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 micrograms 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.

Eosinophil chemotactic activity of topical PAF on the human nasal mucosa.

Ten patients with strictly seasonal allergic rhinitis were challenged with 132 micrograms PAF-acether in each nasal cavity outside their relevant pollen season. Cells from the nasal mucosa were collected by nasal lavage prior to and every second hour up to 8 h after the PAF challenge. At the same times the volume of methacholine-induced secretory responsiveness was measured. A brush specimen was harvested from the nasal mucosa prior to and 8 h after the PAF challenge. PAF led to an increase in the number of eosinophils from an initial 6.1 to 64.4 per glass 2 h later. The number of eosinophils in the nasal lavage fluid then decreased to its initial baseline value. By 8 h after PAF challenge the number of eosinophils collected with the brush was still elevated as compared to the initial brush sample (3.1 vs 24.1). PAF did not produce any change in methacholine-induced secretory responsiveness at any time. It appears that PAF possesses eosinophil chemotactic properties in the human nasal airway without altering the nasal secretory responsiveness. This confirms previous findings that the induction of nasal responsiveness is a more complex phenomenon than just the recruitment of eosinophils into the airway mucosa.

Eosinophils, secretory responsiveness and glucocorticoid-induced effects on the nasal mucosa during a weak pollen season.

This study examined the seasonal effects on eosinophils and secretory responsiveness of the nasal mucosa in 22 patients with allergic rhinitis due to birch pollen (11 patients received placebo and 11 budesonide, 200 micrograms once daily in each nostril). The pollen counts during the study season were too low to produce a significant symptomatology. Hence, our findings demonstrate threshold alterations of the airway mucosa in allergic rhinitis and their inhibition by anti-inflammatory drug intervention. The patients were monitored for 8 weeks with daily recordings of pollen counts and symptom scores. Once every week a series of laboratory tests was carried out: the local eosinophil influx was determined using a Rhinobrush technique; the levels of eosinophil cationic protein (ECP) were analysed in nasal lavage fluids; and the secretory response to intranasal methacholine was measured. Treatments started after a 2-week run-in period. The proportion of eosinophils increased markedly in the placebo group and was elevated also during the last two study weeks when the pollen counts were practically nil. The secretory responsiveness to methacholine increased during the pollen season and returned to baseline towards the end of the study period. The topical glucocorticoid treatment reduced the proportion of eosinophils, the ECP levels, and the secretory response to methacholine compared to placebo. We conclude that the increased traffic and activity of eosinophils and less conspicuously the increased secretory responsiveness are expressions of the mucosal inflammation that precede the development of symptoms in seasonal allergic rhinitis.

Allergen-induced changes in nasal secretory responsiveness and eosinophil granulocytes.

The release of toxic granule proteins from the eosinophil granulocytes is generally believed to play a crucial part in the development of allergen-induced lesions of the barrier function leading to such clinical features of continuous allergic airway disease as oedema, hypersecretion, changes in responsiveness to specific and non-specific stimuli and, in the case of the lower airways, bronchoconstriction. In the upper airways, a nasal challenge/rechallenge model has proved useful in the study of the allergic inflammatory response in hay fever patients both in experimental settings and during natural pollen exposure. Repeated nasal lavage procedures and challenges with methacholine following an initial challenge with different doses of allergen or placebo were performed in 16 hay fever patients. Following an immediate allergic reaction, a statistically significant increase in the secretory response to methacholine was seen 30 min after challenge with the higher doses of allergen (p less than 0.01) but not after the lowest dose or placebo. An influx of eosinophil granulocytes was seen within 30-60 min of the allergen challenge regardless of the dose (p less than 0.01). The activation of these cells was measured by the increased levels of ECP (eosinophil cationic protein) in the nasal lavage fluid. No relationship was found between individual changes in eosinophils or levels of ECP and changes in the secretory response to methacholine or nasal symptoms. This lends further support to our previous observations that eosinophil granulocytes are not necessarily linked to allergen-induced changes in nasal secretory responsiveness.

Macrophages on the nasal mucosal surface in provoked and naturally occurring allergic rhinitis.

Macrophages are the most common cell type residing in the lumen of the lower airways. However, very little is known about the presence and putative pathogenic implications of macrophages in the upper airways. Using specific immunohistochemical techniques, the presence of and changes in macrophage density were studied before and after allergen exposure in the laboratory and during natural allergen exposure of subjects with seasonal allergic rhinitis. The monoclonal antibody EBM 11 combined with the alkaline phosphatase-anti-alkaline phosphatase-technique was applied on cytospin-prepared slides. In the challenge experiment, 0.5 +/- 0.2% (mean +/- SEM; n = 10) of the total cell number were positive for the EBM 11 marker before challenge, thereby not differing from the controls (0.2 +/- 0.2%; mean +/- SEM; n = 3). Local allergen challenge induced an increase of these cells to a peak of 1.3 +/- 0.4% after 4 h (p less than 0.05). During seasonal exposure there was also a similar increase, from 0.7 +/- 0.2 to 1.3 +/- 0.3% (p less than 0.05; n = 11) in placebo-treated patients and from 0.7 +/- 0.2 to 1.6 +/- 0.4% (p less than 0.05; n = 11) in patients treated with topical glucocorticoids. There was, however, no direct relationship between nasal symptoms and number of macrophages present on the mucosal surface. The study indicates that macrophages are involved in the inflammatory processes of allergic rhinitis.

Effect of a single dose of a topical glucocorticoid and a cyclo-oxygenase inhibitor on allergen-induced changes in nasal reactivity.

The inflammatory response of airway mucosa to allergen exposure is a complex phenomenon featuring symptoms, the influx of inflammatory cells, the release of mediators, and changes in local reactivity. These features and their pharmacological modifications can be successfully studied in nasal challenge models. We performed a nasal allergen challenge followed by a rechallenge with allergen 24 h later in order to monitor changes in specific reactivity due to the initial allergen challenge. Symptoms were monitored, as was the generation of TAME-esterase activity in nasal lavage fluids. Prior to each challenge a nasal brush specimen was taken. In a double blind, cross-over, double-dummy manner the patients were pretreated with placebo, a single dose of 200 micrograms of budesonide (topical corticosteroid) given 2 h prior to rechallenge with allergen or 600 mg ibuprofen (cyclooxygenase inhibitor) given per os t.i.d. to steady state starting 24 h prior to the initial allergen challenge. Treatment with ibuprofen induced a slightly lower composite symptom score (P less than 0.05) at the initial allergen challenge when compared with placebo. No differences were noted in the relevant TAME-esterase activities. The allergen challenge resulted in significantly increased proportions of eosinophils in the brush specimens 24 h after the initial allergen challenge (P less than 0.001) with no differences between the different treatment alternatives. At rechallenge there was a reduction in the symptoms of secretion and nasal blockage in both groups receiving active treatment compared with placebo (P less than 0.05), whereas the number of sneezes was not affected and no differences were noted in TAME-esterase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergen-induced increase in nonspecific nasal reactivity is blocked by antihistamines without a clear-cut relationship to eosinophil influx.

Antihistaminic compounds have been suggested to possess other properties besides H1-receptor antagonism. To evaluate whether two different antihistamines could inhibit local eosinophil infiltration and allergen-induced nonspecific nasal hyperreactivity, 15 subjects with seasonal allergic rhinitis participated in a double-blind, randomized, placebo-controlled study outside the pollen season. At steady-state levels of either 60 mg of terfenadine, twice daily, cetirizine, 10 mg once daily, or placebo, a nasal methacholine challenge was performed before and 24 hours after a nasal allergen challenge. The volume of the methacholine-induced nasal secretions was measured. The response to allergen was determined with a scoring technique. Cells from the nasal mucosal surface were harvested with the aid of a rhinobrush. Both antihistamines induced a similar (p less than 0.01) reduction in nasal symptoms after the allergen challenge compared with placebo. Both antihistamines inhibited the increased nonspecific nasal reactivity induced by methacholine 24 hours later (p less than 0.05). The allergen challenge induced an increase in surface eosinophils, which, however, appeared unaffected by any of the active treatments. Since histamine per se does not induce changes in nonspecific reactivity, we suggest that the antihistamines possess other properties besides being H1-receptor antagonists.

Changes in non-specific nasal reactivity and eosinophil influx and activation after allergen challenge.

It has been suggested that the eosinophilic granulocyte plays a crucial role in the genesis of increased reactivity of the airways. In order to characterize changes in non-specific reactivity in the upper airways following a nasal allergen challenge further 16 subjects with strictly seasonal allergic rhinitis were studied. They were challenged with allergen outside the relevant pollen season and monitored at intervals for a period of 24 hr for nasal symptoms, changes in nasal reactivity, eosinophil influx and activation, and markers of inflammation. The same challenge sequence without an initial allergen challenge was used as a control. A symptom score technique was used to record nasal symptoms and methacholine challenges were used to monitor changes in non-specific reactivity. A nasal lavage was made prior to each methacholine challenge to monitor the influx of cells, specifically eosinophils, and to determine changes in the levels of eosinophil cationic protein (ECP) and TAME-esterase activity. Cells from the mucosal surface were also collected with a Rhinobrush prior to the allergen challenge as well as at the 24-hr follow up. The allergen challenge induced a five-fold increase in non-specific nasal reactivity, as measured by the methacholine challenges, at the 2-hr follow up from 0.051 ml +/- 0.012 (mean +/- s.e.m.) to 0.255 +/- 0.062 (P less than 0.01) and a significant increase was also noted at all observation points, whereas no increases could be observed in the control setting.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cyclophosphamide pretreatment on autoimmune encephalomyelitis in rats.

We studied the effect of a low dose cyclophosphamide (CY) treatment on the clinical course of experimental autoimmune encephalomyelitis (EAE) in rats from three resistant or low-susceptible strains: Fischer, Brown-Norway, PVG, and the F1 hybrid between the two former strains. Treatment with 40 mg/kg two days before immunization resulted in a marked potentiation of EAE development in Fischer and PVG rats, but not in BN rats or F1(BN X F) hybrids. The effect of the CY treatment was a short period of severe lymphoid cell depletion with an increase in the quotient between T cells reacting with w3/25 monoclonal antiserum and such reacting with ox-8 antiserum, indicating a relative reduction in suppressor/cytotoxic cell counts. Treatment of Fischer or PVG rats, after CY treatment, for five days with thymic hormone factor (THF) normalized T cell ratios and restored the rats to a state of low susceptibility. It is concluded that Fischer and PVG rats have an EAE suppressive mechanism dependent on CY-sensitive suppressor lymphocytes, while there may be other mechanisms of resistance to EAE in BN rats.

Back-crossing F1 (BN X PVG) rats with the PVG strain gives hybrids with high natural killer (NK) cell activity.

The genetic regulation of rat natural killer (NK) cell activity against the lymphoma YAC-1 in two rat strains, BN and PVG, with low and intermediate NK activity respectively, was studied. The F1 (BN X PVG) and the BN X F1 (BN X PVG) hybrids were both found to have NK activity intermediate between the BN and PVG parental strains, whereas approximately half of the PVG X F1 (BN X PVG) had high NK activity. No correlation to AgB types was found. Apparently at least two genes regulate NK activity in the rat, neither of which appears to be linked to the major histocompatibility complex.