Interactions between Leukotrienes and Other Inflammatory Mediators/Modulators in the Microvasculature

PER HEDQVIST, NARINDER GAUTAM, and LENNART LINDBOM

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

	INTRODUCTION

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Throughout its many years as a powerful smooth muscle stimulant of unknown chemical structure, slow-reacting substance of anaphylaxis (SRS-A) remained an intriguing entity, possibly implicated as a mediator of hypersensitivity reactions, in particular those concerned with allergic asthma. Elucidation of the chemical structure of SRS-A, and the realization that it was not a single substance but rather a mixture of interrelated leukotrienes (LTs), necessitated reappraisal of earlier data about the effects of SRS-A in pulmonary tissue. Furthermore, as the LT family grew larger, interest turned also to other tissues and organ systems, with the ultimate goal to disclose specific targets for the various LTs. It is now generally accepted that the LTs collectively provoke contraction of vascular and nonvascular smooth muscle, enhanced vascular permeability, and accumulation and activation of leukocytes. The LTs often operate with a potency that far exceeds that of traditional autacoids, and they have obvious key targets of action within the pulmonary and cardiovascular systems. It has been conclusively documented that LTs are important mediators in bronchial asthma, and data are accumulating that they are involved in a number of other disease states, such as rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, and cardiac disorders.

This article summarizes the microvascular actions of LTs formed via the 5-lipoxygenase pathway, and the interplay of these LTs and some other eicosanoids and histamine in the process of inflammation.

	LEUKOTRIENE ACTION IN INFLAMMATION

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Acute inflammatory reactions are characterized by a series of vascular events, including changes in vessel caliber, increased vascular permeability, and recruitment of leukocytes. These events are triggered by inflammatory stimuli, such as pathogens, injurious agents, and antigen-antibody reactions, and are mediated by substances generated in tissue fluids or released from tissue cells as preformed packages or after de novo synthesis. A role as inflammatory mediators has been ascribed to the LTs because of increased LT production during inflammation in a number of different systems (1), and their ability to evoke cardinal signs of inflammation. The vascular effects of the cysteinyl-LTs (LTC₄, LTD₄, and LTE₄) include vasoconstriction, endothelial contraction and extravasation of plasma (4). On the other hand, the most prominent action of the dihydroxy acid LTB₄ is recruitment of leukocytes (4, 5, 8), but it may also induce degranulation and lysosomal enzyme release in neutrophils (9, 10), and provoke neutrophil-dependent hyperalgesia (11).

More detailed information about the microvascular mechanisms for LT-induced inflammatory reactions has been obtained by intravital microscopy of tissues such as hamster cheek pouch, rabbit tenuissimus muscle, and rat mesentery. Thus, the cysteinyl-LTs have been shown to provoke concentration-dependent extravasation of plasma, with a potency more than 1,000 times that of histamine (4). The increase in permeability is localized almost exclusively to postcapillary venules, and electron microscopy studies have documented that markers for the plasma proteins leak out through gaps between adjacent and contracted endothelial cells (4, 7). LTB₄, on the other hand, causes leukocytes to adhere to the endothelium in venules of all sizes, and, with some latency, to emigrate to the extravascular interstitium (12). This process is accompanied by plasma leakage, which may occur without formation of visible endothelial gaps but requires intact adhesive function of the leukocytes (12). Observations indicate that LTB₄-induced leakage of plasma proteins may be separated from that of leukocyte transmigration (16). In these experiments, the kinetics of leukocyte-induced changes in endothelial barrier function were studied by means of confluent monolayers of endothelial cells (ECs), cultured on permeable membranes and mounted in a two-compartment diffusion chamber. Transendothelial chemotactic stimulation of leukocytes resting on ECs in the upper compartment induced a prompt decline in transendothelial electrical resistance (TEER), followed by an increase in protein flux and transmigration of leukocytes. Adding the chemoattractant together with leukocytes in the upper compartment provoked leukocyte adhesion, a fall in TEER and an increase in protein permeability, but no transmigration of leukocytes. Inhibition of leukocyte adhesion to the EC monolayer by pretreatment with anti-CD18 monoclonal antibody (MAb) prevented all responses to chemotactic stimulation.

	LEUKOTRIENES AS MEDIATORS OF INFLAMMATION

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Topical antigen challenge in cheek pouches of hamsters immunized to give rise to allergic type I inflammatory reactions results in a sequence of microvascular events characterized by a brief phase of arteriolar constriction, followed by arteriolar vasodilatation and extensive postcapillary extravasation of plasma. With a slower onset, the antigen challenge is also accompanied by an increase in venular leukocyte adherence and subsequently emigration of leukocytes (17). With the advent of drugs that selectively inhibit the target action or biosynthesis of the LTs, the model has been used to study the role of endogenously formed LTs in mast cell-dependent allergic inflammation. The animals were pretreated with antihistamines and inhibitors of prostaglandin biosynthesis in order to provide an experimental condition dissociated from influence of liberated histamine and prostaglandins. The results of these experiments (17) indicate a significant role for LTs as mediators of microvascular reactions in type I allergic inflammation. Thus, the acute microvascular events in response to antigen challenge, i.e., transient arteriolar constriction, followed by plasma leakage and accumulation of leukocytes, were fully mimicked by the combined action of LTB₄ and LTC₄ in low nanomolar concentrations. Second, the microvascular components of the response to antigen challenge were profoundly inhibited by antileukotrienes, in such a way that cysteinyl-leukotriene receptor type 1 (Cys-LT₁) antagonists almost abolished vasoconstriction and plasma leakage, and 5-lipoxygenase (5-LO) inhibitors substantially reduced leukocyte accumulation in addition to suppressing plasma leakage. Third, both LTB₄- and LTC₄-like immunoreactive substances were formed and released to the interstitial fluid in response to antigen challenge.

	LIPOXINS IN INFLAMMATION

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The lipoxins represent a group of arachidonic acid derivatives that may interfere with LT actions in the microvasculature. Biosynthesis of lipoxins can be initiated by the 15-lipoxygenase pathway, but their formation is also linked to LT generation, because LTA₄, unstable precursor to the LTs, may serve as substrate for intracellular and transcellular synthesis of lipoxins (22). The lipoxins have vasoregulatory properties and they stimulate generation of nitric oxide, which may then mediate a component of lipoxin-induced vasodilatation (23). Some effects of lipoxins are antagonistic to LT actions, including LTB₄-induced chemotaxis, leukocyte-endothelial cell adhesion, and plasma leakage (19, 22). Some of these effects are suggested to be due to downregulation of adhesion molecules (24). Lipoxins may thus have the potential to function as feedback modulators of LT action in inflammation.

	VASODILATING PROSTAGLANDINS IN INFLAMMATION

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The discovery that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit prostaglandin biosynthesis (25), and that the antiphlogistic potency of different NSAIDs correlates with the degree of inhibition of prostaglandin formation, has stimulated research aimed at disclosing the role of vasodilating prostaglandins in microvascular control and inflammation. It has been proposed (the two-mediator hypothesis) that vasodilating prostaglandins act in concert with permeability-increasing mediators to increase the inflammatory response (26). Accordingly, it has been shown that vasodilating prostaglandins, like several unrelated vasodilators, enhance leukocyte extravasation and accompanying leakage of plasma evoked by different chemotactic mediators (27).

However, there are numerous in vitro observations indicating that vasodilating prostaglandins can inhibit mediator release from inflammatory cells, such as neutrophils, mast cells, and macrophages, and that NSAIDs may enhance evoked release of mediators (20). Evidently, the same pattern may also be present under in vivo conditions, as noted in the hamster cheek pouch. Thus, it has been shown that NSAIDs may enhance immunologically evoked mediator release from the mast cells as well as ensuing microvascular effector responses, and that both effects are reversed by coapplication of the NSAID and low nanomolar concentrations of PGE₂ or PGI₂ (17, 18, 34).

The rational explanation for these seemingly discordant findings is that vasodilating prostaglandins operate on two distinct levels, causing inhibition of mediator release from the mast cells and enhancement of target action of liberated mediators. Through these two independent mechanisms vasodilating prostaglandins may act to strengthen or suppress inflammation, depending on prevailing local conditions such as basal blood flow and the site of prostaglandin formation.

	HISTAMINE IN INFLAMMATION

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As noted in the preceding section, vasodilating prostaglandins enhance LT-induced leakage of plasma and accumulation of leukocytes. Histamine, in its role as vasodilator, also potentiates target microvascular actions of the LTs (17). However, it has been documented that histamine and LTC₄ in threshold concentration can act synergistically to cause a dramatic increase in vascular permeability by a mechanism that is unrelated to changes in vessel tone and blood flow, and thus clearly separated from prostaglandin-mediated enhancement (35, 36). The mechanism for this synergism has not been settled, but it requires intact H₁ and Cys-LT₁ receptors, and may be related to the capacity of histamine and LTC₄ to provoke functional gaps between adjacent endothelial cells.

Observations that antihistamines may reduce allergen- induced leukocyte accumulation (37, 38) imply that histamine, which per se lacks chemotactic properties, may act in concert with chemotactic inflammatory mediators to enhance leukocyte recruitment. This possibility has been explored in the hamster cheek pouch, using a threshold concentration of LTB₄ and low-level concentration of histamine (36, 39). This combination strikingly enhanced the microvascular effects of LTB₄ with respect to both leukocyte accumulation and plasma leakage. However, PGE₂ also enhanced the responses to LTB₄, thus indicating the presence of a blood flow-dependent mechanism. Intravital microscopy studies of the microcirculation of the rat mesentery may shed some light on this flow dependency. Thus, it has been shown that leukocyte rolling along the venular endothelium represents a first critical step in the process of leukocyte recruitment, and that the degree of rolling apparently determines the magnitude of leukocyte firm adhesion to the endothelium (40). Moreover, histamine causes a significant and concentration-dependent increase in leukocyte rolling, which correlates with the histamine-induced vasodilation (36, 41). Finally, histamine causes formation of gaps in the endothelial lining (42), and it may have a direct stimulating effect on the endothelial cells promoting sustained leukocyte adhesion (43). The two latter observations may help explain why histamine appears more potent than other vasodilators, e.g., PGE₂ and acetylcholine, in enhancing chemotactically induced leukocyte recruitment.

	CONCLUSIONS

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It is well established that LTs may be released from both blood-borne and tissue-residing cells, and that they, in minute concentrations, provoke local tissue edema and accumulation of phagocytizing cells. Observations that selective inhibitors of LT biosynthesis and action attenuate important events in immunologically induced inflammation indicate that endogenous LTs may be significant mediators of inflammatory reactions. In a complex reaction, such as inflammation, a number of mediators and modulators with different targets are likely to be present. The biologic response to an external or internal stimulus is therefore not expected to be exerted by LTs alone but rather represents the composite result of interactions with the goal to maintain homeostatic control in the intact organism. Vasodilating prostaglandins, lipoxins, and histamine are examples of endogenous substances that may interact with LTs in the inflammatory process. The vasodilating prostaglandins, often referred to as proinflammatory, have the potential both to enhance and inhibit different events in inflammation. Judging from the cheek pouch model of mast cell-dependent inflammation, inhibition predominates. However, factors such as the site of prostaglandin production and the magnitude of local blood flow will influence the final result, and may in other instances change the balance in favor of enhancement. The lipoxins apparently lack ability to stimulate inflammation. Rather, a prime effect may be inhibition of neutrophil recruitment and switching of the cellular response toward monocytes, thus promoting wound healing and repair events (23). Finally, the remarkable synergism between histamine and LTs in causing extravasation of macromolecules and recruitment of phagocytizing cells may be regarded as a rapid and efficient upregulation of the host defense, but it also represents a potential risk in cases of misdirected inflammation.

	Footnotes

Correspondence and requests for reprints should be addressed to Per Hedqvist, M.D., Department of Physiology and Pharmacology, Karolinska Institutet, S171 77 Stockholm, Sweden.

Acknowledgments: Supported by grants from the Swedish MRC (14X-4342; 04P-10738), the Swedish Foundation for Health Care Sciences and Allergy Research (A98110), and the Karolinska Institutet.

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