The pathogenesis of allergenic asthma has been described in two pathogenetic theories (Fig 1).
The direct theory is derived from the original observations of allergists that some patients with allergic rhinitis, especially children, have atopic bronchospasm as well. Specific IgE-antibody is fixed to airways, and bivalent linking with specific antigen-E (pollen, dander) results in initiation of the synthesis and secretion of mediators of inflammation by respiratory mast cells. Histamine and other mediators cause bronchoconstriction by direct stimulation of airway smooth muscle contraction. Histamine is the best studied mediator of this reaction and has been shown to cause bronchoconstriction through stimulation of the Hi-receptor on airway smooth muscle. Hr-receptors are present on both airways and mast cells; these receptors may inhibit release of histamine from respiratory mast cells and may inhibit airway smooth muscle contraction.
In the indirect theory of asthma, histamine is regarded as being relatively unimportant as a direct bronchoconstrictor. This theory is derived from the observation of Gold and coworkers from a canine model of asthmatic bronchoconstriction. These investigators administered aerosolized As–carts suum antigen unilaterally to one lung of natively allergic dogs and observed that bronchoconstriction occurred bilaterally. Administration of atropine or cooling of the ipsilateral vagus nerve blocked bronchoconstriction to unilaterally inhaled Ascaris antigen in both lungs. It was concluded that mast cell secretion did not cause direct bronchoconstriction in this canine model and that an afferent vagal irritant (rapidly-adapting) receptor was stimulated by mast cell degranulation. Bronchoconstriction occurred from efferent vagal output after amplification of the irritant receptor stimulus in the central nervous system.
In contrast to the canine model, the irritant receptor does not appear to play a significant role in human atopic asthma. Rosenthal and co-workers have shown that cholinergic blockade diminishes the irritant receptor response to bronchial challenge with methacholine and citrate, but does not alter the response to antigenic challenge in the same atopic humans. They concluded that parasympathetic reflexes are not a major component of the human response to antigen-induced bronchospasm.
Much adult asthma, however, is nonatopic, and nonspecific irritant receptor response may be of prime importance in these situations. Empey et al showed that asthmatic humans with respiratory infections had increased bronchial reactivity, which resembled that of asthmatics. This acquired hyper-reactivity could be blocked with inhaled atropine. After resolution of the respiratory infection, airway reactivity returned to normal and the acquired hyperreactive response was lost. Similar airway hyperreactivity occurs in normal humans after inhalation of ozone. Viral infections and ozone may lower the threshold of rapidly adapting receptors, making normal persons potential asthmatics.
Other factors may also account for differences in airway response between asthmatic and nonasthmatic individuals. Some investigators have demonstrated a marked variability in histamine response in humans and dogs which is not observed for other constrictor agonists. One recent investigation has shown non-reflex vagal augmentation of histamine-induced bronchoconstriction in canine airways (see below). Antonissen and co-workers have proposed that smooth muscle contraction dynamics may be altered by repeated antigenic challenge. Dogs repeatedly sensitized with bovine serum albumin acquired airway smooth muscle hypercontractility in comparison to littermate controls.
Figure 1. 1. Direct Theory: Antibody is fixed to respiratory mast cells. Bivalent cross-linking with specific antigenE causes mast cell synthesis and secretion of mediators, which act directly on airway smooth muscle to cause bronchoconstriction. 2. Indirect Theory: Bronchoconstriction results from stimulation of afferent vagal irritant receptors, and the response is amplified in the central nervous system causing reflex, cholinergically mediated bronchoconstriction. Histamine is one of a number of possible stimuli to the irritant receptor, but histamine does not cause direct bronchoconstriction. Reflex bronchoconstriction may account for some non-atopic types of asthma in humans, but is probably not important in human atopic asthma (see text).