Role of Tachykinins in Asthma and Allergic Disease - New Insights to Neuroimmune Biology - page 165

9.2 Localization and Production of Tachykinins
in the Airways
The tachykinin peptide family is one of the largest peptide families described in the
animal organism. They have been isolated from invertebrate, protochordate, and ver-
tebrate tissues. Tachykinins , defined as peptides having the characteristic C-terminal
pentapeptide F-X-G-L-M-NH 2 , are identified as aromatic when X is an aromatic
amino acid residue (F or Y) or aliphatic when X is an aliphatic amino acid residue
(V or I). All tachykinins are amidated at the C-terminus, and this is crucial for their
biological activity [4] . The four major mammalian tachykinins are substance P, neu-
rokinin A, neurokinin B, and the recently discovered hemokinin 1 [7] .
Mammalian tachykinins are derived from three preprotachykinin genes that,
according to the Human Genome Organization (HUGO) Gene Nomenclature
Committee ( http:// www.gene.ucl.ac.uk/nomenclature/ ) are known as TAC1, TAC3,
and TAC4. The TAC1 gene (previously known as the PPT-I or PPT-A gene) codes for
substance P, in addition to neurokinin A and its extended forms [8-10] . The TAC3
gene (also known as PPT-II or PPT-B) encodes the sequence for neurokinin B [11] .
Hemokinin 1 is coded by the TAC4 gene (or PPT-C) [12,13] .
Tachykinins (substance P, neurokinin A, and neurokinin B) have previously been
considered a neuropeptide group because of their widespread distribution in the cen-
tral and peripheral nervous systems (capsaicin-sensitive primary afferent neurons and
capsaicin-insensitive intrinsic neurons). This terminology is no longer used, because
their presence in a variety of nonneuronal structures has been demonstrated repeat-
edly [4,14] . Furthermore, mRNA expression studies suggest that hemokinin 1 has a
unique distribution outside neuronal tissues [15] .
In the airways, a distinct subpopulation of primary afferent nerves that are char-
acterized by their sensitivity to capsaicin are considered to be the principal source
of substance P and neurokinin A [16,17] . Although these tachykinins can also be
expressed in capsaicin-resistant neurons [18,19] , capsaicin pretreatment of experi-
mental animals caused an almost total depletion of substance P and neurokinin A
immunoreactivity [17,20] . Radioimmunoassay and immunohistochemistry demon-
strated substance P- and neurokinin A-positive nerves beneath and within the epithe-
lium, around blood vessels and submucosal glands, and within the bronchial smooth
muscle layer [17,21] . In guinea pigs, airway sensory nerves containing tachykinins
are easily located, but in human airways, tachykinergic innervation is sparse. In the
bronchial tree, tachykinergic sensory innervation originates from the (right) vagus
nerve, whereas in the lung the fibers are of both vagal parasympathetic and thoracic
spinal origin [17] . Additional, nonneuronal sources of tachykinins in the airways
have been reported. Chu and colleagues demonstrated staining for substance P in the
airway epithelium [22] , and Maghni and co-workers reported the presence of sub-
stance P in airway smooth muscle cells [23] . There is also evidence for the produc-
tion of substance P by eosinophils, monocytes and macrophages, lymphocytes, and
dendritic cells [24-27] . Immunoreactivity for neurokinin B has not yet been found in
the airways. Polymerase chain reaction (PCR) techniques demonstrated transcripts