Role of Tachykinins in Asthma and Allergic Disease - New Insights to Neuroimmune Biology - page 167

on the endothelium of both veins and arteries [37] . Inflammatory cells such as mac-
rophages, lymphocytes, neutrophils, dendritic cells, and mast cells also express func-
tional tachykinin NK 1 receptors [24,26,27,38,39] .
9.3 Role of Tachykinins in Respiratory Pathophysiology
Tachykinins elicit a broad spectrum of biological activity (in the cardiovascular,
gastrointestinal, urogenital, immune, and nervous systems), which may vary in dif-
ferent species and even in the various strains of single species [4] . This strongly sup-
ports the concept of a general, important functional significance of these peptides.
However, mice with a disrupted preprotachykinin I gene (TAC1 gene, encoding for
substance P and neurokinin A and its extended forms) or a disrupted tachykinin NK 1
or NK 3 receptor gene (the TACR1 and TACR3 genes) remain in good health and fer-
tile, which demonstrates that neither the tachykinins substance P and neurokinin A,
nor the tachykinin NK 1 and NK 3 receptors, are essential for life and health, at least
in mice.
The adequate stimuli for tachykinin release from the sensory nerves in the airways
are of chemical nature (especially chemicals that are produced during inflammation
and tissue damage). Given this fact, it can be suggested that tachykinin release occurs
only in response to pathological, rather than physiological, conditions. However,
because an important interaction exists between the airways and the external envi-
ronment, this can also be interpreted as a mechanism to detect potential hazardous
stimuli and to react physiologically to such stimuli.
9.3.1 Airway Smooth Muscle Tone and Airway Responsiveness
The bronchoconstrictor effect of exogenous substance P was first reported in 1977 in
guinea pigs and cats. Since then, substance P has been shown to cause dose-dependent
bronchoconstriction in various animal species, both in vitro and in vivo [40-42] .
Exogenous tachykinins are also contractors of human airways. This too has been
demonstrated both in vitro and in vivo . Substance P contracts human bronchi and
bronchioles, but is less potent than histamine or acetylcholine in doing so [41,43] .
Neurokinin A is a more potent constrictor and is, on a molar basis, 2-3 orders of
magnitude more potent than histamine or acetylcholine. Neurokinin B does not exert
a contractile action on human airways [44] . The tachykininergic contraction was
demonstrated to become more important in more distal airways [45] . In vivo , inha-
lation or intravenous infusion of tachykinins also influences bronchomotor tone in
humans, although the observed effects are rather small. Intravenously administered
substance P had demonstrable effects on the vascular smooth muscle and control of
ventilation, but showed little effect on airway function [46] . Another study reported a
bronchodilating effect of intravenous substance P while neurokinin A-induced bron-
choconstriction [47] . Inhalation of substance P or neurokinin A did not influence
airway conductance in healthy individuals [48] , unless the activity of the degrading
enzyme neutral endopeptidase was blocked by thiorphan [49] .