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
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
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
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
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
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.