Prejunctional factors potentially increase sensitivity. They include increased access of the agonist to the “milieu interne” on account of epithelial damage and shedding, such as by major basic protein or viral infections ( a ).
The epithelial tight junctions may be abnormally permeable ( b ), and there may be impairment of epithelial metabolic functions, such as the production of epithelial derived relaxant factor (EDRF) or of endopeptidases. Epithelial cells may also produce mediators and cytokines that lead to secondary recruitment of cells and thus enhance the inflammatory response.
The increased inflammatory infiltrate, microvascular congestion, and plasma exudation ( c ) leads to mucosal and submucosal swelling; by itself it will onlt raise flow resistance by a small amount, but more importantly subsequent smooth muscle contraction results in a greater luminal narrowing and a greater increase in resistance due to the thicker airway wall internal to the smooth muscle.
Activated inflammatory cells, such as macrophages, mast cells, eosinophils, lymphocytes and neutrophils ( d ) which are present in increased numbers in airways of asthmatics, release inflammatory mediators and cytokines. Such mediators include prostaglandins, leukotrienes, adenosine-mono-phosphate, platelet activating factor, and multiple interleukins, which have all been shown to increase non-specific responsiveness. Also mediators and cytokines may be released from epithelial cells ( e ).
Dysfunction of the autonomic nervous system has been incriminated, such as increased cholinergic reflex activity ( f ) and enhanced neurotransmission in cholinergic ganglia. There is no convincing evidence that there is a primary defect in the adrenergic system. Excitatory nonadrenergic noncholinergic (eNANC) traffic ( f ) also amplifies prejunctional bronchoconstrictor stimuli. Recent but controversial experiments suggest that there is a deficiency in vaso-active intestinal peptide, one likely neurotransmitter of non-adrenergic relaxation, and an increase in nerves containing substance P, a likely transmitter of non-cholinergic excitation [1-2]. Apart from that there may be direct nerve stimulation (axon reflexes) by substances delivered to the airway mucosa ( b ), or indirectly via ganglion cells ( g ).
Prejunctional stimuli may be enhanced by decreased breakdown or removal of substances ( h ), or alternatively attenuated by their clearance via the blood stream.