C G Persson

In vivo restitution of airway epithelium

Epithelial shedding occurs in health and, extensively, in inflammatory airway diseases. This study describes deepithelialisation, reepithelialisation and associated events in guinea-pig trachea after shedding-like epithelial denudation in vivo. Mechanical deepithelialisation of an 800-μm wide tracheal zone was carried out using an orotracheal steel probe without bleeding or damage to the basement membrane. Reepithelialisation was studied by scanning- and transmission electron microscopy and light microscopy. Nerve fibres were examined by immunostaining. Cell proliferation was analysed by [3H]-thymidine autoradiography. Immediately after epithelial removal secretory and ciliated (and presumably basal) epithelial cells at the wound margin dedifferentiated, flattened and migrated rapidly (2–3 μm/min) over the denuded basement membrane. Within 8–15 h a new, flattened epithelium covered the entire deepithelialised zone. At 30 h a tight epithelial barrier was established and after 5 days the epithelium was fully redifferentiated. After completed migration an increased mitotic activity occurred in the epithelium and in fibroblasts/smooth muscle beneath the restitution zone. Reinnervating intraepithelial calcitonin gene-related peptide-containing nerve fibres appeared within 30 h. We conclude that (1) reproducible shedding-like denudation, without bleeding or damage to the basement membrane, can be produced in vivo; (2) secretory and ciliated cells participate in reepithelialisation by dedifferentiation and migration; (3) the initial migration is very fast in vivo; (4) shedding-like denudation may cause strong secretory and exudative responses as well as proliferation of epithelium, and fibroblasts/smooth muscle. Rapid restitution of airway epithelium may depend on contributions from the microcirculation and innervation.

Prevalence of nasal symptoms and their relation to self-reported asthma and chronic bronchitis/emphysema

We read with interest the paper by MONTNÉMERY et al. [1] reporting nasal symptoms in patients with asthma and chronic bronchitis/emphysema (CBE). This study is of particular interest since it is the first, to our knowledge, to assess nasal symptoms in CBE. It seems that the results can be interpreted since an agreement ofy70% was found between the diagnosis of asthma or CBE made in the study and a doctor9s diagnosis. However, some patients with CBE may be falsely classified and may have other respiratory diseases, including asthma. Moreover, patients aged 29 yrs are unlikely to have CBE and the authors showed, in another paper [2], that the prevalence of CBE was 3.3% in subjects aged between 20–29 yrs. In order to reinforce the results of the study, it would have been interesting to study the association of nasal symptoms with asthma and CBE depending on the age groups. A second point, regarding this study may be discussed. The characteristics of nasal symptoms appear to differ in asthma and CBE. In their first paper, MONTNÉMERY et al. [2] reported allergic eyenose catarrh (hay fever). It would also be interesting to discuss this association with asthma and CBE. Finally the authors reported that nasal symptoms probably due to nonallergic mechanisms (provoked by cold air/damp air) were significant risk factors for asthma. This is in accordance with the results from an analysis of the European Community Respiratory Health Survey data, showing that rhinitis is associated with an increased risk of asthma in nonatopic subjects with normal immunoglobulin-E levels [3].Little information is available on associations between rhinitis and chronic bronchitis/emphysema (CBE). Self-reported upper airway symptoms, asthma, and CBE were examined in 12,079 adults living in southern Sweden. The response rate was 70% (n=8,469), of whom 33% reported significant nasal symptoms: a blocked nose was reported by 21%; sneezing by 18%; nasal discharge by 17%; and thick yellow nasal discharge by 5.7%. Nasal symptoms and combined nasal and self-reported bronchial disease were generally more common among smokers than nonsmokers. There was little overlap between asthma and CBE, but 46% of those with asthma and 40% of those with CBE had significant nasal symptoms. Best predicting factors (odds ratios >3) for asthma and CBE were nasal symptoms due to exposure to animals and damp/cold air, respectively. One-third of an adult, southern Swedish population, had significant allergic and/or nonallergic nasal symptoms. Nasal symptoms were frequently found to coexist with both asthma and chronic bronchitis/emphysema, suggesting that pan-airway engagement is common in both diseases. Differing associations between types of nasal symptoms and allergic and irritant triggers of nasal symptoms, with regard to asthma and chronic bronchitis/emphysema, emphasize the different natures of these bronchial diseases.

Degranulation patterns of eosinophil granulocytes as determinants of eosinophil driven disease

BACKGROUND Degranulation of eosinophils in target tissues is considered a key pathogenic event in major chronic eosinophilic diseases. However, because of a lack of appropriate methods, little is known about degranulation of eosinophils in common eosinophilic diseases. METHODS Using transmission electron microscopic (TEM) analysis, a novel approach has been devised and validated to quantify eosinophil degranulation in human tissues (assessed in individual cells as percentage granules with structural signs of protein release). Biopsy specimens from patients with inflammatory bowel disease, allergic rhinitis, asthma, and nasal polyposis were evaluated. RESULTS All conditions displayed a similar degree of local tissue eosinophilia, with no differences being observed in eosinophil numbers in the airway mucosa of patients with airway diseases and the colonic mucosa of those with inflammatory bowel disease (IBD). In contrast, marked differences in the mean (SE) extent of eosinophil degranulation were observed between the patient groups; IBD 9.3 (1.4)% altered granules, artificial and natural allergen challenge induced allergic rhinitis 67.8 (6.8)% and 86.6 (3.0)%, respectively, asthma 18.1 (2)%, and nasal polyposis 46.6 (7.6)%. CONCLUSIONS This study provides the first quantitative data which show that different eosinophilic conditions, despite having similar numbers of tissue eosinophils, may exhibit markedly different degranulation patterns. The present assessment of piecemeal degranulation would thus make it possible to delineate the conditions under which eosinophils are likely to contribute to disease processes. This novel type of analysis may also guide and validate anti-eosinophilic treatment options.

Mucosal output of eotaxin in allergic rhinitis and its attenuation by topical glucocorticosteroid treatment

Background Eotaxin is a chemokine that attracts and activates eosinophils. The present study examines the occurrence of eotaxin in nasal mucosal surface liquids in patients with seasonal allergic rhinitis without allergen exposure and during repeat allergen challenge with and without topical glucocorticosteroid treatment. The number of subepithelial eosinophils and mucosal outputs of bulk plasma (α2‐macroglobulin) and eosinophil cationic protein (ECP) are also examined.

Effects of topical budesonide and levocabastine on nasal symptoms and plasma exudation responses in seasonal allergic rhinitis

This study compares the effects of two topical nasal treatments for allergic rhinitis, budesonide and levocabastine, on symptom development during seasonal pollen exposure. Additionally, the protective effects of drug treatments on allergen‐challenge‐induced responses (symptoms and microvascular exudation of plasma) are examined late into the pollen season. Forty‐four patients with seasonal allergic rhinitis to birch pollen participated in this single‐blind, randomized, and placebo‐controlled study. Topical nasal treatment with either levocabastine (200 p.g b.i.d.: n = 16), budesonide (200 μg b.i.d.; n = 16), or placebo (n= 12) was instituted before the start of the pollen season and continued for 5 weeks until the end of the birch pollen season. The participants kept diaries for scores of nasal and ocular symptoms. Nasal allergen challenges with increasing doses of a birch pollen extract (102, 103 and lC SQ‐U) were carried out both before, when patients were asymptomatic and without treatment, and late into the pollen season. A nasal lavage followed each challenge, and the lavage fluid levels of albumin were measured as an index of the acute inflammatory response of the allergic mucosa. The birch pollen season was rather mild, producing only small increases in nasal symptoms. Budesonide treatment reduced the total nasal symptoms compared to placebo (P<0.01) and to levocabastine (P<0.05), while levocabastine treatment did not differ significantly from placebo. Ocular symptoms and use of rescue medication did not differ between placebo and the active treatments. At the end of the pollen season, both treatments reduced allergen‐challenge‐induced nasal symptoms compared to placebo (P<0.01). Only budesonide reduced allergen‐challenge‐ induced increments of albumin levels in postchallenge nasal lavage fluids (P<0.05, in comparison with placebo). The results suggest that budesonide reduces both seasonal and allergen‐challenge‐induced nasal symptoms, while levocabastine is effective against allergen‐challenge‐induced symptoms also during the season. In addition, the topical steroid treatment, but not the antihistamine, inhibits the inflammatory exudation evoked by allergen challenge in patients with active seasonal disease.

Mucosal exudation of plasma is a noninjurious intestinal defense mechanism

We have demonstrated in sensitized rats that the immediate response to endointestinal challenge with allergen (10‐6 M ovalbumin) is characterized by mucosal exudation of plasma with little or no concomitant change in the mucosal absorption capacity. The luminal entry of plasma macromolecules also leaves the light microscopic structure and the ultrastructure of the mucosa unaffected. It is possible that the plasticity of epithelial zonulae occludens allows a noninjurious and unidirectional paracellular flux of extravasated plasma into the gut lumen. We propose that inflammatory‐stimulus‐induced mucosal exudation of plasma belongs to the first‐line defense mechanisms of the intact lining of the intestine.

Terbutaline and adrenaline inhibit leakage of fluid and protein in guinea-pig lung

The effect of terbutaline (0.3 mg/kg s.c.) and adrenaline (0.1 and 0.3 mg/kg s.c.) on histamine--aerosol-induced increase in lung weight and dye content was studied in conscious guinea pigs, previously given Evans blue dye. Both drugs prevented the effects of histamine. It is concluded that terbutaline and adrenaline have a pronounced anti-permeability effect in guinea-pig lungs inhibiting the histamine-induced microvascular efflux of fluid and protein.

Relaxant effects of xanthines, a β2-receptor agonist and Ca2+ antagonists in guinea-pig tracheal preparations contracted by potassium or carbachol

Potassium (124 mM K+ Krebs) produced a biphasic contractile response in the guinea-pig isolated trachea. An initial phasic contraction was followed by a larger and sustained contraction. Repeated potassium-induced contractions in spontaneously contracted guinea-pig tracheas were not reproducible. However, reproducible K+ responses were obtained in the presence of indomethacin (10(-6) M) that almost abolished the spontaneous tone. This suggested that endogenous cyclooxygenase products were variably released by K+ and interfered with its contractile effects. Both phases of K+-induced contractions were inhibited in Ca2+-free/EGTA Krebs. In contrast, about 80% of the contractile response to carbachol persisted in this medium. Tracheas contracted by potassium (indomethacin present) were completely relaxed by theophylline and enprofylline but only partly relaxed by terbutaline. All bronchodilators completely relaxed carbachol-contracted preparations. Each bronchodilator was 2-3 times less potent to relax K+- than carbachol-induced contractions. In sharp contrast, two Ca2+ antagonists, verapamil and nimodipine, preferentially relaxed K+-induced contractions. The results obtained with Ca2+ antagonists, which are poorly effective in asthma, compared to the established antiasthma drugs, xanthines and beta 2-receptor agonists, may indicate that depolarization-induced mechanisms contribute little to bronchoconstriction in asthma.

Allergen challenge-induced extravasation of plasma in mouse airways

Mouse models are extensively used to study genetic and immunological mechanisms of potential importance to inflammatory airway diseases, e.g. asthma. However, the airway pathophysiology in allergic mice has received less attention. For example, plasma extravasation and the ensuing tissue‐deposition of plasma proteins, which is a hallmark of inflammation, has not been examined in allergic mice.

Novel peripheral neurotransmitters and control of the airways

This review deals with airway effects produced by nonadrenergic, noncholinergic nerves and neuropeptides, and with the use of capsaicin to examine the roles of C-fiber nerve ending