Leukotrienes in Rhinitis

PETER H. HOWARTH

University Medicine, Southampton General Hospital, Southampton, United Kingdom

	INTRODUCTION

TOP INTRODUCTION MECHANISMS OF SYMPTOM... MUCOSAL INFLAMMATION AND... EVIDENCE OF LEUKOTRIENE RELEASE... RELEVANCE OF LEUKOTRIENES TO... CONCLUSIONS REFERENCES

Allergic rhinitis is characterized by the symptoms of nasal itch, sneezing, rhinorrhea, and nasal stuffiness with, in addition, in more severe and chronic disease the development of mucosal swelling that results in impaired sinus drainage, loss of sense of smell, and alteration in eustachian tube function (1). These symptoms and disruption of normal function are consequent on the local release of mediators from activated cells within the nasal mucosa, through interactions with end-organ receptors (2). In this respect the nose differs from the lower respiratory tract in that symptom expression and disordered function are secondary to stimulation of neural, glandular, and vascular components and does not involve airway smooth muscle constriction.

	MECHANISMS OF SYMPTOM GENERATION IN RHINITIS

TOP INTRODUCTION MECHANISMS OF SYMPTOM... MUCOSAL INFLAMMATION AND... EVIDENCE OF LEUKOTRIENE RELEASE... RELEVANCE OF LEUKOTRIENES TO... CONCLUSIONS REFERENCES

Apart from a compliant anterior nasal vestibule, the nasal air passages are contained within a bony cavity and cannot be constricted by extralumenal forces, unlike the lower airways. Nasal obstruction within the upper airways is vascular in nature, arising because of engorgement of the venous sinusoids within the turbinates, which when swollen impede nasal airflow. The nasal vascular structure is complex, with arterioles beneath the basement membrane feeding subepithelial and glandular capillary networks that empty via cavernous sinusoids into draining venules. There are also anteriovenous (a-v) anastomoses diverting blood directly from the arterial to the venous system. It has been estimated that under normal conditions 60% of the total nasal blood flow is shunted through these a-v anastomoses. The cavernous sinuses, which comprise a plexus of venous capacitance vessels, are most dense in the inferior and middle turbinates. Their capacitance volume is under neural regulation, with intrinsic sympathetic tone limiting the sinusoidal capacity.

The nasal vasculature can also be influenced by humoral factors. Such factors may either constrict the sinusoids and improve airflow or conversely, as is more likely in disease, increase nasal blood flow and restrict venous sinusoidal drainage and thereby induce nasal congestion. This effect may be due to a direct action on the vasculature or may arise indirectly after sensory neural stimulation. Activation of both reflex cholinergic pathways as well as the antidromic release of neuropeptides from nonadrenergic noncholinergic neural networks can lead to vasodilation. The local release of neuropeptides such as substance P, calcitonin gene-related peptide, and neurokinin A can induce vasodilation either through a direct effect on the vasculature or indirectly through their ability to modify sympathetic ganglionic neurotransmission. In addition to the influence of humoral factors on the state of engorgement of the nasal venous tissue, such factors may also alter vascular permeability and, by enhancing plasma protein extravasation, contribute to anterior nasal secretions. Superficial fenestrated capillaries are found beneath the basement membrane and around glands. An expansion of the interendothelial pore size allows unfiltered plasma to leak into the surrounding tissue on account of the intravascular hydrostatic pressure. The degree of extravasation will thus be determined by the active separation of the endothelial cells, the transendothelial pressure gradient, and the magnitude of blood flow. A redirection of the blood flow from a-v anastomoses toward the superficial capillary network would favor plasma protein exudation.

Anterior nasal secretions will also be derived from discharge from the goblet and serous glands within the airway epithelium and from submucous and anterolateral deep glands within the airway submucosa. Glandular secretion is under neural regulation, predominantly parasympathetic. Thus stimulation of the afferent sensory neurons results in reflex glandular secretion (3, 4). In addition, stimulation of sensory nerve endings induces nasal discomfort/itch and also, with some stimuli, sneezing.

	MUCOSAL INFLAMMATION AND POTENTIAL LEUKOTRIENE GENERATION IN RHINITIS

TOP INTRODUCTION MECHANISMS OF SYMPTOM... MUCOSAL INFLAMMATION AND... EVIDENCE OF LEUKOTRIENE RELEASE... RELEVANCE OF LEUKOTRIENES TO... CONCLUSIONS REFERENCES

Allergic rhinitis is characterized by mucosal inflammation (2) with an accumulation of mast cells and eosinophils within the airway epithelium and leukocytes, in particular eosinophils, within the submucosa (5). Nasal smears in seasonal rhinitis have also identified an increase in surface basophils (8, 9). These inflammatory cells are in an activated state, with ultrastructural features on transmission electron microscopy of degranulation. All these cells have the capability of generating leukotriene mediators in addition to their ability to release other mediators that are also of potential relevance to symptom generation in rhinitis, such as histamine, prostaglandins (PGs), and kinins.

Mast cells generate leukotriene C₄ (LTC₄) as their major 5-lipoxygenase product, in the range of 5-30 ng/10⁶ cells (10, 11). It is potentially possible that larger quantities may be generated and released in vivo, as studies of cultured human lung mast cells suggest that immunologic LTC₄, LTB₄, and PGD₂ release from these cells, cocultured with fibroblasts, is increased in comparison with recently dispersed and similarly activated cells (12). It is likely that cytokines generated from the fibroblast support matrix, such as stem cell factor or nerve growth factor, which promote mast cell growth and development, provide a microenvironment that influences 5-lipoxygenase activity (13). Basophils have the potential to generate comparable quantities of LTC₄ as mast cells (16, 17). Human eosinophils also contain lipoxygenase enzymes. The major 5-lipoxygenase product of arachidonic acid cleavage from the cell phospholipid membrane is LTC₄, with lesser quantities of LTB₄ and LTD₄ also being synthesized (18). Human eosinophils also possess 15-lipoxygenase activity, generating in vitro 15-hydroxyeicosatetraenoic acid (15-HETE) and 5-, 8-, and 14,15-dihydroxyeicosatetraenoic acid (14,15-DHETE) (19, 20). The ability of eosinophils to release LTC₄ is greatly enhanced if these cells have been primed by cytokines such as interleukin 3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (21). As human eosinophils can generate IL-3, IL-5, and GM-CSF (22, 23), this may thus serve an autocrine function, enhancing their leukotriene synthesis.

	EVIDENCE OF LEUKOTRIENE RELEASE IN RHINITIS

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Nasal lavage has been used to recover nasal airway lining fluid to investigate changes in leukotriene levels in this biological fluid in relationship to disease. This has been undertaken both under challenge situations (allergic and nonallergic) as well as in naturally occurring disease.

Nasal Allergen Challenge

Several studies have identified clear increments in LTC₄, LTD₄, and LTE₄ levels in nasal lavage fluid in association with the immediate nasal response (24). This is accompanied by lavage changes in histamine, tryptase, and prostaglandin D₂ indicative of mast cell degranulation. Repeated nasal lavage sampling after allergen challenge has revealed a peak in LTC₄ immunoreactivity 5 min postchallenge, which remains elevated 30 min postchallenge but returns to baseline levels by 60 min (27). This peak in LTC₄ recovery and its subsequent decline is paralleled by subjective reporting of nasal obstruction, rhinorrhea, nasal itch, and sneeze. The specificity of these sulfidopeptide-leukotriene changes for the allergic response has been suggested both by the lack of change in LTC₄ levels in nasal lavage in rhinitic subjects after saline, methacholine (26), or bradykinin (28) nasal challenge and, by the failure to detect elevations in nonatopic healthy volunteers, with nasal allergen challenge (29).

Allergen-related increments in LTB₄ and 15-HETE are also described during the immediate nasal response (30, 31). Repeated nasal lavage 4-12 h postchallenge reveals a second increment in both LTB₄ and LTC₄ (30, 32). There is no increase in tryptase or PGD₂ during these and later time points after nasal allergen challenge although nasal lavage histamine levels increase. As tryptase and PGD₂ are both mast cell derived but histamine may be mast cell or basophil derived, these findings have been interpreted as indicating the relevance of basophil degranulation to the late nasal response. Consistent with this is the increased recovery of basophils but not mast cells in lavage during the late response (33). The late changes in LTB₄ do not, however, appear specific for the challenge, as late elevations in this arachidonic acid metabolite can be identified in nonatopic as well as atopic individuals after nasal allergen challenge and thus are a reflection of the repeated nasal lavage procedure.

Nonallergen Challenge

In addition to elevations in peptide-leukotrienes in nasal lavage after allergen challenge, immediate changes in LTs are also described during the nasal response to cold air (34) and to nasal acetylsalicylic acid (ASA) challenge in aspirin-sensitive but not aspirin-insensitive rhinitic subjects or in healthy controls (35, 36). In contrast to allergen-induced changes, which resolve by 60 min postchallenge, ASA-induced changes in LTs are still evident 60 min postchallenge (36). This increase in leukotrienes in nasal lavage fluid is coincidental with the reporting by the sensitive patients of increased nasal secretion and nasal blockage, along with the identification of a significant increase in albumin levels in the lavage. Parallel measurements of PGE₂, PGF₂, PGD₂, 15-HETE, and LTB₄ have also been undertaken in association with saline and ASA challenge (36). No change in LTB₄ levels is apparent despite the increase in LTC₄/LTD₄. Consistent with the inhibitory effect of ASA on cyclooxygenase enzymes, through its acetylation of the critical serine residue required for arachidonate binding by the enzyme, pretreatment induces a decrease in the concentration of PGE₂, PGF₂, and PGD₂ in the lavagate. These changes, with the exception of that for PGE₂, are, however, all solely present in the ASA-insensitive patients, with no change in PGF₂ or PGD₂ lavage levels evident in ASA-sensitive patients. There is thus no simple relationship evident between cyclooxygenase inhibition and enhanced LT production, as no change in lavage levels of peptide-leukotrienes was evident in the ASA-insensitive subjects.

Naturally Occurring Disease

Elevated levels of immunoreactive LTC₄/LTD₄ have been reported in nasal lavage fluid in both perennial allergic rhinitis (37) and in seasonal allergic rhinitis (38). Elevated levels of leukotrienes are also reported in nasal polyp tissue (39) a disease associated with tissue eosinophil recruitment.

	RELEVANCE OF LEUKOTRIENES TO DISEASE PATHOGENESIS IN RHINITIS

TOP INTRODUCTION MECHANISMS OF SYMPTOM... MUCOSAL INFLAMMATION AND... EVIDENCE OF LEUKOTRIENE RELEASE... RELEVANCE OF LEUKOTRIENES TO... CONCLUSIONS REFERENCES

An understanding of the relevance of lipid mediators within the nose has been determined both from topical challenge studies and from investigations of the effects of pharmacological intervention.

Nasal Challenge Studies

Nasal insufflation studies show that both LTC₄ and LTD₄ induce an increase in nasal airway resistance (NAR), as measured by rhinomanometry (27, 40, 41). The nasal obstructive response to LTD₄ is more prolonged than that obtained with histamine when the two agonists are adjusted to produce a similar maximal response (40). Studies to investigate effects of these two mediators within the nose have been undertaken both in asymptomatic grass pollen-sensitive subjects (27) and in house dust mite-sensitive perennial rhinitics (40). In the former group, single-dose challenges suggested that for a comparable maximal increase in NAR, LTC₄ was approximately 10 times as potent as histamine on a weight-per-volume basis. In contrast, the study of 14 patients with active rhinitis indicated that on a weight-per-volume basis LTD₄ was 5,000 times as potent as histamine in achieving a 150% increase in NAR (40).

The nasal challenge studies with LTC₄ and LTD₄ have consistently identified no effect on nasal pruritis or sneezing, in contrast to the effects of nasal histamine insufflation. Although one study reported an acute nasal secretory response with LTD₄ nasal challenge (40), which was minimal in comparison with histamine, this has not been identified in other studies. It is possible that this small change in anterior nasal secretions could be accounted for by an increase in nasal vascular permeability. Laser Doppler flow studies within the nose have identified that, in addition to the effects on the venous sinusoids within the turbinates, there is also a dose-related increase in nasal mucosal blood flow (41). Leukotriene D₄ nasal challenge over a concentration range of 10-40 µM (approximately 5-20 µg) induces a 10-15% increase in mucosal blood flow. A similar change in mucosal blood flow was identified when the same concentrations of histamine were applied topically to the nose in the same subjects.

Influence of Therapeutic Intervention

The effects of leukotriene receptor antagonists or 5-lipoxygenase inhibitors have been investigated in a limited number of studies in both the allergen challenge setting and in clinical rhinitis.

Nasal challenge. An early study, investigating the nasal protective effects of an oral LTD₄ antagonist, L-649,923, failed to demonstrate any protective effect on the acute nasal response to allergen challenge (42). This lack of effect likely reflects the inefficacy of this compound at the dose administered, rather than the noninvolvement of leukotrienes, as subsequent studies with 5-lipoxygenase inhibitors in a nasal allergen challenge setting have identified airway-protective effects (43, 44). Both the 5-lipoxygenase inhibitor zileuton and the subsequently developed, more potent 5-lipoxygenase (5-LO) inhibitor A78773 have been reported to modify allergen-induced nasal congestion, with no significant influence on induced sneezes or nasal itch (43, 44). This suggests that leukotrienes are predominantly involved in allergen-induced vascular changes rather than in stimulation of afferent sensory neural pathways. This vascular effect is also indicated by the protective effect of A78773 on allergen-induced changes in plasma protein exudation (44). The 5-LO inhibitor zileuton has also been shown to inhibit nasal symptom expression and the lavage increase in leukotrienes associated with positive aspirin challenge in salicylate-sensitive subjects (45). No studies have investigated the influence of therapeutic intervention on the cellular components of inflammation in atopic upper airways disease. The identification that an LTD₄ antagonist, MK-571, partially inhibits allergen-induced eosinophil recruitment in the guinea pig conjunctiva (46) does, however, suggest a potential for LT receptor antagonists or 5-LO inhibitors to modulate not only the plasma protein extravasation in allergic airway inflammation but also to influence tissue cell recruitment.

Clinical disease. There is limited information concerning the effects of leukotriene receptor antagonists in naturally occurring disease and the data available are conflicting. One initial double-blind, randomized, placebo-controlled study during the pollen season reported that the oral LT receptor antagonist, zafirlukast, reduced the level of symptom reporting (approximately 20-30% reduction) in pollen-sensitive seasonal rhinitis (47). What was surprising from this study, in view of the information available from the allergen challenge studies, was that this compound reduced not only nasal obstruction but also sneezing and runny nose. This improvement was not consistent, however, as the study investigated four separate doses of zafirlukast (10, 20, 40, and 100 mg) and only the 20- and 40-mg doses had this protective effect, with the 100-mg dose being no different from placebo. A subsequent, more extensive study of seasonal allergic rhinitis with the LT receptor antagonist montelukast at two doses, 10 and 20 mg, failed to identify any significant effect on rhinitis symptom reporting relative to placebo in a 2-wk treatment period (48). Interpretation of this study is also difficult, however, as a positive treatment control with the H₁-antihistamine loratadine, in a parallel group of patients was also no different from placebo in reducing nasal symptom reporting. The combination of montelukast (10 mg) with loratadine (10 mg) was also assessed in this study as a further treatment group. This combination was significantly better than placebo in reducing symptom expression in rhinitis and also in improving a Quality of Life score. Interestingly, both montelukast and loratadine as sole therapies were found also to improve Quality of Life scores, in comparison with placebo, despite their apparent lack of effect in reducing rhinitis symptom scores.

Although the clinical information is limited, these studies suggest that drugs that modify the actions of leukotrienes are likely to have an insignificant role as a sole therapy in rhinitis, but that on account of their complementary modification of the disease that the combination of H₁ and Cys-LT₁ receptor antagonists are likely to have a greater effect in modifying disease symptom expression than either receptor antagonist administered as a single therapy. Further studies assessing this in both seasonal and perennial disease are thus warranted. The appreciation that prostaglandins and kinins, which are also released in association with the disease, can also contribute to nasal symptom expression, in particular nasal blockage, may, however, limit the complete efficacy of such an oral combination.

	CONCLUSIONS

TOP INTRODUCTION MECHANISMS OF SYMPTOM... MUCOSAL INFLAMMATION AND... EVIDENCE OF LEUKOTRIENE RELEASE... RELEVANCE OF LEUKOTRIENES TO... CONCLUSIONS REFERENCES

It is thus evident that leukotrienes, released in concert with mucosal inflammation, contribute to rhinitis. Their release is evident in both naturally occurring and induced rhinitis and their involvement can be implicated both from challenge studies and from the limited information available from studies involving specific therapeutic intervention. With respect to symptom generation, their major effect appears to be on the nasal vasculature, in inducing nasal congestion and plasma protein exudation. The generation of these mediators in the allergic response is thus one explanation for the lack of benefit of H₁-antihistamines in the treatment of nasal congestion, in contrast to the benefit of this mode of therapy in relieving nasal itch and sneeze and in reducing anterior nasal secretions (49, 50). The limited clinical data raise the possibility of more complex interactions in disease pathogenesis, with some reported modification of neural as well as vascular symptoms. In this respect there appears to be a complementary benefit when an LT receptor antagonist and an H₁ receptor antagonist are coadministered. This role of combination oral therapy warrants further investigation in rhinitis.

	Footnotes

	References

TOP INTRODUCTION MECHANISMS OF SYMPTOM... MUCOSAL INFLAMMATION AND... EVIDENCE OF LEUKOTRIENE RELEASE... RELEVANCE OF LEUKOTRIENES TO... CONCLUSIONS REFERENCES

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