In addition, eosinophils release major basic protein, a granule-derived protein that has potent toxic effects on the respiratory epithelium. The sulfidopeptide leukotrienes and various other mediators, in concentrations that are too small to cause bronchial smooth muscle contraction, can induce an increased contractile response to other bronchoconstrictor substances, resulting in bronchial hyperreactivity. After inhaling microgram quantities of this substance, healthy volunteers acquire a heightened sensitivity to methacholine that can last up to four weeks. Furthermore, when the thickness of an airway wall is increased by edema and cellular infiltration, any degree of smooth muscle contraction will cause greater airflow obstruction than in an airway of normal wall thickness. The consequence of increased airway wall thickness in an asthmatic patient would be an exaggerated obstructive response to bronchoconstrictor stimuli, or airway hyperreactivity.
Many questions remain unanswered by the allergen model of the pathogenesis of asthma.
For example, persons with asthma often have no evident sensitivity to allergens, no excess of circulating IgE antibodies, and no increase in the number of mast cells retrievable on lavage of the lung. Furthermore, the asthma in such patients is clinically indistinguishable in its major features from allergen-triggered asthma in patients with atopy. In addition, it is unknown what sustains the airway hyperreactivity observed in asthmatic patients even in the absence of airflow obstruction. An alternative hypothesis for the pathogenesis of asthma implicates abnormalities in the autonomic neural regulation of airway function. Increased stimulation of the afferent limb of the parasympathetic reflex.