Neurogenic Inflammation: Additional Points
William Meggs's recent article, "Neurogenic Inflammation and Sensitivity
to Environmental chemicals" (EHP 101:234- 238), provides a useful
introduction to a rapidly growing area of knowledge in physiology and posits
a number of interesting hypotheses regarding the health effects of airborne
chemicals. Some specific technical points, however, merit comment.
Meggs describes the common chemical sense as "a nasal sensation
provoked by airborne chemicals" (p. 234, my emphasis). This statement
is correct as far as it goes, but it neglects to mention that the trigeminal
nerve also innervates the oral cavity and that ingested irritants
(e.g., capsaicin, the irritant in hot peppers, and allyl isothiocyanate,
the irritant in horseradish) trigger some of the same reflexes as inhaled
irritants. Thus, so-called gustatory rhinitis involves rhinorrhea, nasal
congestion, and facial sweating after ingestion of "hot" (spicy)
foods (1). As to whether the common chemical sense was only "recently
separated" from olfaction as a sensory modality (p. 235), the 1990
study of odor and nasal pungency in anosmics cited by Meggs (2) is
but the latest in a series stretching back over 80 years and utilizing various
tools to separate the two sensory systems (3).
Neuropeptide release occurs in relation to other types of airway reflexes,
some of which do, indeed, involve an efferent limb coming from the central
nervous system, as portrayed in Meggs's Figure 2. Gustatory rhinitis, for
example, involves afferent trigeminal sensory fibers and efferent
facial nerve cholinergic fibers and is blocked by the preadministration
of atropine (1). In contrast to Figure 2, however, the axon reflex
(whereby neuropeptides are released) is a primarily afferent process,
involving release of neuropeptides from varicosities in sensory nerves
(4). Thus, neuropeptide release can be thought of as a local, as
opposed to a central, reflex. What is clear is that a complex interrelationship
exists between local (neuropeptide-mediated) and central (adrenergic, cholinergic,
and nonadrenergic/noncholinergic) airway reflexes. Each of these mechanisms,
as well as mast-cell degranulation (atopy), is subject to various regulatory
factors, ultimately influencing upper and lower airway reactivity to environmental
stimuli.
Meggs briefly mentions the variety of neuropeptides documented in human
airways (substance P, calcitonin gene-related protein, neurokinin A, and
others), but then goes on to focus on the role of substance P. The relative
distribution of neuropeptides and their physiological actions appear to
vary across species, making generalizations difficult at this time (5).
For example, whereas substance P promotes neutrophil and eosinophil chemotaxis
and adhesion, its role in mast cell function appears to be that of potentiating
other stimuli, rather than as an independent stimulus for degranulation,
as Meggs suggests (6).
One aspect of the relationship between neurogenic and immunogenic inflammation
not touched upon in the article is the fact that individuals with a history
of atopy seem to be at higher risk of reactivity to airborne irritants,
even when there is no evidence of an allergic mechanism of response. Thus,
while both Bascom et al. (5) and Cummings et al. (7) observed
a higher prevalence of environmental tobacco smoke (ETS)-related upper airway
symptoms among subjects with a history of atopy, neither assays for allergic
mediators in nasal lavage fluid (5) nor skin test reactivity to tobacco
leaf extracts or tobacco smoke condensates (8) suggests an allergic
mechanism of response. These data are consistent with a role for neuropeptides
in the genesis of ETS-related nasal symptoms, as well as a modulatory effect
of atopy upon neuropeptide release (9). Thus, atopy may constitute
one of the most important "disorders of regulation of neurogenic inflammation"
referred to by Meggs (p. 236).
An understanding of respiratory tract responses to irritant chemicals
requires familiarity with concepts in allergy/immunology, sensory science,
and toxicology. Meggs has made an important and accessible contribution
to the literature by discussing neurogenic inflammation as a component of
the airway response.
Dennis Shusterman
Air Toxicology and
Epidemiology Section
Office of Environmental
Health
Hazard Assessment
California Environmental Protection Agency
References
1. Raphael GD, Baraniuk JN, Kaliner MA. How and why the
nose runs. J Allergy Clin Immunol 87:457-467(1991).
2. Cometto-Muniz JE, Cain WS. Thresholds for odor and nasal
pungency. Physiol Behav 48: 717-725(1990).
3. Parker GH. The reactions of smell, taste, and the common
chemical sense in vertebrates. J Acad Natl Sci Phil 15:221-234(1912).
4. Barnes PJ. Neuropeptides in the respiratory tract: parts
I and II. Am Rev Respir Dis 144: 1187-1198;1391-1399(1991).
5. Bascom R, Kulle T, Kagey-Sobotka A, Proud D. Upper respiratory
tract environmental tobacco smoke sensitivity. Am Rev Respir Dis 143:1304-1311(1991).
6. Tam EK, Hua X-Y. Substance P augments tracheal mast
cell release induced by electrical stimulation [abstract]. Am Rev Respir
Dis 147: A711(1993).
7. Cummings KM, Zaki A, Markello S. Variation in sensitivity
to environmental tobacco smoke among adult non-smokers. Int J Epidemiol
20:121-125(1991).
8. Stankus RP, Sastre J, Salvaggio JE. Asthma induced by
exposure to low molecular weight compounds and cigarette smoke. In: Current
pulmonology, vol 9 (Simmons DH, ed). Chicago:Year Book, 1988;369-394.
9. Bascom R. Differential responsiveness to irritant mixtures:
possible mechanisms. Ann NY Acad Sci 641:225-247(1992).
Neurogenic Inflammation: Literature on Toluene Diisocyanate
I am writing in regard to the article by William Meggs in the August
1993 edition of EHP (101:234-238). I was surprised to see that in
a review article of this type, the author made no mention of the work of
our group on the well-known chemical sensitizer toluene diisocyante and
its action on capsaicin-sensitive primary afferents. For your information,
I enclose a list of papers in question:
Mapp CE, Boniotti A, Graf PD, Chitano P, Fabbri LM, Nadel
JA. Bronchial smooth muscle responses are inhibited by ruthenium red and
by indomethacin. Eur J Pharmacol 200:73(1991).
Mapp CE, Boniotti A, Graf PD, Plebani M, Masiero M, Fabbri
LM, Ciaccia A. Role of metabolites of arachidonic acid in toluene diisocyanate-induced
contraction on guinea-pig bronchi. Eur Respir J 4:435(1991).
Mapp CE, Boniotti A, Papi A, Chitano P, Coser E, Di Stefano
A, Saetta M, Ciaccia A, Fabbri LM. The effect of compound 48/80 on contractions
induced by toluene diisocyanate in isolated guinea-pig bronchus. Eur J Pharmacol
248:67- 73(1993).
Mapp CE, Boniotti A, Papi A, Chitano P, Saetta M, Di Stefano
A, Ciaccia A, Fabbri LM. The effect of phosphoramidon and epithelium removal
on toluene diisocyanate-induced contractions in guinea-pig bronchi. Eur
Respir J 5:331-333(1992).
Mapp CE, Boniotti A, Papi A, Maggi CA, Di Stefano A, Saetta
M, Ciaccia A, Fabbri LM. Effect of bumetanide on toluene diisocyante-induced
contraction in guinea-pig airways. Thorax 48:63-67(1993).
Mapp CE, Chitano P, Fabbri LM, Patacchini R, Maggi CA.
Pharmacological modulation of the contractile response to toluene diisocyanate
in the rat isolated urinary bladder. Br J Pharmacol 100:886-888(1990).
Mapp, CE, Chitano P, Fabbri, LM, Patacchini R, Santicioli
P, Geppetti P, Maggi CA. Evidence that toluene diisocyanate activated the
efferent function of capsaicin-sensitive primary afferents. Eur J Pharmacol
180:113 (1990).
Mapp CE, Graf PD, Boniotti A, Nadel JA. Toluene diisocyanate
contracts guinea-pig bronchial smooth muscle by activating capsaicin-sensitive
sensory nerves. J Pharmacol Exp Ther 256:1082-1085(1991).
Cristina Mapp
Università di
Padova
Padova, Italy
Response to Shusterman and to Mapp
There has been an explosion of investigations into the basic science
of neurogenic inflammation and its regulation in recent years, and it was
beyond the scope of my review to give an exhaustive bibliography of the
field. I apologize to those investigators whose excellent and relevant works
were not included in the discussion. I am grateful to Dennis Shusterman
for his clarifying remarks. The relationship between sensitivity to airway
irritants and atopy is a complicated one that needs further study. In my
clinical experience, there are patients with chemical irritant rhinitis
or asthma who are not atopic, atopic individuals who are not sensitive to
chemical irritants, and an overlap group. Study of these groups may clarify
this issue. It is my opinion that over the next few years we will move beyond
the basic science of neurogenic inflammation to learn that it plays a major
role in clinical medicine and environmental health and that a number of
disorders are exacerbated by environmental chemicals interacting through
sensory nerves to produce neurogenic inflammation. This knowledge will be
useful to patients and clinicians as well as to regulators.
William Meggs
East Carolina University
Greenville, North Carolina
Whose Sperm?
This letter is prompted by the illustration accompanying a news item,
"Sperm: Down for the Count," (EHP 101:283) with substantial
attribution to Sharpe and Skakkebaek. The problem is not with the content
of the text, but with the illustration. It is evident that the illustration
on page 283 is a portion of a seminiferous tubule from a rat and not a human.
This is readily discernible by the hook-shaped nuclear morphology of the
spermatids, near the lumen and elsewhere in the illustration. The appearance
of a human seminiferous tubule is very different, although certainly illustrations
of a human seminiferous tubule could have been provided by Skakkebaek or
individuals resident at NIEHS. I recognize that the caption to the illustration
includes the words "and animals," but association of the illustration
with a text devoted primarily to humans strikes me as imprudent.
I considered ignoring this inconsistency, but thought it appropriate
to call it to your attention because of the otherwise excellent quality
of Environmental Health Perspectives.
R. P. Amann
College of Veterinary Medicine
and Biomedical Sciences
Colorado State University
Fort Collins, Colorado
Editor's Note: The forum article on sperm counts was not derived directly
from Sharpe and Skakkebaek, but merely sypnopsized a report authored by
them. Unfortunately, we were unable to obtain a photomicrograph of human
sperm in time for publication and used the photomicrograph of rat sperm
as an alternative. The photomicrograph was kindly provided by Bob Chapin
of the Systems Toxicity Branch of NIEHS.
Last Update: August 18, 199
