cooperation between
the nitric oxide and prostaglandin arms of mucosal defence. For
example, in impaired nitric oxide-mediated vasodilation in the
gastric mucosa, there is a compensatory increase in the reactivity
of the gastric microcirculation to prostaglandins. When the gastric
epithelium is exposed to an irritant, one of the most rapid and
important responses is an increase in mucosal blood flow. The
aim of this hyperemic response is to remove, dilute and buffer
any back-diffusing toxins or acid. This response is mediated by
sensory afferent neurons just beneath the epithelium, which are
activated by the back-diffusing acid. These neurons release the
vasodilator, calcitonin gene-related peptide, which then dilates
submucosal arterioles through a nitric oxide-dependent pathway.
In experimental portal hypertension, the hyperemic response of
the gastric microcirculation to topical application of an irritant
is impaired,[47] and as a result the stomach is much more susceptible
to injury induced by irritants.[48] However, this impairment of
the nitric oxide-dependent vasodilation pathway is to some extent
compensated for by a hyper-responsiveness to prostaglandins.[47,49]
The major clinical problem with the use of NSAIDs to treat inflammatory
conditions is that suppression of mucosal prostaglandin synthesis
leads to significant tissue damage and bleeding. Since nitric
oxide exerts many of the same actions as prostaglandins to maintain
mucosal integrity, NSAID derivatives that include a nitric oxide-releasing
moiety have been developed. These drugs have the anti-inflammatory,
analgesic, antithrombotic and antipyretic properties of native
NSAIDs but spare the gastrointestinal tract.[5052] The nitric
oxide released maintains gastric blood flow and inhibits the leukocyte
adherence that is stimulated by the NSAID portion of the molecule.[50,51]
Nitric oxide is a potent vasodilator. The amount released from
these new nitric oxide-NSAIDs is enough to protect the mucosa
but not enough to affect systemic arterial blood pressure.[50]
[Table of contents]
Although there is some redundancy in the roles of prostaglandins
and nitric oxide in mediating the various components of mucosal
defence, such as bicarbonate secretion and mucosal blood flow,
there is also some cooperation between these two groups of mediators.
For example, prolonged suppression of the synthesis of one class
of mediator appears to lead to either greater production of or
reactivity to the other class. Both prostaglandins and nitric
oxide exert important immunomodulatory activities, which may be
extremely important when the mucosa is inflamed. In the case of
the novel nitric oxide-releasing NSAID derivatives, the similarity
in the actions of prostaglandins and nitric oxide in modulating
mucosal defence may be exploited in the design of drugs with reduced
gastrointestinal toxicity.
[Table of contents]
Dr. Wallace is a Medical Research Council of Canada (MRC) Senior
Scientist, an Alberta Heritage Foundation for Medical Research
Scientist and holder of the Crohn's and Colitis Foundation of
Canada Chair in Intestinal Disease Research. The author is supported
by grants from the MRC and from the Crohn's and Colitis Foundation
of Canada. The publication of this article was supported in part
by a grant from the Fonds de la recherche en santé du Québec.
The author would like to thank the Crohn's and Colitis Foundation
of Canada for its sponsorship of the invited speakers' program.
[Table of contents]
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[Table of contents]
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