U. Pipkorn

The‘nasal pool’device applies controlled concentrations of solutes on human nasal airway mucosa and samples its surface exudations/secretions

A‘nasal pool’(NP) device, a compressible plastic container with an adapted nozzle, was used to perform a continuous 10‐min nasal provocation and lavage. This novel technique brings known concentrations of agents into contact with a large and defined area of the nasal mucosal surface for extended periods of time. Simultaneously, the surface exudations/secretions of the same nasal mucosa are effectively sampled by the NP fluid. A concentration‐response study of histamine (80, 400 and 2000 μg/ml) was performed in 12 normal subjects on three different occasions. Exudation of plasma albumin into the lavage fluid was measured to quantitate the histamine‐induced airway inflammation. The effect of the dwell time on exudation was examined using histamine (400 μg/ml) instilled in the nasal cavity for time periods from 10 sec to 10 min. The time course of histamine‐induced plasma exudation response was studied by exposing the mucosa to histamine (400 μg/ml) for 12 min, with the NP renewed every minute. Allergen‐provocations were performed in subjects with hay fever and TAME‐esterase activity in the returned lavage fluid was determined to indicate the degree of response. Histamine produced a concentration‐dependent increase in albumin levels in the NP fluid; 123·3 ± 25·6, 213·8 ± 19·7 and 430·2 ± 32·0 μg/ml (mean ± s.e.m.), respectively. The time‐course study demonstrated that plasma exudation into the lumen occurred promptly and that the exudation response reached a maximum after exposure to histamine for 6–10 min. The dwell‐time experiments supported this finding. After 10 min the exudation appeared to decline despite the continued presence of histamine. Allergen provocation resulted in a concentration‐dependent increase in TAME‐esterase activity of the NP‐fluids. It is concluded that the NP technique provides new possibilities in studies of pathophysiology and pharmacology of human airway mucosa. With the NP technique controlled concentrations of mediators, drugs, tracers, etc. can be applied for desirable lengths of time on a well‐defined mucosal surface area. This particular area is gently and effectively lavaged during the presence of the NP fluid and when the fluid is recovered by decompressing the NP device.

Effects of topical treatment with H1 and H2 antagonists on clinical symptoms and nasal vascular reactions in patients with allergic rhinitis

Fifteen asymptomatic subjects with allergic rhinitis participated in a double‐blind, randomized, crossover, placebo‐controlled study. The subjects were pretreated intra‐nasally with a single dose of a selective H1 receptor antagonist, levocabastine, and/or selective H2 receptor antagonist, ranitidine, prior to a nasal allergen challenge. The nasal symptoms obtained at the challenge were assessed using a scoring technique 15 min after the allergen exposure. The nasal airway resistance was determined twice prior to and once after the allergen challenge using anterior rhinomanometry. The nasal mucosal blood flow was determined before and 15 min after allergen challenge using the 133Xe wash‐out technique. After pretreatment with the H1 antagonist there was a statistically significant reduction in the number of sneezes and rhinorrhea compared to pretreatment with placebo. Pretreatment with the H2 receptor significantly decreased the rhinorrhea but not the sneeze. The nasal blockage was unaffected by both the H1 and the H2 antagonists. Pretreatment with the H1 and/or the H2 antagonists inhibited the reduction in the nasal mucosal blood flow induced by the allergen challenge to a significant degree. The present findings suggest that topical treatment with the highly selective histamine antagonist, levocabastine, inhibits allergen‐induced reflex‐mediated symptoms. H1 and H2 receptors do not appear to be involved in the regulation of the tone of the capacitance vessels. This indicates that a more complex mechanism participates in the induction of nasal blockage than the direct effect of histamine on H1 and H2 receptors on the capacitance vessels of the nasal mucosa alone. Both H1 and H2 receptors are of importance for the regulation of nasal mucosal blood flow during the allergic reaction.

Glucocorticoid-induced attenuation of mucosal exudation of fibrinogen and bradykinins in seasonal allergic rhinitis

The mucosal plasma exudate with its proteins, enzymes, derived peptides, and matrix molecules is an important factor in inflammatory airway diseases. This study investigated whether topical glucocorticosteroid treatment influences mucosal exudation of bulk plasma (fibrinogen) and the generation of plasma‐derived mediators (bradykinins) in seasonal allergic rhinitis. Twenty‐two patients with birch‐pollen‐induced allergic rhinitis participated in a double‐blind, randomized, placebo‐controlled study during the birch pollen season in 1989. After a 2‐week run‐in period, the participants received treatment with budesonide (200 μg per nasal cavity and day) or placebo. The patients kept a diary to record their daily nasal symptoms (itching, sneezing, nasal blockage, and secretion). The amount of birch pollen in the air was determined with the aid of a Burkhard pollen trap. A nasal lavage was performed once a week, and the levels of bradykinins and fibrinogen were determined in the lavage fluid samples. The birch pollen season was very mild, resulting in only minor nasal symptoms. In spite of the low pollen exposure, treatment with budesonide reduced the lavage fluid levels of both bradykinins and fibrinogen. The present results show that topical glucocorticosteroid treatment attenuates plasma exudation and the generation of plasma‐derived mediators in seasonal allergic rhinitis. This action may not result from simple vascular antipermeability effects of the drug but may rather reflect the anti‐inflammatory efficacy of topical glucocorticoids in the airway mucosa.

Topical vasoconstrictor (oxymetazoline) does not affect histamine-induced mucosal exudation of plasma in human nasal airways

Mucosal exudation of almost unfiltered plasma proteins, plasma‐derived mediators and fluid has recently been advanced as a major respiratory defence mechanism. Oxymetazoline chloride is a commonly used decongestant agent. By reducing blood flow it may reduce mucosal exudation and thus compromise the mucosal defence capacity. This study examines the effect of topically applied oxymetazoline on histamine‐induced plasma exudation into human nasal airways. Twelve normal volunteers participated in a double‐blind, randomized, cross‐over and placebo‐controlled study with pretreatment with a single dose oxymetazoline chloride (5 μg or 50 μg; a dose previously known to reduce nasal mucosal blood flow by almost 50%) prior to the histamine challenge sequence. Nasal lavages were performed every 10 min for 140 min, and three histamine challenges were performed at 30‐min intervals during this period. The concentrations of two exudative indices, N‐alpha‐tosyl‐l‐arginine methyl ester (TAME)‐esterase activity and albumin, were measured in the nasal lavage fluids. Nasal symptoms (sneezing, nasal secretion and blockage) were assessed by a scoring technique.

Long-term treatment with budesonide in vasomotor rhinitis.

Twelve patients entered a long-term study of budesonide treatment in vasomotor rhinitis. The efficacy of the treatment was studied. Possible systemic side effects were studied via an ACTH stimulation test prior to and during treatment. The local effect in the nasal mucosa was studied by means of a nasal biopsy before and after one year of treatment. The treatment has proved effective, while producing no systemic or local side effects during a one-year treatment period.

Vascular effects of topically applied bradykinin on the human nasal mucosa

To evaluate the vascular effects of topically applied bradykinin on the human nasal mucosa, 13 asymptomatic hay fever patients and 11 non-allergic subjects were challenged with diluent or bradykinin in three increasing doses. Mucosal blood flow was determined with the 133Xenon wash-out method and expiratory peak flow measurements used to assess nasal airway resistance before and after challenge. Nasal symptoms were recorded. Nasal secretion quantity was measured from preweighed paper handkerchiefs. Bradykinin induced a slight increase in nasal airway resistance which was similar in both allergic and non-allergic subjects. Nasal secretion was clearly increased after challenge with bradykinin compared with challenge with diluent in both allergic and non-allergic subjects. Bradykinin did not, however, induce any change in mucosal blood flow in either group. The present findings could be explained by direct effects of bradykinin on the vascular bed without reflex activity. Bradykinin would then induce an increase in vascular permeability with subsequent oedema formation and increased amounts of fluid on the mucosal surface. In contrast to allergen challenge, bradykinin challenge had no effect on the resistance vessels, changes of which had previously been shown to be largely reflex-mediated.

Mucosal blood flow in the human nose following local challenge with histamine

Nasal blood flow was measured using the 133Xe wash‐out method in 10 non‐allergic subjects and 13 asymptomatic hay fever patients. Determinations were made before and 15 min after challenge with diluent, 0.13 mg, 1.3 mg and 13 mg of histamine/nasal cavity. Nasal symptom scores were recorded. The nasal inspiratory peak flow was determined simultaneously in the hay fever patients. No differences in blood flow or symptom score recordings were found between the normal subjects and allergic patients under basal conditions or after histamine challenge. The nasal blood flow increased after challenge with the highest histamine dose. The increase was 34% (P< 0.05) from baseline in normals and 47% (P<0.05) in allergies. There was a dose‐dependent increase in nasal symptom scores following histamine challenge, again with no difference between normal and allergic subjects. The nasal peak flow decreased in a similar manner with a maximum decrease of 74% (P< 0.001). The present study gives further support to the notion that histamine is not the only mediator involved in vascular reactions during allergic rhinitis.

Reflex Activation in Allergen-induced Nasal Mucosal Vascular Reactions

Subjects with allergic rhinitis were challenged unilaterally with diluent and increasing doses of allergen. Challenge with the highest dose of allergen was also carried out after topical anesthesia of the nasal cavity using lidocaine. In the contralateral, unprovoked nasal cavity the mucosal blood flow was determined using the 133Xenon wash-out technique and the nasal airway resistance was determined by rhinomanometry before and after challenge. Nasal symptom scores were estimated 15 min after each challenge. Blood flow in the nasal mucosa in the unprovoked right nasal cavity decreased in a dose-dependent manner for th two highest doses of allergen where a reduction of 21% (p less than 0.05) and 26% (p less than 0.01) was obtained. Nasal airway resistance increased somewhat after the highest dose (p greater than 0.05). Topical anesthesia in the provoked nasal cavity inhibited the decrease in blood flow in the unchallenged nasal cavity. These findings suggest that the changes in the tone of the resistance vessels, but not the capacitance vessels, which are induced by allergen, are largely reflex-mediated.

The effect of topical nasal anaesthesia on allergen‐induced symptoms, obstruction and blood flow

The effect of topical anaesthesia on the nasal mucosa before and after allergen challenge was evaluated in 12 subjects with strictly seasonal allergic rhinitis. A single‐blind randomized placebo‐controlled design was used. The nasal challenge was carried out after pre‐treatment of the nasal cavity with 52 mg of lidocaine/nasal cavity, or placebo applied topically in spray form. The number of sneezes was counted. The amount of nasal secretion was estimated by weighing used paper handkerchiefs. The capacitance and resistance vessel reactions were monitored by determining nasal peak flow and 133Xe wash‐out respectively. After placebo pre‐treatment the two doses of allergen induced moderate symptoms and vascular changes. Pre‐treatment with local anaesthesia did not affect any of the symptoms nor did it affect the decrease in the tone of the capacitance vessels. It was found that topically applied lidocaine per se did not have any effect on nasal mucosal blood flow as measured using the 133Xe wash‐out technique. However, the local anaesthesia did block the allergen‐induced increase in the tone of the resistance vessels. In conclusion, a redundancy of systems appears to be involved in nasal allergic reactions. Although a reflex‐induced mechanism may well play a significant role in the induction of the signs and symptoms of nasal allergic reactions, the redundancy of systems involved may well override any reduction in one single system, as appears to be the case in the present study. Lidocaine peer se did not influence the nasal mucosal blood flow.

H1-antagonists as a tool in clarifying the pathophysiology of nasal allergy

Various mediator systems have been stressed as important in the generation of the signs and symptoms of allergic disease such as hay fever. Nevertheless, in the upper airways, histamine is still the only mediator which behaves consistently in terms of release at appropriate challenge, produces all the major symptoms of rhinitis at a local challenge, and the specific antagonist influences the signs and symptoms of rhinitis in the challenge situation as well as during natural allergen exposure. Although the majority of hay fever symptoms are influenced by H1‐receptors, there are exceptions. An important one is the symptom of nasal blockage, which is due to tissue oedema and a decrease in the tone of the capacitance vessels. Another point to be stressed is that histamine alone does not induce any protracted mucosal inflammatory response with associated symptoms, influx of eosinophils and increase in responsiveness that is associated with the exposure to allergen. Nevertheless, from a clinical point of view, antihistamines are still valuable pharmacological agents for the clinical management of hay fever symptoms.