Systemic immunologic and inflammatory aspects of allergic rhinitis.

Allergic rhinitis is a common chronic condition that is characterized by inflammation of the nasal mucosa. Although allergic rhinitis is a condition with upper respiratory symptoms, there is a growing body of evidence to suggest that allergic rhinitis may be linked to the development of systemic allergic manifestations that include allergic asthma. The evidence reveals that individuals with allergic rhinitis are sensitized to the eliciting allergens and exhibit cutaneous and respiratory hypersensitivity responses on exposure to the allergen. On exposure to a nasal allergen, circulating immunoglobulin E levels increased and remained elevated 2 weeks after the initial provocation. Patients with allergic rhinitis exhibit peripheral eosinophilia and basophilia, the magnitude of which correlates with the severity of symptoms. Additionally, there are several links between allergic rhinitis and asthma. First, 85% to 95% of patients with allergic asthma report rhinitis symptoms, and the severity of the 2 conditions increases in parallel on exposure to an allergen. Second, nasal administration of allergens can provoke impaired lower airway airflow in 25% to 30% of individuals and cause airway eosinophilia, as evidenced by increased numbers of eosinophils in sputum and mucosal biopsy specimens. Third, the treatment of seasonal allergic rhinitis with both systemic (eg, antihistamines) and local agents (eg, glucocorticosteroid analogues) can alleviate the symptoms of asthma. In summary, evidence that associates allergic rhinitis with systemic immunologic and inflammatory processes is growing, thereby warranting further in-depth investigation.

Inhibition of the response to nasal provocation with bradykinin by HOE-140: efficacy and duration of action.

The present studies were undertaken as a first step to evaluate the potential usefulness of the bradykinin antagonist HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis. Intranasal single-dose administration of HOE-140, at doses up to 500 micrograms, was safe and well tolerated. Bradykinin-induced symptoms and increased vascular permeability could be inhibited, in a dose-dependent manner, by preadministration of HOE-140 5 min prior to kinin challenge. The results of dose-ranging experiments suggested that bradykinin and HOE-140 were approximately equipotent at bradykinin receptors. Preadministration of HOE-140 2 h before kinin challenge caused a significant but much weaker level of inhibition than that seen with 5-min preadministration. Comparison of data with those obtained during dose-ranging studies suggested that more than 90% of the administered HOE-140 was lost during this 2-h period. We conclude that topical HOE-140 is an effective inhibitor of the effects of bradykinin on the nasal mucosa but that the short duration of action of this drug may severely limit the utility of HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis.

Allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine.

Bradykinin reduces airflow in asthmatic patients via indirect mechanism(s), possibly involving sensory nerve stimulation and increased vascular permeability. We hypothesized that allergen inhalation, which affects reactivity of nerves and vessels, would differentially alter reactivity to bradykinin and the smooth muscle spasmogen methacholine. We compared reactivity to methacholine and bradykinin 1, 2, 4, 7, 11, and 14 days after allergen provocation in 12 atopic asthmatic patients with stable baseline reactivity to bradykinin. Maximal allergen-induced shifts from baseline in reactivity were 0.73 +/- 0.12 log unit for bradykinin compared with 0.27 +/- 0.13 log units for methacholine (P = 0.0005). Nine subjects showed significant increases in bradykinin reactivity, with four subjects increasing reactivity by > 1 log unit. Moreover, the maximal mean change in bradykinin reactivity occurred 2 days postallergen. Thus, allergen-induced changes in reactivity to bradykinin and methacholine differ in magnitude and time course. Bradykinin inhalational challenge provides a sensitive index of the airway's response to allergen.

Nonallergic rhinitis. Pathophysiology and models for study.

Nonallergic rhinitis is a diagnosis of exclusion which is given to patients who suffer perennial nasal congestion, rhinorrhea, and/or sneezing with no identifiable allergic etiology. Because there is still no clear understanding of the pathophysiology, it is possible that a number of different disease processes may be included within this clinically defined entity. This report does not attempt to present an overall discussion of the clinical approaches to patients with nonallergic rhinitis. Instead, an outline is presented of various research approaches which may be used in its study. A number of nasal provocation models using nonallergic stimuli are available for application in the laboratory. These include intranasal methacholine challenges, intranasal histamine challenges, nasal inhalation of cold dry air, and intranasal capsaicin challenges. These models provide certain insights into mechanisms of nonallergic hyper-responsiveness. An additional approach to the study of nonallergic rhinitis is to examine available therapies, allowing the clinician to evaluate various pathways of importance in the disease process. These approaches provide a certain understanding of this common but perplexing entity, although further study is still required.

The human nasal response to capsaicin.

Airway sensory nerves play a role in reactions to inhaled allergens, irritants, and physical stimuli. Capsaicin, the pungent principle of hot peppers, stimulates a subcategory of sensory nerves. To study the consequences of selective activation of airway sensory nerves in the human nose, we administered capsaicin nasal challenges to eight volunteers (four normal subjects and four subjects with perennial allergic rhinitis). Capsaicin (20 mumol/L), when sprayed into the nose, induced burning, rhinorrhea, and lacrimation. Capsaicin also induced a significant increase in total protein content of nasal lavage fluid after challenge compared with vehicle (increase from before challenge to 1 minute after challenge, 172 +/- 55 vs 46 +/- 29 micrograms/ml, p < 0.001). In contrast to many animal studies, capsaicin did not increase vascular permeability in the airway, because albumin content of nasal lavage fluid was not increased (p = 0.86). On the other hand, lactoferrin, a marker of glandular secretion, was increased (p < 0.005). Repetitive capsaicin challenge every 10 minutes led to tachyphylaxis of symptoms, total protein secretion, and lactoferrin secretion. Compared with vehicle, unilateral capsaicin (6 mmol/L) disk challenge induced significant secretion both ipsilateral (21.3 +/- 4.2 vs 4.9 +/- 2.1 mg, p < 0.01) and contralateral (18.2 +/- 4.4 vs 7.4 +/- 1.9 mg, p < 0.04) to challenge. Thus we have shown that capsaicin challenge to the human nose leads to airway sensory nerve activation. Further, we have demonstrated that capsaicin stimulates a predominantly central neuronal response and that the induced secretory response is of glandular rather than vascular origin.

Reflex activation of nasal secretion by unilateral inhalation of cold dry air.

Exposure to cold dry air induces rhinorrhea and other nasal symptoms in many persons. To evaluate whether this response involves a neurogenic component, we delivered a unilateral cold dry air (UniCDA) nasal challenge to volunteers with previously documented reactivity to cold dry air. We measured their nasal secretory responses bilaterally using small filter paper discs to absorb secretions from the nasal mucosa. UniCDA increased nasal secretion both ipsilateral (p < 0.001) and contralateral (p < 0.001) to the challenge when compared with control challenge. Topical atropine (0.225 mg), a muscarinic antagonist, inhibited ipsilateral secretion (p < 0.002) when given ipsilateral to UniCDA. When atropine was given contralateral to UniCDA, there was a trend toward reduction of contralateral secretion but no effect on ipsilateral secretion. Topical anesthesia with lidocaine given ipsilateral to UniCDA inhibited ipsilateral (p < 0.02) and contralateral (p < 0.05) secretion immediately after challenge. Topical anesthesia did not inhibit methacholine-induced nasal secretion. Thus, UniCDA stimulates reflex secretion both ipsilateral and contralateral to challenge which is inhibitable by interrupting either the efferent or the afferent arm of the reflex arc. This human in vivo model supports the importance of neural mechanisms in airway responsiveness to an environmental stimulus.

Local application of atropine attenuates the upper airway reaction to cold, dry air.

In some individuals, inhalation of cold, dry air (CDA) provokes symptoms of rhinitis, accompanied by an increase in the levels of inflammatory mediators and markers of plasma leakage of recovered nasal lavages. Because rhinorrhea is a major component of this reaction and because nasal glands are heavily innervated by the parasympathetic system, we assessed the effect of atropine on the nasal reaction to CDA. Using a double-blind, randomized, crossover design, we administered a total dose of 0.5 mg of atropine or placebo intranasally to 18 volunteers before provocation with CDA. The reaction was monitored with symptom scores and by measuring the concentrations of histamine, N-alpha-p-tosyl-L-arginine methyl ester (TAME)-esterase activity and albumin, as well as the osmolality of lavage fluids before and after the provocation. Atropine significantly reduced rhinorrhea, the levels of histamine, and TAME-esterase activity as well as the osmolality of recovered lavage fluids, but had no effect on nasal congestion or albumin. Even with atropine, however, rhinorrhea and TAME-esterase activity were still significantly increased over the prechallenge baseline. Our results demonstrate that atropine-sensitive parasympathetic efferent pathways contribute to the CDA-induced rhinitis. We speculate that (1) the glandular and the vascular events of the upper airway reaction to dry air have different pathophysiologic mechanisms; (2) a significant component of TAME-esterase activity in lavage fluids may be of glandular origin; and (3) in addition to parasympathetic nerve activation, other mechanisms are involved in the upper airway reaction to dry air. The mechanism(s) leading to the reduction of histamine is unknown.

Tryptase and histamine as markers to evaluate mast cell activation during the responses to nasal challenge with allergen, cold, dry air, and hyperosmolar solutions.

We have used assays for histamine and for the specific mast cell enzyme, tryptase, to examine the response of the nasal mucosa to provocation with several different stimuli and to evaluate the reliability of histamine as a marker of mast cell activation. High levels of histamine detected in baseline lavages of some subjects are not associated with any detectable tryptase, suggesting they are not mast cell derived. During pronounced immediate allergic responses, however, mast cell degranulation clearly occurs, and a striking correlation between histamine and tryptase is observed. This correlation is weaker when a more modest allergic response is induced, possibly reflecting differential diffusion of the two mediators across the epithelium. Provocation of susceptible individuals with cold, dry air leads to increased recoveries of both histamine and tryptase, confirming that mast cell degranulation occurs during this reaction. Although hyperosmolarity of the nasal mucosa may contribute to mast cell degranulation induced by cold, dry air, a brief exposure of the nasal cavity to hyperosmolar mannitol was not associated with measurable production of tryptase. The combined use of histamine and tryptase measurements can therefore provide useful evidence regarding the role of mast cell activation in the pathogenesis of inflammatory responses.

The role of leukotrienes in allergic rhinitis: a review.

Leukotrienes are potent proinflammatory mediators. Our understanding of their role in allergic rhinitis has increased, but further, extensive investigation is required. The sulfidopeptide LTs are generated during the immediate response to antigen provocation and are probably increased during the late inflammatory phase and during seasonal exposure. The source of LTC4 in the early allergic reaction includes the mast cell, but other cell types may also contribute. LTD4 causes nasal congestion and increased blood flow, but not sneezing or significant rhinorrhea. Studies in which LT generation was pharmacologically reduced support a role for these mediators in allergic rhinitis. There is now a need to evaluate the more potent, recently developed, LT antagonists in rhinitis. These agents should help establish the relative importance of LTs to the many other inflammatory mediators that are implicated in the pathogenesis of allergic rhinitis. Such knowledge will broaden and improve our choice of therapeutic modalities for this disease.

Steroid-induced reduction of histamine release does not alter the clinical nasal response to cold, dry air.

In some persons, cold, dry air (CDA) provokes symptoms of rhinitis that are associated with increased levels of histamine and other inflammatory mediators in nasal lavages. Because the patterns of mediators released during the early reaction to antigen and CDA-induced rhinitis are similar, we believe that mast cell activation is part of the reaction to CDA. In view of our previous finding that 1-wk pretreatment with topical steroids reduced symptoms and mediator release in the early nasal response to antigen of allergic subjects, we examined the effect of beclomethasone dipropionate on the response to CDA. Using a double-blind, crossover design, 84 micrograms of beclomethasone or placebo were administered in each nostril twice a day to 13 volunteers for 7 days prior to CDA challenge. The reaction to CDA was monitored by measuring the levels of histamine, N-alpha-p-tosyl-L-arginine methyl ester (TAME)-esterase activity and albumin in nasal lavages before and after provocation. Overall symptom scores, as well as scores for rhinorrhea and congestion, were also obtained. Cold, dry air challenge resulted in elevation over baseline of all parameters after placebo pretreatment. After beclomethasone, a significant reduction in histamine levels, but not in TAME-esterase activity or albumin levels or in number of symptoms, was observed. These results indicate that 1-wk pretreatment with beclomethasone affects mast cells, reducing histamine release after CDA, as it did in antigen-induced rhinitis. They also indicate that histamine may not be essential for the development of the immediate nasal reaction to CDA.

In vivo and in vitro effects of antihistamines on mast cell mediator release: a potentially important property in the treatment of allergic disease.

A nasal antigen challenge model of allergic individuals was used to evaluate whether antihistamines could inhibit human mast cell and basophil mediator release in vivo. In placebo-controlled trials, topically applied azatadine base, a tricyclic antihistamine with in vitro antirelease action, effectively reduced symptoms and mediator levels in nasal lavage fluids after antigen challenge, suggesting mast cell inhibition. Both terfenadine and cetirizine, systemically administered antihistamines, were clinically effective in reducing sneezing and changes in vascular permeability. Only terfenadine significantly reduced histamine in antigen-induced nasal secretions. However, cetirizine did reduce the level of leukotriene C4 in these fluids. These results indicate that some antihistamines may be capable of suppressing mediator release from nasal mast cells. The significance of this property in those compounds' overall clinical effect is unclear because of their other concomitant activities.

The osmolality of nasal secretions increases when inflammatory mediators are released in response to inhalation of cold, dry air.

Inhaling cold, dry air nasally induces in some persons symptoms of rhinitis that are associated with an increase in the level of mast-cell-associated mediators in nasal lavages. The present study, directed at understanding the mechanism of this reaction, showed that 9 subjects who displayed symptoms and inflammatory mediator release had significant (p less than 0.01) increments in nasal fluid osmolality, whereas the osmolality of the fluids of 6 subjects unaffected by cold, dry air challenge did not differ from baseline. Significant correlations were found between the mediator concentration and the osmolality of recovered nasal lavages (rs = 0.617, p less than 0.02; rs = 0.679, p less than 0.01 for histamine and TAME-esterase(s), respectively). No changes in the osmolality of nasal secretions were found in atopic subjects undergoing nasal challenge with antigen, despite the generation of symptoms and significant elevations in the levels of inflammatory mediators in their nasal lavages. Because increasing the osmolality of the medium surrounding isolated mast cells in vitro triggers mediator secretion, these observations support the concept that the response to cold, dry air nasal inhalation is caused by the release of mediators secondary to an increase in the osmolality of the mucosal secretions.

Theophylline reduces histamine release during pollen-induced rhinitis.

In an attempt to understand how theophylline achieves its in vivo therapeutic effect, a double-blind crossover study of the effect of theophylline on the immediate response of the upper airways to challenge with antigen was performed. Ten subjects with allergic rhinitis were challenged with increasing doses of antigen extract, and their responses were assessed by counting the number of sneezes and measuring the level of histamine, N-alpha-p-tosyl-L-arginine-methyl ester-esterase activity, and kinin in nasal secretions. One-week premedication with theophylline led to serum levels in the therapeutic range (8 to 21 micrograms/ml). There were significant reductions in both the physiologic response to antigen challenge and the appearance of mediators in secretions after drug administration as compared to placebo. These data suggest that theophylline, at therapeutic blood levels, achieves at least part of its in vivo efficacy by reducing the release of histamine and other mediators from mast cells/basophils.

Local generation of sulfidopeptide leukotrienes upon nasal provocation with cold, dry air.

In order to assess whether sulfidopeptide leukotrienes are generated following nonimmunologic stimulation of inflammatory cells in vivo, 11 subjects complaining of symptoms of rhinitis when exposed to cold and dry environments were challenged by nasal breathing, first with warm, moist air and then with cold, dry air. Nasal lavages with normal saline were performed before and after each exposure. Immunoreactive leukotriene in the lavage fluids was significantly increased following cold, dry air exposure (2.6 ng/ml) compared with that after warm, moist air exposure (0.7 ng/ml) or at baseline (0.4 ng/ml) (p less than 0.01 in both instances). Six more subjects, denying cold-air sensitivity, were subjected to the same protocol and had no mediator and symptom score changes after cold, dry air challenge. Leukotriene changes after cold, dry air were highly concordant with increments in histamine, prostaglandin D2,N-alpha-tosyl-L-arginine methyl ester (TAME) esterase(s) activity and symptom scores (p less than 0.001). Separation of leukotrienes by high performance liquid chromatography in the nasal washes of 3 subjects showed variable amounts of LTC4, D4, and E4, suggesting metabolism of the former to the latter 2. To our knowledge, this is the first in vivo demonstration of leukotriene production in response to a physical stimulus, and it suggests a possible role of these and other inflammatory mediators in pathologic conditions, such as exercise-induced asthma, that involve physical causative factors.

Kininogens in nasal secretions after allergen challenge.

Allergic individuals and nonallergic controls were subjected to nasal challenge with allergen; and nasal washes, obtained before and after challenge, were assayed for high molecular weight kininogen (HMWK), total kininogen (TK), albumin and kinins. Following challenge of allergic individuals, HMWK, TK, kinin and albumin all increased dramatically, correlating (p less than 0.001) with the onset of clinical symptoms and with increases in histamine and TAME-esterase activity. No such increases were seen upon challenge of nonallergics. The time course of appearance and disappearance of the kininogens, kinins and albumin were all highly correlated (p less than 0.001 in each case) by linear regression analysis, as were the increases in kinin and each of the proteins during antigen titrations. For each individual, the plasma ratio of HMWK/TK was similar to the ratio of these two proteins in post-challenge nasal washes from the same individual. These findings are consistent with the hypothesis that, during the allergic reaction, vascular permeability increases, allowing a transudation of kininogens from plasma into nasal secretions, where they can provide substrate for kinin-forming enzymes.

Kinins as mediators of human allergic reactions.

We have demonstrated that kinins are generated following nasal challenge with allergen of allergic (5.6 +/- 0.17 ng/m-), but not nonallergic (0.04 +/- .02 ng/ml), individuals (n = 8 in each case). The presence of kinin was highly correlated with that of histamine and TAME-esterase activity and with clinical symptoms (p less than 0.001). In a double blind, placebo-controlled study, topical administration of the drug Azatadine, which inhibits mast cell mediator release in vitro, reduced the clinical response to allergen challenge and reduced the concentrations of kinins, histamine, and TAME-esterase activity observed following allergen challenge. In addition to the immediate response to allergen, some individuals experience a recurrence of symptoms some 3-12 hours after challenge; in seven such individuals (13.5 +/- 3.2 ng kinin/ml in the immediate reaction), there was a second increase in nasal kinins (2.95 +/- 1.4 ng/ml) during this late reaction, again correlating with increases in histamine and TAME-esterase activity. HPLC analysis revealed that a mixture of bradykinin and lysylbradykinin is produced during both responses. Finally, 12 subjects with a history of nasal symptoms upon exposure to cold, dry air (CDA) were compared to five asymptomatic individuals in a nasal challenge system involving nasal breathing of CDA and warm, moist air (WMA). For the symptomatic group the levels of kinin in nasal lavages were significantly increased after CDA (2.9 +/- 0.8 ng/ml) compared to baseline (0.06 +/- 0.01 ng/ml) or WMA (0.3 +/- 0.07 ng/ml). Kinin generation again correlated with increases in histamine, PGD2 and TAME-esterase activity and with onset of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)