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Viral respiratory infections exacerbate asthma in many patients. We hypothesized that one mechanism by which this effect occurs may include potentiated or altered mediator release by mast cells and/or basophils to favor the development of late-phase asthmatic reaction (LAR). Therefore, we studied eight subjects with allergic rhinitis before and during an experimentally induced rhinovirus 16 (RV16) infection. We determined levels of plasma histamine and tryptase, and we observed the associated patterns of airway obstruction that developed following inhaled antigen challenge. Bronchial responsiveness to histamine, methacholine, and antigen were all significantly increased during the RV16 illness. Further, the incidence of LAR was significantly higher (five of eight) during the infection than before (one of eight; p = 0.014). In addition, in those patients whose pattern of response following antigen challenge converted from an immediate response only before infection to a dual response (immediate + late phase) during infection, plasma histamine concentrations after challenge were significantly greater than in those whose pattern of response did not change. We conclude that one mechanism by which RV16 infection increases the likelihood of LAR could include enhanced mediator release from pulmonary mast cells or from circulating or recruited basophils.

The pathogenesis of the late asthmatic response has been of interest due to the fact that its development has been associated with airway obstruction, airway inflammation, and airway hyperresponsiveness: all features of chronic asthma. In order to study more precisely late responses, a number of animal models have been developed. Previous reports have described alterations in airway mechanics at both 3 to 6 and 17 h after antigen challenge in sensitized guinea pigs. In these experiments, however, animals were challenged through the nose with aerosolized antigen, and airway conductance was measured using whole body plethysmography while the animals breathed through the upper airways. In rats similarly challenged, the predominant immediate change in resistance occurs in the upper airways. The purpose of this study, therefore, was to evaluate the contribution made by both the upper and lower airways to late changes after allergen challenge in guinea pigs. Outbred female Hartley guinea pigs were actively or passively sensitized (IgG1 antibody response) to three different antigens and challenged either by direct tracheal insufflation (sheep gamma globulin [SGG] or oxazolone-human serum albumin [OX-HSA]) or by aerosolization (ovalbumin [OA]). Lung resistance (RL) and dynamic compliance (Cdyn) were measured in anesthetized guinea pigs through a tracheostomy tube, and specific airway conductance (SGaw) was measured in unanesthetized, nose-breathing guinea pigs using a whole body plethysmograph. Late responses were defined as a RL greater than the mean + 2 SD RL or as a decrease in SGaw from baseline greater than 2 SD from the placebo-challenged (bovine serum albumin) group.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic nervous system function has been studied both in vitro and in vivo using a variety of methodologies. In asthmatic patients, beta-adrenergic hyporesponsiveness and alpha-adrenergic and cholinergic hyperresponsiveness can be frequently demonstrated. These observations have provided support for the beta blockade theory of asthma, advanced in the late 1960s by Andor Szentivanyi's experiments involving sensitized rodents. However, in addition to asthma, aberrations in autonomic nervous system function have been noted in other individuals including cystic fibrosis patients and their parents, patients with emphysema and bronchitis, and in patients (allergic rhinitis and atopic dermatitis) who have demonstrable IgE antibody responses to a variety of antigens. Thus, although these defects are not specific for asthma, it is noteworthy that these conditions share many clinical features; the ultimate phenotypic expression of these abnormalities may depend on both genetic and environmental factors that have yet to be defined.

Pulmonary antigen challenge in sensitized individuals results in isolated immediate, isolated late, or dual reactions consisting of both an immediate and late change in airway function. The immediate response appears to be dependent on the presence of IgE antibody and mast cell mediator release. Although the late phase of dual responses is considered to be related to or a continuum of the immediate hypersensitivity response, its precise pathogenesis remains to be determined. To increase both the sensitivity and specificity of analyzing the pathogenesis of IgE-dependent pulmonary responses, we have used a Sprague-Dawley rat model system in which rats are passively sensitized with a murine monoclonal IgE anti-dinitrophenol (DNP) antibody prior to challenge with DNP-bovine serum albumin (DNP-BSA). Pathogen-free rats were injected with IgE or saline in a randomized blinded protocol, and in 24 to 48 h were anesthetized with urethane (1.2 g/kg intraperitoneally) and instrumented to measure lung resistance (RL) and dynamic compliance (Cdyn). Rats were then challenged with aerosolized DNP-BSA (10 mg/ml), and RL and Cdyn monitored through 7 h after challenge. Both RL (0.30 +/- 0.10 versus 0.13 +/- 0.02 cm H2O/ml.sec-1) and Cdyn (0.41 +/- 0.10 versus 0.25 +/- 0.08 ml/cm H2O) were significantly different (p less than 0.05) in sensitized rats compared to control rats immediately after challenge. No late changes were observed in either the treated or control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Granulocytes from 21 nonasthmatic cystic fibrosis (CF) patients were isolated and the effects of isoproterenol, histamine, and prostaglandin E1 upon zymosan-induced beta-glucuronidase release was measured. Granulocytes from CF patients contained significantly less total beta-glucuronidase activity compared with those from control subjects, but response to zymosan stimulation was normal. Compared with those from control subjects, the granulocytes from CF patients with severe airway disease (% predicted FEV1 less than 60) had significantly reduced responsiveness to isoproterenol, which correlated with both the % predicted FEV1 values and the NIH clinical score. In this same population of CF patients, granulocyte responsiveness to PGE1 was also decreased compared with that of the control subjects, but the degree of impairment was not as severe as that observed with isoproterenol nor did it correlate with disease severity. Histamine responsiveness, however, was normal. Our findings suggest that abnormal beta-adrenergic responses may reflect the severity of airway disease and clinical score.

Pulmonary antigen challenge in sensitized individuals elicits immediate and late phase responses (LPR). While mast cells and tissue inflammation are thought to be vital to the development of the LPR, the precise pathogenesis of these responses remains under investigation. Using the Sprague-Dawley rat as a model to study cutaneous LPR, we have previously demonstrated that rat cutaneous LPR are mast cell-dependent and are histologically characterized by early (1-8 h) neutrophil-rich and late (8-24 h) mononuclear cell-rich infiltrates. To compare and contrast this cutaneous response with IgE-dependent pulmonary inflammatory responses, we performed bronchoalveolar lavage (BAL) analyses of pulmonary inflammation following specific antigen challenge in actively immunized [IgE anti-ovalbumin (OA) antibody] and BAL and histologic analyses in passively sensitized [mouse hybridoma anti-dinitrophenyl (DNP) IgE antibody] rats. Following direct insufflation of OA into the trachea, actively sensitized animals demonstrated an increased number of polymorphonuclear leukocytes (PMNs) at 4 h in BAL fluid. These cell numbers were significantly increased over controls by 24 h following challenge. In addition, rats passively sensitized for 72 h with anti-DNP IgE hybridoma antibody (PCA = 1:10,000) were challenged with DNP-BSA aerosols. Examination of BAL fluid 1 to 2 h following challenge revealed significantly increased numbers of PMNs which returned to normal levels by 24 h. Numbers of lymphocytes and macrophages were unchanged compared to controls. Microscopic examination of lung tissue revealed alveolar and interstitial edema at 2 h following challenge and a focal peribronchiolitis characterized by a predominantly mononuclear cell infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Isoproterenol (ISO), histamine (HIS), and prostaglandin E1 (PGE1) inhibit the in vitro release of the lysosomal enzyme, beta-glucuronidase, from polymorphonuclear leukocytes (PMN) during incubation with complement-coated zymosan particles. In asthma, this granulocyte response to ISO and HIS is impaired. Using this in vitro cell model to assess granulocyte beta-adrenergic response, we studied 23 patients with chronic obstructive pulmonary disease (COPD). All had long-standing disease and severe obstruction (FEV1 = 37.5% of predicted). The granulocyte response to HIS challenge in patients with COPD was normal when compared to control subjects, in contrast to the response from the asthmatic group. The granulocyte response to ISO challenge in patients with COPD, however, was reduced compared to control subjects, but not to the degree found in the asthmatics. This demonstrated that reduced granulocyte response to ISO is not limited to asthmatics, but can be found as well in other obstructive diseases of the lung.