Toxicology of Industrial Compounds

130 PULMONARY HYPERREACTIVITY TO INDUSTRIAL POLLUTANTS
Subsequent re-epithelialization and probable reinervation of bronchial
mucosa might drastically alter the threshold of the receptors and cause
airways hyperreactivity. It has been hypothesized that damage to airway
epithelium by irritant chemicals could decrease the threshold of sensory
endings within the mucosa, resulting in increased afferent and efferent vagal
activity. Airway mucosal inflammation, activation of airway afferent
nerves, and the release of low-molecular-weight neuropeptides as
mediators of inflammation are known to affect the tonus of the airway
smooth muscle and may play a crucial role in the acute increase in airway
hyperresponsiveness occurring after exposure to irritant or inflammatory
stimuli. Additionally, inflammatory mediators may further attract and
activate inflammatory cells, which themselves release a whole array of
chemotactic and cytotoxic mediators that serve to perpetuate and amplify
the inflammatory response. This complex interaction of different factors
may result in epithelial desquamation, mucus gland hyperplasia, smooth
muscle hypertrophy, and eventually render the airways hyperreactive to
specific as well as nonspecific stimuli.
Increased bronchial irritability, or hyperresponsiveness, to a wide variety
of chemical agents and physical stimuli is also a major characteristic
feature of bronchial asthma and the reactive airways dysfunction syndrome
might clinically be indistinguishable from the asthma syndrome. Also for
the latter, particular attention has been placed on the role of inflammation
mediated influx of cells, mediator release and the interaction of irritant
induced neurogenic and inflammatory factors. Neural control of airway
caliber is far from being simple and it is likely to contribute to airway
narrowing and bronchial hyper-responsiveness. Myelinated and
nonmyelinated nerve fibers (C fibers) are involved in the sensory irritation
response and their stimulation may result in release of specific
neuropeptides, known to be potent releasers of mediators from airway
mast cells (Barnes et al., 1991a, b; Nielsen, 1991). Specific neuropeptides
are also known to attract eosinophils which can be stimulated to release
cytotoxic mediators that may exacerbate these pseudoallergic-like
responses even further. Experimental and clinical studies have intimated
that there is reason to suspect that acute exposure to brief high-level
concentrations of asthmagenic chemicals and the development of increased
airway hyperresponsiveness are associated. Thus, it could be assumed that
specific mast cell sensitization—in combination with neurogenic stimuli—
amplify the inflammatory process and airway hyperresponsiveness. The
corresponding increase in vagal activity would increase reflex release of
acetylcholine and, correspondingly, may enhance airway responsiveness
following the exogenous administration of cholinergic agents.
Animal models of airway inflammation might allow us to investigate this
relationship further. Models of allergic pulmonary inflammation have been
developed in various animal species (Kips et al., 1992), using different