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initially appeared somewhat site-specific. Early studies showed NOS presence in bronchial
epithelial cells with little in the respiratory terminal bronchi, smooth muscle cells or alveolar
sacs. However, this changed following stimulation of the iNOS enzyme, when there was some
mild uniform labelling of epithelium in large cartilaginous airways with iNOS in normal
trachea and main bronchi, but with much grcatet labelling in the more peripheral bronchi'
This was first demonstrated when comparing normal and inflamed rat lung samples that had
been stimulated with intra-tracheal lipopolysaccharide, and in human tissue from four airway
and ten parenchymal specimens obtained from uninvolved areas of surgical tumour resections
stimulated with TNF0. While the presence of the constitutive forms along the bronchi before
the infective stimulation seemed appropriate given the eNOS and nNOS activity in
physiological regulation, it was uncertain why iNOS should be seen there. The researchers
suggested that it may be in response to continual low grade induction of iNOS activity in
response to airborne toxins (Hamid, Springall et al. 1993; Kobzik, Bredt et al' 1993)'
Turning from the presence of the enzymes to NO itself: when administered exogenously, NO
gas was shown to relax tracheal and airway smooth muscle in vitro taken from different
sources such as bovine trachea, guinea pig trachea and human airway smooth muscle (Jansen'
Drazen et al. 1992). The gas also had the capacity to relax tissues that had previously been
constricted with methacholine, histamine or leuktriene Da (Jansen, Drazen et al. 1992; Gaston,
Drazen et al. Igg4). NOS inhibition resulted in exaggerated bronchosconstrictor responses in
animal models (Ricciardolo, Mistretta et al. 1996; Nogami, Umeno et al' 1998; Boer'
Duyvendak et al. 1999) and human specimens (Ricciardolo, Di Maria et al. 1997; Taylor,
McGrath et al. 1998). These responses suggested that NO had a role in modulating basal
airway tone both directly and via the NANC nerves and, as discussed previously in Chapter 2,
is now thought to be one of the main mediators for regional airflow and blood flow matching'
The reaction products of NO such as s-nitrosoglutathione and s-nitrosalbumin also had
bronchodilator effects (Jansen, Drazen et al. lgg2; Asano, Chee et al. 1994; Gaston, Drazen et
al. 1994;Gaston, Drazen et al. 1994; Bannenberg, Xue et al. 1995) with lower levels noted in
asthmatics (Gaston, Sears et al. 1998). In the lung, low concentrations of NO caused ainvay
smooth relaxation during bronchospasm (Buga, Gold et al. 1989; Jansen, Drazen et al' 1992;
Gaston, Drazen et al. Igg4). As seen systemicallY, the NO production from the eNOS
isoenzyme was found to maintain vasomotor tone (Stamler, Osborne et al. 1993)' Pulmonary
arterial endothelial cells released NO in response to acetylcholine and bradykinin agonists
which relaxed pulmonary arterial, venous and lymphatic smooth muscle (Crawley, Liu et al'
1990; Dinh-Xuan, Higenbottam et al. 1991). Release of NO from endothelial cells in the
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