The homeostatic rôle of bronchoconstriction.

This article argues in favour of the hypothesis that the homeostatic rôles of bronchoconstriction are to retract the airway tree during expiration, and to assist in the expulsion of mucus from peripheral airways by increasing the velocity of outgoing air. In asthma, this function may be dangerously exaggerated because of the presence of unusually viscous airway secretions and the remodelling of airway walls.

Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody.

Fibrosis in the reticular layer beneath the epithelial basement membrane is a feature of airway remodeling in human asthma. We previously reported the presence of subepithelial fibrosis (SEF) in a disease model of atopic asthma in which mice were sensitized and intratracheally challenged with ovalbumin (OVA) (Blyth and colleagues, Am. J. Respir. Cell Mol. Biol. 1996;14:425-438). Here, we describe further studies to quantify the degree of SEF after its induction by repeated exposure of the airways to allergen. The amount of subepithelial reticulin in the airways of animals challenged three times with 80 microg OVA was typically increased 1. 4-fold. The increased amount of reticulin showed no reduction after a 50-d period after the third allergen challenge. A reduction in SEF was achieved by daily treatment with dexamethasone (DEX) for 8 d during the allergen challenge period, or by treatment with anti-interleukin-5 antibody (TRFK5) at the time of allergen challenge. Postchallenge treatment with DEX for 15 d resulted in significant resolution of previously established SEF. Severe nonallergic inflammation during repeated exposure of airways to lipopolysaccharide did not induce SEF. The results indicate that development of SEF is associated with eosinophil infiltration into airways, and may occur only when the inflammatory stimulus is allergic in nature.

Induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone.

We recently described a murine model of atopic asthma in which a marked, extensive hyperplasia of airway goblet cells is induced by repeated challenge of ovalbumin (OA)-sensitized mice with intratracheally administered allergen (Am. J. Respir. Cell Mol. Biol. 1996;14:425-438). We report here the time course of the duration of this feature and of its spontaneous resolution in the absence of further allergen exposure. Induction of severe neutrophilic inflammation in the airways by repeated intratracheal administration of lipopolysaccharide failed to induce goblet cell hyperplasia (GCH) to as great a degree as that induced by allergen, suggesting that nonallergic inflammation is a relatively poor inducer of this phenotype change in mice. When a "subclinical" infection of the lungs with the human A2 strain of respiratory syncytial virus was superimposed on the model of atopic asthma, recruitment of monocytes and lymphocytes to the airways was enhanced and a discharge of goblet cell mucin contents was observed. This may partly explain the respiratory difficulty that typifies virally induced exacerbations of asthma in humans. Daily systemic treatment of sensitized mice with dexamethasone during the period of allergen challenge produced a dose-related suppression of developing GCH, while similar treatment during the period following the establishment of extensive hyperplasia induced an accelerated resolution toward a normal epithelial phenotype. These results confirm and extend the relevance of this model as a representation of the human disease.

Lung inflammation and epithelial changes in a murine model of atopic asthma.

A murine model of allergen-induced airway inflammation and epithelial phenotypic change, and the time-courses of these events, are described. Mice were sensitized to ovalbumin using an adjuvant-free protocol, and challenged by multiple intratracheal instillations of ovalbumin by a non-surgical technique. Many of the characteristic features of human atopic asthma were seen in the mice. A marked eosinophilic infiltration of lung tissue and airways followed allergen challenge, and its severity increased with each challenge, as did the number of eosinophils in the blood. Lymphocytes, neutrophils, and monocytes also invaded the lungs. Airway macrophages showed signs of activation, their appearance resembling those recovered from antigen-challenged human asthmatic airways. The airway epithelium was thickened and displayed a marked goblet cell hyperplasia in terminal bronchioles and larger airways. After repeated challenges, the reticular layer beneath the basement membrane of the airway epithelium showed fibrosis, reproducing a commonly observed histologic feature of human asthma. Goblet cell hyperplasia began to appear before eosinophils or lymphocytes had migrated across the airway epithelium, and persisted for at least 11 days after the third intratracheal challenge with ovalbumin, despite the number of inflammatory cells in the lungs and airways having decreased to near-normal levels by 4 days. Plugs of mucus occluded some of the airways. These results indicate that some of the phenotypic changes in airway epithelium that follow an allergic response in the lung can be initiated before the migration of eosinophils or lymphocytes across the epithelial layer.

Repeated measurement of respiratory function and bronchoconstriction in unanesthetized mice.

A noninvasive forced oscillation technique was used to determine respiratory function in unanesthetized and spontaneously breathing mice. Pseudorandom noise pressure variations in a frequency range of 16-208 Hz were applied to the body surface, and the flow response was measured at the nose. From the pressure-flow relationship, respiratory transfer impedance was calculated. Study of intra-animal variability on a short- and a long-term basis revealed that the real part of respiratory transfer impedance was reproducible within 9%. The imaginary part appeared less reproducible (within 22%). Furthermore, bronchoconstrictive responses were investigated and analyzed by evaluation of respiratory resistance as measured at 16 Hz (Rrs16). During the first 15 min after ovalbumin challenge in ovalbumin-sensitized mice, Rrs16 was significantly increased [49 +/- 7% (SE)]. Inhalation of methacholine in untreated mice induced an increase in Rrs16 of 75 +/- 16% (SE). In saline-challenged animals, no significant changes were observed. This method enables evaluation of long-term respiratory function in mice and appeared to be a sensitive measure for bronchoconstriction.

Some effects of histamine in the depolarized rat uterus.

1. The relaxant effect of histamine in the isolated rat uterus remained after the preparation was depolarized in a potassium Ringer.2. The effect was abolished by the calcium-chelating agent, ethyleneglycol bis-aminoethyl ether-tetraacetic acid (EGTA).3. Histamine caused relaxation during calcium-induced contractures in a depolarized uterus treated with EGTA, but did not produce relaxation during barium-induced contractures.4. While responses of a normally polarized rat uterus to acetylcholine were inhibited by histamine, those of a depolarized uterus were enhanced by histamine. The inhibitory effects of isoprenaline and papaverine on acetylcholine responses were maintained in depolarized preparations.5. Both the enhancing effect of histamine on responses to acetylcholine and the relaxation of calcium-induced contractures were abolished by burimamide, indicating that H(2)-receptors mediate the effects of histamine in the depolarized tissue.6. A reduction in the rate of exchange of calcium across the depolarized cell membrane was demonstrated with high concentrations of histamine.7. The results are consistent with the hypothesis that in the rat uterus, the stimulation of H(2)-receptors by histamine is accompanied by a reduction in calcium exchange across the membrane which may result in a decrease in the concentration of free intracellular calcium available to stimulate contraction of the myofilaments. Histamine may act by increasing the binding of calcium within the cell.

The effect of histamine on the electrical activity of rat uterus.

Histamine produces a reduction in the spike frequency and the degree of depolarization which accompany spontaneous and induced contractions of rat uterus. Concentrations of 0.5 mug/ml can cause complete inhibition of both mechanical and electrical activity without producing any change in the resting membrane potential. Concentrations as high as 100 mug/ml cause no appreciable change in membrane potential.