Remodeling in Asthma and Chronic Obstructive
Lung Disease
PETER K. JEFFERY
Imperial College at the Royal Brompton Hospital, London, United Kingdom
Asthma and chronic obstructive lung disease (COPD) are both in-
flammatory conditions of the lung associated with structural “re-
modeling” inappropriate to the maintenance of normal lung func-
tion. The clinically observed distinctions between asthma and
COPD are reflected by differences in the remodeling process, the
patterns of inflammatory cells and cytokines, and also the pre-
dominant anatomic site at which these alterations occur. In
asthma the epithelium appears to be more fragile than that of
COPD, the epithelial reticular basement membrane (RBM) is sig-
nificantly thicker, there is marked enlargement of the mass of
bronchial smooth muscle, and emphysema does not occur in the
asthmatic nonsmoker. In COPD, there is epithelial mucous meta-
plasia, airway wall fibrosis, and inflammation associated with loss
of surrounding alveolar attachments to the outer wall of small air-
ways: bronchiolar smooth muscle is increased also. Emphysema is
a feature of severe COPD: in spite of the destructive process, alve-
olar wall thickening and focal fibrosis may be detected. The hyper-
trophy of submucosal mucus-secreting glands is similar in extent
in asthma and COPD. The number of bronchial vessels and the
area of the wall occupied by them increase in severe corticoste-
roid-dependent asthma: it is likely that these increases also occur
in severe COPD as they do in bronchiectasis. Pulmonary vascula-
ture is remodeled in COPD. In asthma several of these structural
alterations begin early in the disease process, even in the child. In
COPD the changes begin later in life and the associated inflamma-
tory response differs from that in asthma. The following synopsis
defines and compares the key remodeling processes and proposes
several hypotheses.
Keywords: airways; asthma; chronic bronchitis; COPD; emphysema;
lung; remodeling
Asthma and chronic obstructive lung disease (COPD) are rel-
atively nonspecific clinical terms used to describe two differ-
ing patterns of airflow obstruction with respect to reversibility,
spontaneously or in response to treatment. In reality asthma
and COPD are not single entities; each has a spectrum of re-
versibility and there is “overlap,” most likely associated with
the varying extent and the “mix” of both structural and in-
flammatory changes and the predominant anatomic site within
the lung at which these occur (Figure 1). The premise herein is
that the clinically observed distinctions between asthma and
COPD, at least in individuals selected from polar ends of the
clinical spectrum, should be reflected in contrasting patterns
of inflammatory cells and cytokines and by differences in the
magnitude, anatomic site, and nature of the remodeling pro-
cess (1). The present synopsis briefly introduces the differ-
ences with respect to inflammation and then focuses on the
structural changes, the last collectively referred to as “remod-
eling.”
( Received in original form June 6, 2001; accepted in final form September 7, 2001 )
Correspondence and requests for reprints should be addressed to Peter K. Jeffery,
D.Sc., Ph.D., Lung Pathology Unit, Royal Brompton Hospital, Sydney Street, Lon-
don SW3 6NP, UK. E-mail: p.jeffery@ic.ac.uk
Am J Respir Crit Care Med Vol 164. pp S28–S38, 2001
DOI: 10.1164/rccm2106061
Internet address: www.atsjournals.org
DESCRIPTION AND DEFINITIONS
Inflammation
Asthma and COPD are both chronic inflammatory conditions
of the conducting airways and lung parenchyma. However,
immunohistology of bronchial biopsies demonstrates differ-
ences in the predominant inflammatory cells: biopsies from
nonsmoking mild allergic asthmatics have increased numbers
of activated CD4 (T helper) lymphocytes and eosinophils
and variably reported increases of mast cells. In contrast, the
chronic inflammation of smokers with COPD is predomi-
nantly of tissue CD8 (T suppressor/cytotoxic) lymphocytes,
macrophages, and, variably, neutrophils (2). While inflamma-
tion appears to be present at all sites within the lung in both
conditions, the predominant anatomic site at which the struc-
tural changes occur differs. In COPD it is mainly destruction
(or failure to repair) of the lung parenchyma leading to em-
physema (Figure 2) and there are also important structural al-
terations that occur in varying degree to small bronchi and
membranous bronchioli (i.e., airways  2 mm in diameter).
The relative contributions that the structural alterations at
these two sites make to the airflow obstruction in each patient
will vary. In asthma, large airways and small airways are al-
tered structurally but, in the asthmatic nonsmoker, there is no
parenchymal destruction. However, the walls of the conduct-
ing airways in asthma are thickened by between 50 and 300%
of normal and there is lumenal narrowing, which is further
compromised by excessive mucus admixed with an inflamma-
tory exudate (Figure 3). In cases of fatal asthma, the longer
the duration of asthma, the thicker the airway wall. However,
it has been suggested that airway wall thickness per se is not a
requirement for asphyxic fatality as a group of relatively
young asthmatics (i.e., with a relatively short history of
asthma) had an airway wall thickness not significantly differ-
ent from that of nonasthma controls. It is surmised that lume-
nal secretions and plugging were the greater contribution to
asthmatic death in these young cases of fatal asthma (3). Each
tissue structural component, as well as inflammatory cell infil-
tration and edema, can contribute to the observed thickening;
however, in the last-mentioned study it was thickening of the
adventitial layers that was most pronounced in the older
group with the longest duration of disease.
Inflammation and Relationship to Remodeling
Acute inflammation is the response of vascularized tissue to
injury: the inflammatory reaction is designed to protect the
host and to restore tissue and its function to normal. One gen-
erally accepted proposal is that the accelerated decline in
forced expiratory flow over time in COPD, and that which oc-
curs also in an important subset of asthmatics, is the direct re-
sult of a switch from acute, episodic, to chronic inflammation
and to consequent parenchymal and airway wall remodeling,
respectively (4). The proposal is attractive but, as yet, there is
no convincing evidence that the remodeling process is depen-
dent on the prior development of chronic inflammation. It is
equally plausible that the processes responsible for the devel-
Jeffery: Remodeling in Asthma and COPD
Figure 1. Venn diagram illustrating the overlap between the chronic
inflammatory conditions of asthma and COPD.
opment of chronic inflammation are distinct from those re-
sponsible for remodeling (Figure 4). The last consideration
has important implications for the design of disease-modifying
therapy: those agents that are effective anti-inflamatory com-
pounds will not necessarily prevent or attenuate the process of
remodeling.
Definition
The concept of “remodeling” implies that a process of “mod-
eling” must have preceded it. We have seen in the article by
Warburton and colleagues in this issue (pp. S59–S62) that the
lung, in utero, undergoes extensive modeling and remodeling
yet these processes are entirely appropriate to the normal pro-
cess of lung development. Many of the cytokines and growth
factors thought to be proinflammatory in asthma and in COPD
are also expressed normally without detriment to the develop-
ing lung. These include members of the fibroblast growth factor
family, the transforming growth factor family, epithelial-derived
growth factor, granulocyte-macrophage colony-stimulating fac-
tor, platelet-derived growth factor, vascular endothelial growth
factor, and hepatocyte growth factor (4, 5) (see also the article
by Warburton and colleagues). Accordingly the working defi-
nition of remodeling proposed herein recognizes that the pro-
cess of remodeling per se is not of necessity abnormal. It is an
alteration in size, mass, or number of tissue structural compo-
nents that occurs during growth or in response to injury and/or
inflammation. It may be appropriate, as in normal lung devel-
opment or that which occurs during acute reaction to injury,
or “inappropriate” when it is chronic and associated with ab-
normally altered tissue structure and function as, for example,
in asthma, COPD, or fibrosing alveolitis.
In wound healing (in the skin) there is an appropriate re-
sponse: clot formation, swelling/edema, rapid restitution of
the denuded areas by epithelial dedifferentiation, and prolif-
eration and migration from the margins of the wound. This is
normally associated with an inflammatory reaction: that is,
early infiltration of the injured tissue by neutrophils and later
by lymphocytes and macrophages. Reticulin is deposited
within days and this may mature to form interstitial collagen, a
scar, within 2–3 wk. In addition, healing may involve contrac-
tion of the surrounding tissue in the case of an open wound, by
myofibroblasts that may proliferate transiently in relatively
large numbers (6). Vasodilatation, congestion, and mucosal
edema are also cardinal signs of acute inflammation and the
angiogenesis of the granulation tissue is an integral part of the
S29
Figure 2. Gross appearance of the cut surface of a lung, illustrating the
characteristic distribution of centracinar emphysema, restricted to the up-
per aspects of each lobe scale. (Printed by permission from Professor B.
Heard.)
reparative response (7). Thus, normal tissue architecture and
function are restored consequent to an entirely appropriate
inflammatory and remodeling process. Each of these stages in
normal wound healing and many of the inflammatory cell
types and cytokines involved (e.g., transforming factor ) ap-
pear also in asthma and in COPD, but in asthma both the in-
flammation and remodeling persist and the consequences are
inappropriate to the maintenance of normal (airway) function.
The reasons for the persistence are unknown but may be the
result of repeated inhalation of allergen or exposure to high
concentrations of allergen, or infection, or a genetically influ-
enced abnormal host inflammatory response or defect in the
repair process. In COPD the injury is presumed to be due to
repeated exposure to cigarette smoke, environmental and/or
occupational pollutants, chronic (or latent) infection, or an in-
teraction of these. The host responses in asthma and COPD
may of course differ due to differences in genetic makeup or
consequent to developmental abnormality or to the effects of
perinatal environmental exposure: these may be associated
later with differing patterns and sites of chronic inflammation
and inappropriate remodeling.
ALTERATIONS TO LARGE AIRWAYS
Epithelial Injury
Histologically, damage and shedding of the airway surface ep-
ithelium are reported in asthma, postmortem, but this change
S30 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 164 2001

Figure 3. Representation of airways in the normal lung (left) and in

asthma (right), demonstrating the thickening of the airway wall in
asthma due to injury, chronic inflammation, and remodeling of epithe-
lium and subepithelial tissue. The result is encroachment of the airway
lumen and a marked increase in resistance to airflow.

is highly variable: some airways have intact surface epithelium

even in the presence of marked inflammation and other struc-
tural change (8). Loss of epithelium induces a healing process
that results in either complete restoration of the columnar/
cuboidal epithelium with normal proportions of goblet and cil-
iated cells or, if the injury is repeated, squamous cell metapla-
sia and/or goblet cell hyperplasia. Histologically, damage and
shedding of airway surface epithelium are an often-reported
feature of asthma: there are clusters of sloughed epithelial
cells (referred to as Creola bodies) in asthmatic sputa, in-
creased numbers of epithelial cells in bronchoalveolar lavage
(BAL) fluid, and loss of the surface epithelium in biopsy spec-
imens (9–11). Aggregations of platelets together with fibrillary
material, thought to be fibrin, have been observed in associa-
tion with the damaged surface (11). In asthmatics with varying
severity and symptoms the greater the loss of surface epithe-
lium in biopsy specimens the greater the degree of airway re-
sponsiveness (11). However, the loss of epithelium observed
in biopsies of mild asthmatics is highly variable and an unreli-
able end point for determination of extent of injury or the re-
sponse to treatment (12). The variability between specimens
and laboratories is likely due to several factors, including in-
herent fragility of the epithelium in asthmatics, mechanical
Figure 4. Representation of the proposed hypothesis for two distinct
pathways of response to chronic injury: chronic inflammation or re-
modeling. Effective treatment for each of these distinct pathways will
likely need to be different.
Figure 5. The airway mucosa as it appears by light microscopy (LM) of
bronchial biopsies from (A) an atopic asthmatic showing loss of surface
epithelium and early thickening and hyaline appearance of the reticu-
lar basement membrane (RBM) and (B) a heavy smoker with COPD
(FEV1  40% of predicted), demonstrating epithelial squamous meta-
plasia and a thinner RBM of normal thickness. Stained with hematoxy-
lin–eosin (H&E).
stresses imposed during bronchoscopy, and differences be-
tween the types of forceps used, their sharpness and operator
methodology and experience. In contrast, epithelial loss is a
less often reported feature of bronchial biopsies taken from
smokers with bronchitis or COPD when goblet cell hyperpla-
sia and squamous metaplasia are often seen (Figure 5A and
5B) (10, 11, 13).
Injury to superficial epithelium is normally accompanied
by mitotic activity in the remaining cells and rapid restoration
of the denuded surface (14). There are, however, newly emerg-
ing data indicating that the mitotic response in asthma, unlike
COPD, may be abnormally suppressed: the proposal in asthma
is that there may be an abnormal repair response of the epi-
thelium to injury (15). One hypothesis is that chronic injury or
defective repair of the surface epithelium results in its persis-
tent activation and the chronic secretion of a variety of pro-
inflammatory epithelial-derived cytokines and growth factors
that drive both the subsequent chronic inflammatory and re-
modeling responses seen in subepithelial compartments. These
Jeffery: Remodeling in Asthma and COPD
Figure 6. Scanning electron micrographs demonstrating the airway mucosa in (A) a nonasthmatic subject with epithelium attached to reticular
basement membrane (RBM) of normal thickness, beneath which there is interstitial collagen, and (B) a subject with a 25-yr history of asthma but
who died of nonrespiratory causes, demonstrating thickened RBM and damaged epithelium.
factors include epithelial-derived growth factor and granulo-
cyte-macrophage colony stimulating factor and would induce
alterations to the epithelial reticular basement membrane, via
activation of adjacent fibroblasts/myofibroblasts, and deeper
structures including bronchial smooth muscle, mucus-secret-
ing glands, and wall vessels. The release of these and other
molecules including interleukin 8 (IL-8), eotaxin, and RANTES
(regulated on activation, normal T-cell expressed and secreted)
would also provide a chemoattractant gradient to both inflam-
matory and phenotypically altered structural cells (see below).
Reticular Basement Membrane Thickness
Thickening of the lamina reticularis or subepithelial reticular
basement membrane (RBM) is a characteristic change in
asthma (See Figure 5A) albeit subtle differences between
atopic and nonatopic forms of asthma have been reported (16,
17). This example of remodeling, when homogeneously thick-
ened and hyaline in appearance, is highly characteristic and
usually pathognomonic of asthma. The thickening is not found
in smokers with chronic bronchitis or COPD (compare Figure
5A and 5B), providing there is no evidence of reversible air-
ways obstruction (18). The RBM is not present in the fetus (at
least up to 18 wk of gestation) (19) but develops later even in
normal, healthy individuals, presumably during childhood.
Relative to the norm, RBM thickening occurs early in the
asthma process (20), even before asthma is diagnosed (21). In a
collaboration with A. Bush and D. Payne (London, UK) we
have had the opportunity to examine bronchial biopsies from
asthmatic children (n  19) between the ages of 6 and 16 yr
who had remained symptomatic despite relatively high doses
of inhaled corticosteroid. We have compared the RBM thick-
ness with age-matched nonasthmatic children (n  7) undergo-
ing bronchoscopy for other clinical indications and found that
the RBM of the asthmatics was thickened even at this early age
(20). In a further collaboration with K. Guntapalli (Baylor,
Texas) we have had the opportunity to extend the study to in-
clude 10 steroid-naive adult asthmatics (mean age, 28.5 yr), 6
adult asthmatics intubated for life-threatening asthma (mean
S31
age, 34.5 yr), and 8 healthy adult nonasthmatic controls (mean
age, 33.5 yr) (22). The RBM thickness was significantly in-
creased in the asthmatic children compared with the healthy
adult controls but the thickness in the asthmatic children and
the adults with mild and severe asthma was similar. There was
no correlation between RBM thickness and either symptom
duration for asthmatic children or the age or severity for all
the asthmatics.
These results highlight how early and maximal is this char-
acteristic aspect of remodeling and indicates that it is unrelated
to the duration of chronic inflammation and severity of the dis-
ease. Also, the thickening remains even when asthma is mild
and well controlled by antiasthma treatment (23) and it is
present postmortem in patients with a long history of asthma
but who have not died of their asthma (24) (Figure 6). Table 1
shows the data for the comparison of RBM thickness in normal
healthy nonsmokers, smokers with bronchitis, smokers with
chronic bronchitis and COPD, and asthmatics matched for age
and disease severity (23). Apart from the asthmatics receiving
inhaled steroids, none of the others received such treatment.
However, despite their steroid treatment the asthmatics still
had a significantly thicker RBM at either of the two airway lev-
els studied (23). The RBM thickness in the smokers with
chronic bronchitis alone or with COPD was within the normal
TABLE 1. MEAN THICKNESS OF EPITHELIAL RETICULAR
BASEMENT MEMBRANE
Mean Thickness
[m (SEM)]
Airway Level Normal CB Alone CB  COPD Asthma
Lobar 3.7 (0.3) 4.9 (0.2) 4.1 (0.4) 8.3 (0.5)*
Subsegmental 4.3 (0.4) 4.6 (0.2) 4.3 (0.3) 8.3 (0.6)*
Reprinted by permission from Reference 23.
Definition of abbreviations: CB  chronic bronchitis; COPD  chronic obstructive pul-
monary disease.
* p  0.05 compared with Normal, CB alone, or CB  COPD.
S32 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Figure 7. A drawing illustrating the geodesic pattern of airway smooth muscle as it spirals around the airway. (Reprinted by permission from WS
Miller. The Lung. Springfield, IL: Charles C. Thomas; 1937.)
range. One caveat to this apparently clear distinction between
asthma and COPD is that a proportion of patients with COPD
defined clinically by their irreversibility to inhaled -agonist
can be shown to be partially reversible after a (2-wk) course of
oral corticosteroid. Interestingly, this group shows raised levels
of eosinophil cationic protein in their bronchoalveolar lavage
and a significantly thickened RBM in their bronchial biopsies
compared with COPD patients, who have a airflow obstruction
irreversible to oral corticosteroids (18).
Because of the immunopositivity of the RBM for epitopes
recognized in collagen (e.g., types I, III, and V), its thickening
in asthma has been referred to as “subepithelial fibrosis” (25).
In the author’s opinion this is an unfortunate application of
the term “fibrosis” as reticulin, a major component of the
RBM, is ultrastructurally different from the “banded” (65-nm
periodicity) and relatively thicker collagen fibers that lie
deeper in the interstitium of the airway wall. In contrast to in-
terstitial collagen, reticulin fibers are linked to glycosami-
noglycans, fibronectin, and a tenascin-rich matrix (26) that en-
traps a variety of molecules such as heparin sulphate and
growth factors. These entrapped molecules may modulate the
state of differentiation, integrity, and function of the overlying
surface epithelium. The author proposes that the additional
entrapped and adsorbed molecules may also provide an in-
creased osmotic force and gradient that encourages thickening
of the RBM by swelling due to uptake of water. Against the
“fibrotic” theory, the “osmotic” proposal is supported by the
early maximal thickening, which is usually only of the order of
2–3 m and, at most double, its norm and the thickening is not
progressive with time. Unlike fibrotic tissue, the RBM can
also relatively quickly change its reticular state and be “lost”
after allergen challenge, this associated with the subepithelial
accumulation of fibromyocytes (see below). Also, the thick-
ened RBM does not behave as a barrier to the transmigration
of inflammatory cells, which by the release of enzymes (e.g.,
metalloproteases) or via predetermined pores may pass through
it with apparent ease (27). Thickening of the RMB has been
reported to show a positive correlation with airway hyperre-
sponsiveness, the frequency of asthma attacks, and the num-
bers of fibroblasts and “myofibroblasts” that lie external and
adjacent to it (28–30).
VOL 164 2001
The data with respect to increases in the amounts of airway
wall interstitial collagen are controversial. These data show
that with increasing severity of asthma there are increases in
the area of the mucosa staining for collagen (31) but in con-
trast there are other studies finding no such relationship (32).
Our own findings in mild asthma show no differences with re-
spect to collagen or elastic tissue (33). In contrast, airway wall
fibrosis is generally, but not always, considered a feature of
the airways in smokers who develop COPD, albeit these stud-
ies have focused on small rather than large airways (34–36).
Enlargement of Bronchial Smooth Muscle Mass
Bronchial smooth muscle is arranged in a geodesic pattern en-
circling the airway as two apposing spirals: when the muscle
shortens it not only constricts but also shortens the airway
(Figure 7). This may be important as any factor that stiffens
the airway, such as increased RBM thickness, increased col-
lagen deposition, vascular congestion, or edema, will result in
resistance against airway shortening (37). It is hypothesized
that reduction of the capacity to shorten an elastic airway, due
to stiffening, will result in the consequent redirection of the
tension developed by the geodesic/oblique anatomic arrange-
ment of airway smooth muscle such that more of the tension
than normal will resolve in favor of airway constriction than of
airway shortening.
The percentage of the bronchial wall occupied by bronchial
smooth muscle is increased in fatal asthma (38) (Figure 8A). Us-
ing a “point-counting” morphometric technique applied to tis-
sue sections of conducting airways, Dunnill and coworkers
showed that approximately 12% of the airway wall in segmental
bronchi obtained from cases of fatal asthma was composed of
muscle compared with about 5% in normal subjects. Hogg and
colleagues (39, 40) have confirmed this trend in airways larger
than 2 mm in diameter and demonstrated a 2- to 4-fold increase
over normal in the area of the wall occupied by bronchial
smooth muscle. The increase is 4-fold in older (with a longer du-
ration of disease) and 2-fold in younger cases of fatal asthma (3).
The absolute increase in muscle mass is reported to be particu-
larly striking in large intrapulmonary bronchi of lungs obtained
after a fatal attack as compared with that seen in asthmatic sub-
jects dying of other causes (8) (compare Figures 8B and 8C). Oc-
Jeffery: Remodeling in Asthma and COPD
Figure 8. Increased bronchial smooth muscle. (A) A histological sec-
tion of the airway wall of a case of fatal asthma stained with H&E to
show enlarged smooth muscle blocks lying relatively close to the sur-
face epithelium. (B) Scanning electron microscopy of part of the mu-
cosa in a nonasthmatic and (C) fatal asthma, demonstrating the three-
dimensional appearance of the enlarged blocks of bronchial smooth
muscle and dilatation of bronchial vessels, which both contribute to
thickening of the airway wall. There is loss of bronchial epithelium.
casionally, the author (in collaboration with K. Guntapalli and
colleagues) observed that large areas ( 85%) of a bronchial bi-
opsy may be occupied by subepithelial muscle bundles in severe
(intubated) cases of asthma (unpublished, 2001). The increase in
muscle mass may also begin relatively early in the child. In an
ongoing collaboration (with V. Macek and coworkers) we have
identified, in bronchial biopsies, airway smooth muscle in rela-
tively large amounts, close to the epithelium even in children
with asthma (unpublished observations).
Few studies of COPD have focused attention on the larger
(cartilaginous) airways. One systematic study has described
changes in large airway dimensions in relation to the lung func-
S33
tion of patients with COPD (41). These authors tested the hy-
pothesis that airflow obstruction and estimates of small airway
inflammation correlate with large airway wall thickness and
muscle mass. They found that the wall area internal to the mus-
cle was significantly thickened over the entire range of cartilag-
inous airways measured and that this was associated with a re-
duction in FEV/FVC. However, alterations in large airway
smooth muscle mass were not observed and there was no cor-
relation between muscle mass and airflow limitation. Interest-
ingly, there was a positive association between peripheral air-
way inflammation and large airway inner wall area and the
authors argued that their findings and those of others favor in-
flammation as the cause of the increasing inner airway wall
thickness that occurs in both large and small airways in COPD.
There are several proposals for the mechanisms responsi-
ble for the increased smooth muscle mass in asthma: each may
contribute in varying degree and the predominant pathway
may differ from airway generation to generation. Muscle fiber
hyperplasia (42), hypertrophy (43, 44), or other mechanisms
may each contribute. Smooth muscle cell (myocyte) prolifera-
tion resulting in an increase in myocyte number is likely to be
a major contributor to the increase in smooth muscle mass.
Other novel mechanisms may also be responsible. We have
observed that solitary contractile cells, originally referred to as
“myofibroblasts,” appear in substantial numbers after the
late-phase reaction (i.e., in biopsies taken 24 h postchallenge)
in response to experimental allergen challenge (45). The ultra-
structure of these large, irregularly shaped cells (compare Fig-
ures 9A and 9B) demonstrates not only the intracellular pres-
ence of secretory organelles (i.e., rough endoplasmic reticulum
and Golgi apparatus) but also elongate bundles of filaments
with electron-dense condensations that are identical to the
contractile apparatus present in bronchial smooth muscle my-
ocytes. With respect to their cell size and filamentous content
these cells are distinct from the myofibroblasts described by
Roche and colleagues (25). Our original report considered
that the fibroblast was a likely origin of the allergen-induced
myofibroblast and there is in vitro work that supports this
(46). However, 2 yr ago, M. J. Gizycki made the interesting
observation that myocytes of the intact airway smooth muscle
bundles showed ultrastructural evidence of dedifferentiation to
a “secretory” phenotype. Outside the normally occurring
smooth muscle bundles there were solitary contractile cells
that we have previously called myofibroblasts. These solitary
contractile cells were identified at varying positions in the mu-
cosa including a zone immediately adjacent to the surface epi-
thelium. He speculated that, with repeated exposure to aller-
gen, these contractile cells, which he considered should be
called “fibromyocytes,” represent dedifferentiated bronchial
smooth muscle that was in the process of migrating toward the
surface epithelium. He proposed that in response to allergen
challenge in asthma, dedifferentiation of existing smooth mus-
cle myocytes occurs and they migrate, in the form of a fibro-
myocyte phenotype, to a subepithelial site where they may
form new muscle of abnormal phenotype and abnormal func-
tion (45). In this respect, the epithelial injury and smooth mus-
cle response in asthma parallels the findings of the response to
endothelial injury and the associated changes of vascular
smooth muscle in atheroma (47). In atheroma there is trans-
formation of vascular myocytes to a “synthetic” phenotype
and their subsequent migration to the neointima. The capacity
of bronchial smooth muscle myocytes to migrate has been
demonstrated (48). These findings are interesting in the light
of previous comparisons of the inflammation of atheroma and
asthma (47). The author proposes herein that the remodeling
processes associated with injury, inflammation, and smooth
S34 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Figure 9. Transmission electron micrograph of (A) a subepithelial fibro-
blast of normal appearance and (B) a myofibroblast or “fibromyocyte”
in the bronchial mucosa of a mild atopic asthmatic 24 h after experi-
mental inhalational allergen challenge. The number of these cells in-
creases markedly compared with the patients challenged with diluent.
(Reprinted by permission from Reference 45.)
muscle migration and increase in asthma and atheroma are
similar. Figure 10 shows the schema we propose for two novel
pathways to explain the smooth muscle increase in asthma. A
further possibility is that pericytes, immature contractile cells
associated with vessels, may also act as a source of newly
emerging myofibroblasts. There is new experimental evidence
in vivo for the response of airway wall vessels to inhalational
allergen challenge and for a similar dedifferentiation and mi-
gration of vascular myocytes to repeated allergen challenge as
that described above in airway smooth muscle (49). It would
appear that the contribution to inflammation and plasticity of
structural cells has been hugely underestimated both in
asthma and in COPD.
Lumenal Content, Epithelial Goblet Cells, and Submucosal Glands
Many asthmatics suffer from excessive production of mucus,
which, admixed with the inflammatory exudate, forms highly te-
nacious plugs that block the airways and are exceedingly difficult
to clear by cough (50) (Figure 11). There is clearly a component
of mucus to these secretions but the especially high additional
contribution by inflammatory cells and their secretory products
in asthma may explain the sticky nature of these secretions as
compared with the intralumenal mucus of chronic bronchitis.
VOL 164 2001
Figure 10. Schema summarizing the two likely pathways that generate
allergen-induced myofibroblast and fibromyocyte forms. (Reprinted by
permission from Reference 45.)
Epithelial goblet cells and mucus-secreting submucosal
glands are the major sources of lumenal mucus. Goblet cell hy-
perplasia is a feature of the large airways in both asthma (51, 52)
and chronic bronchitis (53). Submucosal gland hypertrophy is
also seen to about the same extent in both asthma and COPD
(38). There are serous and mucous secretory units (acini) in
the glands: it is reported that, while the normal proportions of
serous to mucous acini are retained in asthma there is a dis-
proportionate increase in mucous acini and loss of serous acini
in chronic bronchitis (54). As the serous acini contribute a va-
riety of antibacterial substances including lysozyme, lactofer-
rin, and the secretory component of secretory IgA, their re-
duction during the remodeling process in chronic bronchitis
may be relevant to the ease with which the respiratory tract
becomes chronically colonized by bacteria.
ALTERATIONS TO VASCULATURE
Dilatation of bronchial mucosal blood vessels, congestion, and
wall edema are consistently reported features of fatal asthma
and these can account for considerable swelling and stiffening
of the airway wall (Figure 12) (37, 55, 56). There are indica-
tions that the increased proportion of the wall occupied by
vessel may be due in part to a proliferation of bronchial vessels
(angiogenesis) (57). While angiogenesis has been reported in
mild asthma (58) it is particularly marked in severe corticoste-
roid-dependent asthma (59). Whether these changes are the
consequence of chronic allergic inflammation or due to the re-
sponse to chronic (or latent) viral, mycoplasm, or bacterial in-
fection is not known. While proliferation of the bronchial vas-
culature is a feature of bronchiectasis and occurs in response to
infection, changes to the bronchial vasculature have not been
reported as a particular feature of COPD (55). However, pa-
tients with moderate to severe COPD do have elevated pulmo-
nary vascular pressures during exercise and there are structural
changes in the pulmonary arteries consistent with endothelial
dysfunction and pulmonary hypertension when compared with
patients with minimal or no disease. Small ( 500 m) pulmo-
nary vessels in airway-obstructed smokers show intimal thick-
ening as compared with those of nonobstructed nonsmokers: in
severely obstructed smokers, there is medial hypertrophy also
(60–62). Such structural changes likely contribute to the nar-
rower lumens and vascular obstruction of these vessels. Inter-
estingly, there is infiltration of the pulmonary arterial wall by T
lymphocytes. The CD8 T cell phenotype is increased in both
nonobstructed smokers and smokers with COPD compared
Jeffery: Remodeling in Asthma and COPD
Figure 11. Gross appearance of the cut surface of the lung in a case of
fatal asthma. The airway lumena are completely blocked by sticky se-
cretions composed of mucus admixed with inflammatory exudates.
with nonsmokers and the intensity of the inflammatory infil-
trate has been shown to correlate with both endothelium-
dependent relaxation and intimal thickness (63).
CHANGES TO SMALL AIRWAYS AND LUNG PARENCHYMA
Inflammation and structural alterations occuring in the small
airways and lung parenchyma in COPD are considered the
most important contributors to the airflow limitation and to
the accelerated decline of FEV1 in COPD. Similarly, changes
in small airways in severe asthma may also contribute to the
accelerated decline in a small but significant proportion ( 10%)
of asthmatics and there is currently much interest as to the
role of small airway abnormalities in asthma (Figure 13). This
may be especially important in smokers with asthma, a group
that has been little studied with respect to their inflammation
and remodeling processes.
Inflammation
There is now bronchoscopic evidence of an inflamed bronchi-
olar epithelium in COPD with increased release of proinflam-
Figure 12. Histological transverse section of a bronchus from a case of
fatal asthma. The lumen is blocked with secretions, there is goblet cell
hyperplasia, thickening of the RBM, inflammation, increased smooth
muscle, and marked dilatation and congestion of bronchial vessels.
Stained with H&E. (Printed by permission from Professor B. Heard.)
S35
Figure 13. Bronchiole in a case of asthma showing eosinophilic plug-
ging of the small airway, associated with inflammation and thickening
of the airway wall. The surrounding alveoli remain intact. (Printed by
permission from K. Hamada and colleagues.)
matory cytokines including IL-8 (64). In COPD there is infiltra-
tion of the wall of small airways by CD8 T cells and there is an
increase in the number of pigmented macrophages in both air-
way and alveolar lumena (65). This pattern and the extent of in-
flammation are likely to be associated with thickening of the
airway wall, loss of alveolar–bronchiolar attachments, and con-
sequent loss of elastic recoil and lumenal narrowing (Figure 14).
There is also a strong relationship between respiratory bronchi-
olitis (consisting of accumulations of pigmented macrophages),
peribronchiolar fibrosis, and smoking: the relationship of these
airway changes to septal thickening of surrounding alveolar
walls and the development of patchy alveolar wall fibrosis with
a peribronchiolar distribution (referred to as “respiratory bron-
chiolitis-asociated interstitial lung disease”) is unclear but also
of current interest to the development of both interstitial lung
disease and emphysema (66).
While inflammation in young smokers distinguishes smok-
ers from nonsmokers, it is still not clear which, if any, of the
several small airway lesions, that is, fibrosis, goblet cell meta-
Figure 14. Small airway disease in COPD: a transverse section of a small
airway showing peribronchiolitis consisting predominantly of lympho-
cytes. There is damage and loss of alveolar–bronchiolar attachments as-
sociated with centriacinar emphysema and consequent collapse of the
conducting airway, especially during expiration. Stained with H&E.
S36 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 164 2001

Figure 16. Human lung alveoli as they appear by scanning electron

Figure 15. Plastic cast of the small airways in COPD, showing focal microscopy in a smoker who has developed microscopic emphysema.
stenoses that are responsible for increased resistance to airflow locally. The fenestrae are too small to be seen by the naked eye on gross ex-
(Printed by permission from Professor Bignon.) amination of the lung but likely contribute to loss of lung elastic recoil.

plasia, or smooth muscle mass enlargement, contribute most inflammatory and anti-remodeling therapy to this distal ana-
to the stenotic lesions seen in plastic casts of the small airways tomic site.
(Figure 15) or the increased rate of decline in lung function Finally, this synopsis does not allow consideration of the
characteristic of COPD. In asthma, eosinophilic and T-helper important changes of emphysema in COPD, also likely the
“Type 2” inflammation has been demonstrated in the small consequence of a chronic CD8 cell inflammatory process.
airways and surrounding alveolar walls but there is no associ- The current definition of emphysema excludes the presence of
ated loss of peribronchiolar attachments or emphysema re- obvious fibrosis, yet it is now known that fibrosis may also oc-
ported (67). cur even in the presence of alveolar wall loss (70, 71). The ap-
pearance of the fenestrae of “microscopic emphysema” (Fig-
Goblet Cells ure 16) and subsequent enlargement of alveolar spaces, distal
In contrast to large airways, goblet cells are normally absent or to the terminal bronchiolus, in COPD may thus represent the
sparse in airways less than 2 mm in diameter (i.e., small bron- consequence of lung injury and a failure of adequate repair
chi and bronchioli) but they appear and increase in number in rather than of alveolar wall destruction per se. Thus the focal
these peripheral airways in COPD (68), a process referred to fibrosis that may be identified in some cases of emphysema
as mucous metaplasia. Whether mucous metaplasia occurs also may represent the remainder of a repair process. Further stud-
in asthma is debated. Some investigators suggest that the mu- ies of the mechanisms that balance the production and degra-
cus found at this peripheral anatomic site may be aspirated dation of collagen that occurs during the reparative and re-
from the larger airways rather than being produced locally. modeling response to lung injury may yield important findings
However, the work of Aikawa and colleagues is persuasive and applicable to the treatment or prevention of the parenchymal
indicates that mucous metaplasia is also a feature of asthma, lesions so important to COPD.
when goblet cell degranulation, during a fatal attack, may be
widespread, leading to the release of copious amounts of mu- SUMMARY AND CONCLUSIONS
cus that may remain adherent to the goblet cells (51). Remodeling of the airway wall occurs in both asthma and
COPD, but there are differences in the structures affected and
Smooth Muscle Mass the prime anatomic site at which they occur (see Table 2).
The relative contribution of airway wall smooth muscle mass Early thickening of the epithelial RBM and infiltration of the
to overall airway wall thickness in small airways is much wall by eosinophils and T-helper (CD4) lymphocytes is highly
greater than that in the large airways. Airway smooth muscle
increases significantly in the small airways in COPD (36, 65,
68, 69). In a study of small (membranous) airways of 15 pa- TABLE 2. REMODELING AND INFLAMMATION
tients with COPD compared with the lungs of nonobstructed
subjects and a group of asthmatic patients, it was only the air- Asthma COPD
way smooth muscle area that was significantly increased in Epithelium Fragile Metaplastic
COPD (55). In asthma, the increase in the wall area occupied RBM Thickened Not thickened
by muscle, in absolute terms, is not as striking in small airways Fibrosis Unlikely Present
Vessels Angiogenesis Likely
as in the large (8). It is considered that the increased muscle
BSM Increased (LA) Increased (SA)
mass that occurs at all generations of airway is likely to be the Glands Hypertrophy Hypertrophy
most important abnormality responsible for the increased air- Emphysema No Yes
flow resistance observed in response to bronchoconstricting Inflammation CD4/Th2 CD8 and CD68
stimuli in both asthma and COPD (37). Further studies and a
Definition of abbreviations: COPD  chronic obstructive pulmonary disease; RBM 
greater understanding of the changes occurring in small air- reticular basement membrane; BSM  bronchial smooth muscle; LA  large airway;
ways is required, as is a means of effective delivery of anti- SA  small airway; Th2  helper T cell type 2.
Jeffery: Remodeling in Asthma and COPD
TABLE 3. EFFECTS OF TREATMENT
Effect Steroid LABA
Improves FEV1 Yes Yes
Attenuates constriction No Yes
Anti-inflammatory Yes Yes
Reduces mucus Yes ? Yes
Protects epithelium Yes (?) Yes
Reduces RBM thickness Yes No
Inhibits BSM proliferation No Yes
Inhibits vessel number Yes (?) ? ?
Reduces/prevents edema Yes Yes
Targets LA and SA No No
Definition of abbreviations: LABA  long-acting -agonists; LTRA  leukotriene recep-
tor antagonists; RBM  reticular basement membrane; BSM  bronchial smooth mus-
cle; LA  large airway; SA  small airway.
characteristic of asthma. The RBM thickening does not change
with age, severity, or duration of asthma. The large airway in-
crease in airway smooth muscle is a feature of fatal asthma, as
is the lumenal obstruction due to mixtures of inflammatory
exudate and mucus. The last severely increases surface tension
forces, making the airway difficult to maintain patent in asthma.
Small airway mucous metaplasia, increased muscle mass, air-
way wall fibrosis, emphysema, and infiltration of the airways,
pulmonary vessels, and lung parenchyma by (CD8) T-cyto-
toxic lymphocytes are features of COPD. The predominant
anatomic site of the alterations varies in individuals and will
determine the extent and rate of decline in the airflow ob-
struction that develops. The involvement of small airways
seems to be an important determinant of fixed airflow ob-
struction in both COPD and asthma. In asthma, the remodel-
ing usually begins early, in the child. In COPD, the changes
begin in later life. The nature of the inflammation and its re-
sponse to corticosteroid differ: usually responsive in nonsmok-
ing asthmatics and, for the most part, resistant in smokers with
COPD. We do not fully understand the relationship between
chronic inflammation and remodeling. The relationship be-
tween remodeling and accelerated decline in lung function is
also unclear. We may learn much about the remodeling pro-
cess in asthma from the work already done in the field of vas-
cular research. Finally, it is likely that distinct forms of treat-
ment are required to target separately the inflammatory and
remodeling processes. Table 3 summarizes what we know
about the likely effects of inhaled corticosteroids (P. K. Jef-
fery, unpublished, 2001) and other classes of agent such as
long-acting -agonists and leukotriene receptor antagonists
that may also be beneficial (72). Some, but not all, of the re-
modeling seen in humans can be induced successfully in vivo
(in the rat and more recently the monkey). We look forward
to further results of such experimental investigations that will
help us to unravel some of the many remaining questions that
concern inappropriate remodeling in the conducting airways
and lung parenchyma in both asthma and COPD.
Acknowledgment : The author is indebted to Mr. Andrew Rogers for valu-
able assistance with the illustrations.
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