EDITORIAL FOCUS
The stuff of life: an integrated inflammatory response
Aubrey E.
Taylor
Department of Physiology, College of Medicine, University of South
Alabama, Mobile, Alabama 36688
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ARTICLE |
THE PAPER BY MARTIN ET AL.
(6) in this issue of the American Journal of
Physiology-Lung Cellular and Molecular Physiology presents
important new information concerning the time-dependent effects of two
cytokines, tumor necrosis factor-
(TNF-
), and interleukin-1
(IL-1
), on rat lung airway resistance. There is a large literature
on cytokine and chemokine release and their actions during the
inflammatory response relative to endothelial barrier function, but
little is known about the effects of these important messengers on
airway smooth muscle. The study by Martin et al. contains three very
important findings: 1) after airway constriction with
methacholine, IL-1
and IL-1
plus TNF-
but not TNF-
alone
dilated the airways; 2) when either TNF-
or IL-1
was
given to lungs in which the airways were not constricted, neither
cytokine altered airway resistance; and 3) after 40 min of
challenge with both cytokines, airway resistance began to increase and
was associated with an upregulation of cyclooxygenase-2 (COX-2) mRNA
expression and a "thromboxane-dependent" bronchoconstriction. In
addition to this perfused lung study, another study from this group
(5) adopted the technique of Krumdieck et al.
(4) of using precision-cut lung slices to evaluate the
effects of cytokines on airway smooth muscle tone. A combination of
TNF-
, IL-1
, and interferon-
(IFN-
) contracted airways in
thin lung slices by increasing COX-2 activity and thromboxane release;
yet, these cytokines individually failed to cause airway constriction. These two studies clearly showed that although cytokines such as
TNF-
, IL-1
, and IFN-
individually produce little or no effect on airway resistance, the combined treatment with and IL-1
and TNF-
produced bronchial constriction by upregulating COX-2 and the
subsequent release of thromboxane. Surprisingly, this challenge with
cytokines can produce either dilation or constriction depending on the
state of airway tone and the time expired after introduction of the cytokines.
Interestingly, Khimenko et al. (3) have found that
TNF-
is required to produce ischemia-reperfusion (I/R)
endothelial injury in isolated rat lungs because a specific antibody to
TNF-
blocked I/R injury. However, when TNF-
was placed into the
circulation of a normal lung, no damage occurred to the endothelial
barrier over the same time frame. But, when TNF-
was given to lungs
challenged with I/R, endothelial damage was significantly elevated
(3). This was at first a puzzling finding. But as we
studied the inflammatory response in more depth, we realized that
blocking a particular cytokine may prevent the inflammatory response if
it is a component of a series interaction with other cytokines,
chemokines, leukocytes, and/or endothelial factors, whereas the
cytokine given alone may produce no endothelial damage in normal lungs
in the absence of other required factors.
A recent workshop summary by Crapo et al. (2) clearly
indicates that we must understand the total time frame of the immune response of the lung relative to the actions of alveolar macrophages, T
lymphocytes, B lymphocytes, neutrophils, eosinophils, mast cells, basophils, oxidative stress, prostaglandins, interleukin-10,
transforming growth factor-
, IL-1, and various receptor agonists and
antagonists before we can determine the mechanisms underlying the
development of acute respiratory distress syndrome, asthma,
bronchopulmonary dysplasia, emphysema, lung injury,
interstitial lung disease, and pulmonary hypertension. I would add to
this list that we also must understand the response of helper and
nonhelper T cells, endothelial-neutrophil rolling and adherence
factors, and the subsequent production of IL-1, IFN-
, and TNF-
during the inflammatory responses that result in the endothelial
junction openings that promote fulminating pulmonary edema.
Other questions also come to mind when considering the inflammatory
responses in lungs: how does the inflammatory response affect other
lung functions such as alveolar epithelial transport systems, airway
and vascular smooth muscle, cilia mucus clearance, airway
epithelial cell activity, and airway mucous gland activity?
There is absolutely no doubt that we can now critically study the
response of the lung to inflammation associated with infections, lung
I/R conditions, and the injury associated with remote inflammation such
as seen in the intestinal I/R model of lung endothelial damage (1). The ability of the endothelial and epithelial cells
of the lung to communicate with blood lymphocytes, tissue macrophages, and basophils influences not only the initial degree of lung damage but
also alters the healing process. This system constitutes the most
important and fascinating system in the body, yet it is perhaps the
least understood of all control systems! The ability of the inflammatory system to operate correctly when challenged is the "thing life is made of" because it allows all living
creatures, including humans, to live a long and productive life in a
constantly changing internal and external environment. The immune
response is a wondrous and complicated system that will keep us busy in our laboratories for years to come as we begin to sort out how these
"pheromones" protect our bodies in both health and disease.
The paper by Martin et al. (6) emphasizes the complexity
of this system using a simple research tool, isolated rat lungs, which
clearly show that we need not only evaluate endothelial function during
the inflammatory response but also study the associated changes in
airway and vascular resistances. From their data, it is clear that many
airway diseases may likely result when the inflammatory response goes
"helter-skelter." It is not sufficient to measure the actions of
one or two chemokines or cytokines and from that information
characterize the inflammatory system as it reacts to various lung
insults. Several cells, cytokines, chemokines, and systems obviously
work in concert to produce an effect that the paper of Martin et al.
shows is also a function of time and the subsequent release of
different components that comprise the inflammatory response. During
the ensuing years, the techniques used in this paper and in other
laboratories will provide the necessary information to build a better
understanding of the inflammatory process, and then we will be able to
alter the inflammatory response toward better healing and prevention outcomes.
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FOOTNOTES |
Address for reprint requests and other correspondence: A. E. Taylor, Dept. of Physiology, College of Medicine, Univ. of South Alabama, Mobile, AL 36688 (E-mail:
ataylor{at}jaguar1.usouthal.edu).
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Copyright © 2001 the American Physiological Society