Vol. 85, Issue 4, 1201-1202, October 1998
INVITED EDITORIAL
Invited Editorial on "Comparison between the uptake of nitrous
oxide and nitric oxide in the human nose"
John B.
Morris
Toxicology Program, Department of Pharmaceutical Sciences,
University of Connecticut, Storrs, Connecticut 06269
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ARTICLE |
IN 1924, HAGGARD
(5) stated that "the more soluble the
irritant the greater the damage to the upper respiratory tract since it
is there that a highly soluble irritant is largely removed from the
air." This statement indicates that the phenomenon and mechanisms of
nasal gas scrubbing have long been appreciated. Perhaps spurred by the
discovery that inhaled formaldehyde is a rodent carcinogen, there have
been many studies of mechanisms of nasal gas exchange in laboratory
animals. Surprisingly, there have been few, if any, systematic studies
of gas exchange in the human nose. The recent discovery that the nose
is a significant source of nitric oxide in exhaled air in humans has
spurred interest in this area. The studies described by Kelley and
DuBois (7) in this issue of the Journal have relied on the framework of
knowledge derived from animal studies to examine mechanisms of nitric
oxide disposition and exchange in the human nose.
The mechanisms of gas exchange in the nose are no different than those
in the tracheobronchial tree. Under normal cyclic breathing, exchange
behavior of inhaled gases is quite complex, with uptake occurring
during inspiration and desorption (release) occurring during
exhalation. These complexities have been clearly described by Hlastala
(6). In contrast, gas exchange under constant-velocity continuous flow
is mechanistically simpler, and thus definitive information relative to
uptake pathways can be reliably obtained under these conditions.
Indeed, for this reason, gas uptake has been measured under these flow
conditions in animals for over 50 years (1). The work by Kelley and
DuBois (3, 7) is significant in that it documents a simple noninvasive
procedure by which similar measurements can be made in humans.
Under constant-velocity flow, continued uptake of vapor from the
airstream into nasal tissues is dependent on continued removal of vapor
from the nasal air-to-tissue interface. Were there no such removal,
vapor concentrations at the nasal interface would quickly increase
until the concentrations in the air and tissue sides of the interface
reach equilibrium based on Henry's law. In the rat, continuous
steady-state vapor uptake in the nose can be demonstrated for exposure
periods as long as 1 h (9). With the several-minute exposure period
used in the study of Kelley and DuBois (7), it was possible to
quantitate nitrous oxide uptake under steady-state conditions. It is
these steady-state uptake data that provide the clearest insights into
nasal gas-exchange mechanisms.
At steady state, the rate at which gas enters nasal tissues must
exactly equal the rate at which it is removed from that site. For inert
gases such as nitrous oxide, diffusion to and clearance via the
bloodstream represent the only path of removal (9, 12). Nasal uptake of
inert gases depends on the airflow rate, depth of the air and tissue
phases (which determines the degree of any air- and/or
tissue-phase diffusion limitation), blood flow rate, and solubility of
gas in blood (as measured by the blood-to-air partition coefficient).
The greater the solubility, the greater is the capacity of nasal blood
to carry gas and the greater the uptake efficiency. Sufficient data
have been collected in the rat to define the relationship between
partition coefficient and uptake, and mathematical simulation models
have been developed that incorporate nasal anatomy, airflow patterns,
and gas physicochemical properties (4, 10). Unfortunately, insufficient
data are available on humans to determine whether such models also
apply to uptake in the human nose. By providing data on the effect of inspiratory flow rate on steady-state uptake of the inert gas nitrous
oxide, the study of Kelley and DuBois (7) provides valuable data in
this regard.
Because of limited perfusion rates, the nose has a finite capacity to
scrub inert gases from the airstream. This limitation does not apply to
reactive gases, because such gases can also be removed for the nasal
tissues by direct chemical- and/or enzyme-mediated pathways.
These processes lead to enhanced uptake efficiencies. Nasal uptake of
both metabolized and directly reactive gases has been studied in
animals. For metabolized vapors, not only are uptake efficiencies
greater than can be explained by blood clearance alone, but
pretreatment with metabolic inhibitors dramatically reduces uptake (8,
10). Xenobiotic metabolizing activities in nasal mucosa are quite high,
often higher on a tissue-weight basis than in the liver (2), and nasal
first-pass metabolism of inspired vapors is in many ways analogous to
hepatic first pass metabolism of ingested materials (8).
For highly soluble and directly reactive gases, nasal scrubbing
capacities in excess of 98% have been observed in both rats (11) and
humans (13). This is not surprising because the nose is adapted for
heating and humidifying the airstream, and the dynamics of this process
are similar to those of gas exchange. That the nose is capable of total
scrubbing is an important observation because it indicates that the
documentation of <100% uptake for any specific gas is not reflective
of some inherent incapacity of the nose for total scrubbing but is
reflective of the accumulation of gas at the air-to-tissue interface in
sufficient concentration to retard the uptake process. Therefore,
processes that control the concentration of gas in the nasal tissue
phase (e.g., blood clearance, metabolism, reactivity) also serve to
control uptake. Conversely, appropriate measurement and interpretation
of nasal uptake efficiencies can provide key insights into gas
disposition within nasal tissues. In this context, the conceptual basis
for the approach of Kelley and DuBois (7) is quite clear and logically sound. Nasal uptake of nitric oxide is very much greater than can be
explained on the basis of its solubility, thus indicating that chemical
reactivity is the predominant factor influencing nasal tissue
disposition of this gas. Future studies using the noninvasive technique
of Kelley and DuBois (7) may provide key insights into the critical
reactive pathways for nitric oxide in nasal tissues. Such studies would
not only enhance our knowledge of nitric oxide disposition in humans
but may also enhance our knowledge of the nasal gas-exchange process
itself.
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J APPL PHYSIOL 85(4):1201-1202
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Copyright © 1998 the American Physiological Society
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