Pulmonary Immunobiology and
Inflammation in Pulmonary Diseases
NHLBI Workshop Summary
Published in the Am J Respir Crit Care Med Vol
162. pp 1983-1986, 2000 Internet address: www. atsjournals. org
JAMES D. CRAPO, ALLEN G. HARMSEN, MICHAEL P.
SHERMAN, and ROBERT A. MUSSON
The immune system of the respiratory tract faces
disparate demands, and is a special environment in which antiinflammatory and
inflammatory responses must take place. The lung appears to have adopted novel
pathways of immune control in order to process foreign antigens in a manner
that does not interfere with its primary biologic functions. Understanding the
mechanisms that keep the pulmonary immune system and the associated
inflammatory response in check and yet prepared to respond quickly to
potentially deadly or disease-causing materials is important to developing
knowledge-based approaches to intervention in many pulmonary diseases.
Investigation of pulmonary defense mechanisms offers important opportunities to
define not only lung homeostasis but also the activation pathways that lead to
disordered inflammatory and immune responses, and their contribution to a
variety of idiopathic or progressive and chronic lung diseases. A partial list
of those diseases that need further investigation includes acute respiratory
distress syndrome, asthma, bronchopulmonary dysplasia (BPD), emphysema,
interstitial lung diseases, lung injury, and pulmonary hypertension.
The National Heart, Lung and Blood Institute
sponsored a workshop on August 26- 27, 1999 to review the current state of
knowledge and to discuss opportunities for the investigation of pulmonary
immunobiology and inflammation and their contribution to pulmonary disease.
This report summarizes the discussions that took place and the recommendations
that were generated at the workshop. The major focus of the workshop was
nonspecific (innate) and specific (acquired or adaptive) cellular components of
the immune system as they uniquely function in the lung. The workshop did not
address the acquired "humoral" immune system (e. g., immunoglobulin A activity
in bronchoalveolar lining fluid) or innate mediators of lung inflammation and
their inhibitors. In 1995, a National Institutes of Health conference did
specifically report on mediator- related aspects of inflammation in the airways
(1). The workshop was also not organized around specific pulmonary diseases (e.
g., bronchopulmonary dysplasia, asthma, idiopathic fibrosis) in which the
immune system plays a major role.
The First Line of Pulmonary Defense: Mucociliary
Clearance
The upper respiratory tract removes the vast majority
of inhaled particles, and turbulent airflow deposits most of these particles on
the thin mucus/ serous coating of the nasopharynx. The highly efficient
mucociliary clearance system acts to return most particulate matter to the
posterior pharynx, where it is swallowed. Small concentrations of inhaled
infectious agents and antigens that avoid removal by the mucociliary apparatus
and reach the underlying upper and lower respiratory tract epithelium require
processing by the immune system. The challenge to the pulmonary system is to
accomplish further processing without an inappropriate inflammatory
amplification. Infective agents or amounts of foreign antigenic material (up to
10 10 particles per day) reach the alveolar region (5 3 10 8 alveoli, with a
surface area of about 100 m 2 ) on a regular basis, yet they do not usually
signal a serious threat to the host.
Increased expression of endothelial nitric oxide
synthase is observed in ciliated respiratory epithelium, Clara cells, and type
II pneumocytes in pulmonary inflammation. Exhaled nitric oxide (NO) is also
increased in a number of inflammatory diseases of the lung, and it is therefore
interesting to note that NO enhances ciliary beat activity (2). Preventing
injury to or revitalizing the epithelium of the conducting airways after
endotracheal intubation, inhalation of toxins, and/ or exposure to infectious
agents are important issues in need of additional research.
Cells of the Pulmonary Immune System
The lung is an anatomically complex organ with at
least three distinct compartments, including the airways and airspaces,
interstitium, and vasculature. The airways and airspaces include the nasal
passages, the conducting airways of the lung, and the alveoli. It is not known
how inflammatory and immune responses are targeted to these compartments.
However, antigens and microorganisms can be processed and presented to local
lymphatic tissues when they reach these compartments. The pulmonary immune
system has distinct collections of lymphoid tissue along the respiratory tract,
including the nasal-associated lymphoid tissue (NALT), bronchus-associated
lymphoid tissue (BALT), and lymph nodes that receive drainage from the nose or
lung (3- 6). The roles played by the NALT, BALT, and draining lymph nodes in
the induction and expression of lung immunity are not entirely clear.
Antibodies (e. g., IgA) and immune effector cells in the respiratory tract
lining fluids interact with or immobilize inhaled antigens and microbes at the
same time that the mucociliary clearance apparatus attempts to mechanically
remove them.
Dendritic cells. The lung has a substantial
population of dendritic cells that increase in number in response to various
inflammatory stimuli (7) and about which little is known. Whether dendritic
cells in the lung have unique characteristics, functions, and/ or locations is
not known. Dendritic cell mobility, antigen recognition, and accessory
molecules and their signaling pathways, as well as the effects of cytokines on
their activity, have only been partly defined (5, 8, 9). Other pulmonary cells,
such as B-lymphocytes, interstitial macrophages, epithelial cells, fibroblasts,
fibrocytes, and endothelial cells can be antigen-presenting cells, but current
thinking indicates that dendritic cells are the overwhelmingly important
antigen-presenting cell in the lung. In the neonatal lung, however, prominent
fibrocytes (10) may stimulate naive T cells (11), demonstrating the complexity
of antigen-presenting cells in the pathogenesis of BPD. Thus, the antigen
processing system of the lung has unique characteristics, but remarkably little
is known about this critical step in immune modulation.
Alveolar macrophages. Alveolar macrophages
(AM) are generally recognized as relatively poor antigen-presenting cells (12).
Their primary response to an antigen is to process and clear the antigen
without signaling for an inflammatory response to be amplified. In fact, some
data would suggest that AM commonly function to inhibit amplification of immune
pathways (13). Such behavior would allow AM to clear the normal amounts of
antigenic particles or infective agents that reach the gas-exchanging regions
of the lung without damaging the alveolar capillary membrane. Under normal
conditions, clearance of most antigens appears to be accomplished without
initiating an inflammatory response or activating host immune responses with
subsequent disruption of the delicate alveolar capillary membrane. Thus, there
is a need to understand how AM participate in the induction of an immune
response. Answering the following questions might more fully address the role
of these cells: How many bronchoalveolar macrophages must be stimulated in a
defined region of an airway to provoke a proinflammatory response? How many
receptors and coreceptors must be engaged per macrophage before a response
occurs? Is there a hierarchy of receptors and/ or coreceptors wherein
stimulation by a specific agonist initiates a more profound response than that
induced by another agonist? Answers to these questions would help to better
understand the role of macrophages in other organ systems, but may be
particularly testable in pulmonary airways. Macrophages seem to have the
ability to determine that one microorganism is more dangerous than another
through the use of pattern-recognition receptors (14). It is not known how this
occurs.
T-Lymphocytes. There are substantial
populations of T cells in the lung (15), and these include gd T cells that are
present in higher concentrations than in most other tissues (16). The lung also
contains a relatively high number of CD4 2 /CD8 2 ab T cells. These 2/ 2 ab T
cells are relatively rare in most other tissues, but can constitute as many as
20% of the lymphocytes residing in the lung. The high numbers of 2/ 2 ab T
cells in the lung imply a function for these cells in host defense, but such a
role has not yet been established. The lung also contains a substantial number
of ab T cells that are either CD4 1 or CD8 1 cells. These cells are located
within the airways, alveolar epithelium, and interstitium. The CD4 1 or CD8 1
ab T cells are thought to be relatively hyporesponsive, and have a decreased
proliferative response to mitogen, but appear to be functional after undergoing
a "learning process" (12). Even less is known about lymphocytes in the fetal
and neonatal lung. It has been suggested that there are specific lung receptors
for T cells that allow selective homing of circulating T cells back to the lung
(11, 17). However, the mechanisms that mediate T-cell recruitment to the lung
and determine whether these cells subsequently settle in the lung parenchyma or
airways are not understood. How T cells, which are recruited to the lungs, are
triggered to express their effector functions, and how these functions are
downregulated, also is not known (18). Nor has it been determined how
immunologic memory is expressed in the lung (whether it is locally or
systemically mediated). Understanding immunologic memory in the lung is
considered very important because it must be established in order for
vaccination to be successful. There is no information about how inflammatory
events in utero may influence the generation of memory T cells to
regulate tolerance versus hyperreactivity. Studies of this process following
birth and during infancy, a period when new antigen exposure occurs frequently,
may be immensely valuable in understanding immunologic memory in the lung.
B lymphocytes. Although bronchoalveolar lavage
fluids from humans and laboratory animals contain relatively few B lymphocytes,
these cells are common in the lung interstitium (18). Production of antibodies
by B cells in the respiratory mucosa and associated lymphoid tissues has been
shown to be important in resistance to infectious diseases and in the
pathogenesis of airway hyperresponsiveness (18). Less understood, however, are
the antibody-independent functions of B lymphocytes in the respiratory tract.
Recent studies have indicated that B lymphocytes function in resistance to
influenza in a CD4 1 T-cell- dependent (19) as well as a CD4 1 T-cell-
independent (20) manner. The lung is unique in that antigens can persist in the
alveolar region for relatively long periods, and such preservation may provide
unique pathways for activation of B lymphocytes, although little is known about
this immune processing pathway. Thus, the role of B lymphocytes as either
effector cells in the production of antibodies or as accessory cells in T-cell-
mediated immunity needs to be explored.
Pulmonary Inflammatory Cells
When the infectious or antigenic burden in the lung
becomes too great for quiescent processing, traditional immune cells and/ or
other pulmonary parenchymal cells release mediators that recruit inflammatory
cells, many of which are phagocytes. This section reviews discussions at the
workshop of inflammatory phagocytes and the oxidant stress that these cells and
inflammation create in the lung.
Neutrophils. The lung contains a large number
of neutrophils, and most of these cells are marginated along the walls of the
lung microvasculature. Just as the airways process inhaled infectious agents
and antigenic material, so may the pulmonary circulation also function as a
filter for microorganisms or antigens that enter the systemic circulation but
are not removed by the liver. In humans, the relative roles of endothelium,
pulmonary intravascular macrophages, neutrophils, or other pulmonary cells in
the clearance and processing of microorganisms and antigens from the systemic
venous blood are poorly defined.
The pattern of migration of neutrophils appears to be
unique within the lung. The alveolar epithelial surface contains high
concentrations of adhesion molecules, such as intercellular adhesion
molecule-1, which are more concentrated near the junctions of alveolar type I
epithelial cells and type II epithelial cells (21). Under normal conditions it
is rare to find neutrophils in the pulmonary airways, and neutrophils that
reach the alveolar surface are rapidly cleared, suggesting that under normal
conditions the lung is designed to exclude neutrophils from its alveolar
capillary membrane. Closely regulated neutrophil migration could be a useful
mechanism for allowing neutrophils to conduct surveillance functions while
preventing an inflammatory cascade from being inappropriately initiated on the
alveolar gas-exchange surface. Mechanisms of neutrophil trafficking to the
lung, through the lung, and out of the lung are not well defined. Trafficking
of neutrophils involves a seemingly infinite number of adhesion molecules and
chemoattractants, although the CXC chemokines may be emerging as major
determinants of neutrophil recruitment in the lung.
Neutrophils are the secondary phagocytic defense when
AM fail to protect the lung in adults. In neonates, the numbers and function of
AM are reduced, and neutrophils are essential to host defense against bacteria
(22). Neutrophils may also be important in ingesting and clearing damaged
epithelium from the airways (23). The recent observation that neutrophils
undergo apoptosis rather than necrosis in the airways and alveoli is essential
to defining pulmonary inflammation and repair (24). The finding that
corticosteroids delay neutrophil apoptosis but accelerate eosinophil apoptosis
may be an unsuspected beneficial mechanism of steroid action in allergic
diseases such as bronchial asthma (24). Consequently, there is incomplete
understanding of the role of neutrophils in the defense, injury, and repair of
the immature and mature lung.
Eosinophils, mast cells, and basophils.
Although eosinophils, mast cells, and basophils were not extensively
discussed at the workshop, eosinophils have been identified as playing
important roles in the pathogenesis of pulmonary hypersensitivity diseases,
lung parasitic diseases, lung injury, and fibrosis. As with that of
neutrophils, the accumulation of eosinophils in the lungs is mediated by
chemokines. Mast cells and basophils have also received interest in the
pathophysiology of asthma, but the role of these phagocytes in lung diseases
was not reviewed at the workshop. Investigations of the mechanisms of control
and of the accumulation of these cells in the lung will enhance knowledge about
the pathogenesis of lung diseases and pulmonary hypersensitivity.
Oxidative Stress and Its Control
The presence of inflammatory cells such as
neutrophils or eosinophils in the lung is associated with increased oxidant
injury. These phagocytes and other nonimmune and immune cells may release
reactive oxygen and nitrogen intermediates that cause injury during
inflammation. The lung is uniquely designed to control oxidative stress. Lung
lining fluids are enriched in the antioxidant glutathione, which reaches levels
as great as 100-fold higher than those found in other tissues or in plasma. The
lung also has remarkably high levels of antioxidant enzymes. For example, there
is a high level of extracellular superoxide dismutase in lung (25). Alveolar
type II epithelial cells, particularly in response to inflammatory cytokines,
secrete both NO and extracellular superoxide dismutase, the effect of which is
to maintain proportionally high concentrations of NO or one of its active
adducts in the alveolar interstitium and alveolar lining fluids. Under such
conditions, NO is likely to suppress immune activation by reducing neutrophil
mobility, adhesion, and activation (26). Alternatively, endogenous NO
production may be associated with lung injury during exuberant or chronic
inflammatory states (27). It is likely that damaging reactive nitrogen species
other than NO are generated. The use of inhaled NO and oxygen exposure in the
immature lung for prolonged periods may potentially increase lung injury (28).
The clinical use of inhaled NO creates the need for additional research on
oxidant stress states in the lung, and on the mechanisms of protection from
injury during inhaled NO therapy. Discussion at the workshop acknowledged that
little is known about antioxidant defenses against NO and other reactive
nitrogen intermediates.
Immunomodulators in the Lung
The pattern of production and release of
antiinflammatory and inflammatory mediators when the lung experiences
potentially harmful stimuli is poorly understood. Complement was specifically
discussed at the workshop, and it was concluded that a renewed research into
the role of complement in pulmonary injury is needed. The roles of
proinflammatory agonists, such as arachidonic acid metabolites (thromboxanes
and leukotrienes), cytokines, and chemokines, were not the specific focus of
the workshop. To a limited extent, they were discussed in the context of how
they modulate specific immune cells in the lung. Biologic response modifiers,
such as the E series prostaglandins, transforming growth factor-b, interleukin
(IL)-10, and IL-1 receptor antagonist have expanded the knowledge of
antiinflammatory agents working within the lung. Specifically mentioned at the
workshop were an ever-increasing number of pulmonary cells (e. g., epithelial
serous and Clara cells) and their secretory products (e. g., b-defensin and
CAP-18, and CC10, respectively) that either limit the extent of inflammation or
produce a profound inflammatory response. Many of the mediators in epithelial
fluid, whether they are proteins or lipids, may interact to control the
inflammatory response. The interactions of such substances with each other, and
the different cell surface receptors involved in signaling by these mediators,
require more investigation in order to define the unique immunobiology of the
lung.
Immune System Characteristics That Are Unique to
the Lung
There are many molecules and cells within the lung
that are not thought of as part of the traditional immune system. It has become
apparent that pulmonary epithelium, endothelium, smooth-muscle cells, and
fibroblasts contribute to the initiation and resolution of inflammation in the
lung. Time did not permit full discussion at the workshop of each of these
"accessory" immune molecules or cells, but more attention should be paid to
them in future investigations. An overview of selected topics that were
discussed at the workshop is provided later in this report.
Surfactant. The type II pneumocyte is an
alveolar epithelial cell that has strong resistance to oxidant injury and
thereby maintains its ability to secrete surfactant. It is believed that type
II pneumocytes have a diverse role in pulmonary immunobiology. For example,
they are the source of surfactant proteins A and D, both of which are important
molecules that regulate inflammation in the lung (29). Surfactant lipids
suppress a variety of immune cell functions, most notably lymphocyte
proliferation. Changes in lipid/ protein ratios on the lung surface may also be
important in the immune status of the lung, but this is less well documented.
More information is needed about the scavenger or surveillance functions of
surfactant proteins. Other proteins secreted into bronchoalveolar lining fluid
by epithelial serous cells or Clara cells, such as lactoferrin, b-defensin,
CAP-18, and CC10, may have either pro-or antiinflammatory effects. For example,
surfactant protein D and other proteins in bronchoalveolar fluid may work in
concert with macrophages and epithelial cells to bind and remove inhaled
endotoxin without the initiation of an inflammatory response (30-33).
Respiratory epithelial cells. A variety of
epithelial cells in the respiratory system, specifically serous cells in the
conducting airways, Clara cells in the smaller airways, and alveolar type II
epithelial cells on the alveolar surface, have unique receptors, including
those related to interactions with a 2 -macro-globulin. Such cells are also a
potent source of cytokines in the lung, and secrete a variety of peptide/
protein antibiotics (30- 35). The role of such cells in modulating precise
immune responses needs to be better defined, especially since epithelial cells
are among the first types of cells to interact with foreign materials deposited
in the lung.
Conclusion and Recommendations
The lung is recognized as a unique immunologic organ
that appears to have adapted novel pathways of immune control in order to
process foreign antigens in a manner that does not interfere with its primary
biologic functions. This poorly understood area of lung defense offers
extraordinary opportunities to define not only lung homeostasis but also the
activation pathways that lead to disordered inflammatory and immune responses,
and the contribution of these pathways to a variety of idiopathic or
progressive and chronic lung diseases. Opportunities recommended for future
investigation include:
1. Investigating how the lung determines whether
induction of inflammation and/ or an immune response is appropriate for a
specific foreign material that has entered the lung, and how these responses
are limited once they have been induced.
2. Defining the unique functions of lung dendritic
cells and macrophages in determining how antigens are processed in the lung.
3. Determining the mechanism responsible for unique
neutrophil, monocyte, eosinophil, basophil, and lymphocyte trafficking in the
lung and its compartments, and how pulmonary lymphocyte trafficking is
controlled in both primary and memory immune responses.
4. Determining how environmental factors, prior lung
injury, or previous pulmonary immune responses interact with genetically
determined immune responsiveness to affect subsequent lung inflammatory and
immune responses.
5. Delineating the maturation of the immune system in
the lung, and the way in which environmental factors can affect this process
and subsequent immune responsiveness later in life. 6. Defining unique
relationships between lung structure and inflammatory or immune responses.
List of participants: The authors wish to
thank the participants of the workshop who provided important ideas embodied in
this report. These participants included: Joseph A. Bellanti, Washington,
DC; Mary Ann Berberich, Bethesda, MD; Thomas J. Braciale, Charlottesville, VA;
Victoria Camerini, Charlottesville, VA; Arturo Casadevall, Bronx, NY; F.
Sessions Cole, St. Louis, MO; James D. Crapo, Denver, CO; Carroll E. Cross,
Davis, CA; Jeffrey L. Curtis, Ann Arbor, MI; Claire M. Doerschuk, Boston, MA;
Michael M. Frank, Durham, NC; Bruce A. Freeman, Birmingham, AL; Allen G.
Harmsen, Saranac Lake, NY; Stanley J. Hazen, Cleveland, OH; Gary W.
Hunninghake, Iowa City, IO; Dallas M. Hyde, Davis, CA; Steven L. Kunkel, Ann
Arbor, MI; David B. Lewis, Stanford, CA; Mary F. Lipscomb, Albuquerque, NM;
Thomas R. Martin, Seattle, WA; William J. Martin, II, Indianapolis, IN; Robert
A. Musson, Bethesda, MD; Patricia Noel, Bethesda, MD; Robert North, Saranac
Lake, NY; David A. Schwartz, Iowa City, IO; Michael P. Sherman, Davis, CA;
Susan L. Swain, Saranac Lake, NY; Galen B. Toews, Ann Arbor, MI; Marsha
Wills-Karp, Baltimore, MD; Christopher B. Wilson, Seattle, WA; Jo Rae Wright,
Durham, NC.
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(Received in original form March 23, 2000 and in
revised form June 20, 2000) Workshop sponsored by the National Heart,
Lung, and Blood Institute and held in Bethesda, Maryland, August 26- 27, 1999.
Correspondence and requests for reprints should be
addressed to Robert A. Musson, Ph. D., Division of Lung Diseases, National
Heart, Lung, and Blood Institute, 2 Rockledge Center, Suite 10018, 6701
Rockledge Drive, MSC 7952, Bethesda, MD 20892. E-mail:
rmusson@nih.gov
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