Pharmacological Therapy for Idiopathic Pulmonary
Past, Present, and Future
NHLBI Workshop Summary
Published in the Am J Respir Crit Care Med
Vol 160. pp 1771- 1777, 1999 Internet address: www. atsjournals.
ROBERT J. MASON, MARVIN I. SCHWARZ, GARY W. HUNNINGHAKE,
and ROBERT A. MUSSON
Department of Medicine, National Jewish Medical and Research
Center, Denver; Division of Pulmonary and Critical Care Medicine,
University of Colorado Health Sciences Center, Denver, Colorado;
Division of Pulmonary Medicine, University of Iowa Hospital
and Clinic, Iowa City, Iowa; and Division of Lung Disease,
National Heart, Lung, and Blood Institute, National Institutes
of Health, Bethesda, Maryland
Idiopathic pulmonary fibrosis (IPF) is a devastating illness
for which current therapy is minimally effective. If medical
therapy for IPF is going to improve over the next decade,
controlled clinical trials will be needed to evaluate new
drugs and treatment regimens. To date, very few multicenter
trials have been conducted in IPF compared with diseases with
a similar mortality (Table 1). Current therapy, which usually
includes corticosteroids with or without a cytotoxic agent,
has evolved without the support of large, well-controlled
clinical trials. One reason for the paucity of clinical trials
is that the number of patients is limited and an adequate
trial would require multiple centers in order to recruit sufficient
numbers of patients. Until recently, it was thought that only
5/ 100,000 individuals in the United States develop IPF per
year. However, more recent data indicate that the incidence
is much higher (1). More importantly, multicenter trials require
uniform diagnostic criteria and outcome variables. Although
there have been concerns about diagnostic criteria, substantial
progress has been made recently in our understanding of the
pathogenesis, diagnostic criteria, and outcome variables that
are necessary to support clinical trials in IPF and IPF-related
interstitial lung diseases. Finally, there are candidate new
therapies that are ready for critical evaluation.
IN IPF AND OTHER DISEASES
at 5 yr (13)
FEV1.0 , 30% predicted
at 3 yr (60)
and long-term oxygen therapy
at 5 yr (61)
myocardial infarction (seen in emergency room)
at 5 yr (62)
bypass surgery (3 vessels)
at 4 yr (63)
at 5 yr (64)
at 5 yr (64)
at 5 yr (64)
with variceal bleeding
at 4 yr (65)
of abbreviation: COPD 5 chronic obstructive pulmonary
This report summarizes a workshop sponsored by the National
Heart, Lung, and Blood Institute (NHLBI) and Office of Rare
Diseases on September 9-10, 1998 to review current medical
therapy and opportunities for future investigation of the
pathogenesis and therapy for IPF and related diseases. This
conference was built on the discussions and consensus achieved
at prior NHLBI workshops in 1990 (2) and 1994 (3) and integrated
more recent insights into diagnosis, pathogenesis, and therapy.
Recently, there has been significant progress in case definition
and our understanding of the pathologic spectrum of IPF and
IPF-related interstitial lung diseases (4- 6). A great deal
of effort has been put forward on case definition by international
professional societies and will be published soon. The participants
believe that a consensus can also be reached on the pathologic
classification of IPF, the role of high-resolution computerized
tomography (HRCT) lung scans, and clinical and physiological
criteria for the diagnosis of these diseases. In addition,
there is greater knowledge of the pathogenesis of these diseases
(7-11). The participants also felt that studies on pathogenesis
have pointed to several new independent potential avenues
of therapy and classes of potentially therapeutic agents.
However, there remains variability in the therapeutic response
between IPF and IPF-related illnesses. To increase our understanding
of this spectrum of diseases and their response to therapy,
the participants indicated that specific diagnosis is required,
and this can only be accomplished with a complete clinical,
radiographic, and pathologic assessment of individual cases.
This report draws on the presentations of the participants,
using material they provided, and the recommendations as synthesized
by the organizers and discussants.
Clinical research in pulmonary fibrosis may have additional
benefits for other fibroproliferative diseases such as atherosclerosis,
cirrhosis, and connective tissue diseases. Similarities between
atherosclerosis and pulmonary fibrosis were discussed, and
there were common themes concerning the importance of certain
growth factors, cytokines, and cell-cell interactions. The
biologic principles of pathogenesis and, therefore, the opportunities
for therapy are similar for these diseases. Therefore, the
total benefit from studies of pulmonary fibrosis may also
impact other fibroproliferative diseases. However, pulmonary
fibrosis occurs in the very special microenvironment of the
lung. Although observations made in other fibroproliferative
diseases can guide the design of studies and help prioritize
agents for therapy, the ultimate test still requires specific
evaluation in patients with pulmonary fibrosis. Ultimately,
efficacy of therapy requires formal studies with sufficient
numbers of patients in order to provide convincing results.
CASE DEFINITION OF IPF
IPF is a specific form of fibrosing interstitial pneumonia
limited to the lung and has the histopathologic pattern of
usual interstitial pneumonitis (UIP) upon analysis of a surgical
lung biopsy. The definitive diagnosis of IPF requires a surgical
lung biopsy. Because it remains a diagnosis of exclusion,
a detailed clinical assessment is required to exclude other
diffuse parenchymal diseases. Most patients are over 50 yr
of age and report an insidious onset of progressive dyspnea
and nonproductive cough over months to years. Inspiratory
crackles are noted on examination of the chest and finger
clubbing is present in approximately 25%. Chest radiographs
show bilateral peripheral-based reticular opacities and honeycombing
predominantly involving the lower lung zones. Physiology reveals
reduced lung volumes with restrictive physiology, a diminished
single-breath diffusing capacity, and hypoxemia with exercise.
A concern of the conference participants was that in most
instances the diagnosis of IPF can not be reliably established
without a surgical biopsy. A critical issue for therapeutic
trials is that the investigators must be confident of the
diagnosis of a particular interstitial lung disease, and this
is best achieved by a review panel that should consider all
available information. There are some cases of IPF with significant
pleural based honeycombing on HRCT and without other significant
radiographic abnormalities that can be reliably diagnosed
as IPF with over 90% confidence (12). However, if there is
any doubt in the diagnosis, a surgical biopsy is indicated.
Interpretation of data on the responsiveness to corticosteroid
therapy in earlier studies of IPF is difficult to evaluate
because precise pathologic diagnoses were not established.
For the purpose of future clinical trials, UIP must be differentiated
from bronchiolitis obliterans with organizing pneumonia (BOOP),
nonspecific interstitial pneumonia (NSIP), desquamative interstitial
pneumonia (DIP), acute interstitial pneumonia (AIP), lymphocytic
interstitial pneumonia (LIP), respiratory bronchiolitis associated
interstitial lung disease (RBILD), and chronic hypersensitivity
SUMMARY OF PAST THERAPEUTIC TRIALS
A number of prior studies have evaluated potential therapies
for patients with IPF (5, 13-26). Most of these studies have
evaluated the effects of corticosteroids, cytotoxic agents,
or colchicine, although in a few studies other drugs were
tested (27, 28). In most studies, the number of patients was
too small to determine efficacy, and the design of the studies
did not always include a parallel placebo-controlled group.
Corticosteroids are the mainstay of therapy in IPF. Many
studies, especially early studies, reported that 10 to 30%
of patients with IPF have an initial, objective improvement
with this form of therapy (13-15, 24). Reevaluation of these
studies has questioned whether most of the patients who responded
to therapy truly had IPF (4). There are a number of reasons
for this reevaluation. First, some of the patients in these
studies had a collagen vascular disease and, therefore, did
not have IPF. Second, there were few biopsies performed to
establish a diagnosis of IPF. Thus, it is unlikely that all
of the patients in these studies would be classified as IPF
by our current criteria. Two additional observations suggest
that the responsive patients had a disorder other than IPF.
In general, the patients who responded to therapy were younger
than 50 yr of age and were female. Most patients with these
demographic characteristics do not have UIP on lung biopsy
by our current criteria. Recent studies of well-defined patients
with IPF suggest that few, if any, patients with IPF respond
to corticosteroid therapy. No studies have determined that
corticosteroids alter survival when compared with untreated
Several studies have evaluated the effects of cytotoxic agents
and noted beneficial effects in the treatment of patients
with IPF. An early study from the Brompton Hospital suggested
that therapy with cyclophosphamide and prednisone improves
survival compared with therapy with prednisone alone (16).
However, the same reservations regarding patient selection
that were noted previously for clinical trials of corticosteroids
apply to this study. Others have suggested that cyclophosphamide
slows the decline in pulmonary function in patients with IPF
but does not alter survival (22, 25). Similar observations
and reservations exist regarding the clinical trials on the
efficacy of azathioprine (18).
Two studies evaluated colchicine for the treatment of IPF
(19, 29). One compared prednisone alone to prednisone plus
colchicine and there was no additional benefit of colchicine
(29). In another study, the effects of colchicine alone were
similar to that of prednisone alone (19). None of the patients
had an initial response to therapy, and pulmonary function
continued to decline in all patients. The median survival
was unchanged, suggesting little effect of the drugs. The
only benefit of colchicine therapy was fewer side effects
when compared with prednisone.
As an aggregate, these observations suggest that current
therapy has minimal or no beneficial effect for patients with
IPF. In addition, the two most commonly used agents (prednisone
and cyclophosphamide) are associated with significant side
effects. These observations provide impetus to identify new
forms of therapy for this disease and to define the dose regimen
for maximal benefit with minimal side effects from standard
ETIOLOGY AND PATHOGENESIS
The prior NHLBI-sponsored workshops stressed the need
for genetic markers of susceptibility and for expanded studies
on the genetics and pathogenesis of familial IPF (3). These
issues were reaffirmed at the present meeting, and the development
of new tools for molecular epidemiology and methodological
advances provided by the Human Genome Project provide an opportunity
for important advances. In future clinical trials of patients
with IPF, samples of DNA should be collected for future investigation
of genetic markers. A central repository of DNA samples and
lung biopsies of patients with familial IPF would be useful
and may provide the genetic material for defining this important
subset of patients with IPF. The issue of environmental factors
contributing to the pathogenesis of IPF remains open, and
additional case control studies with matched, well-defined
cases of IPF to define environmental associations would be
informative. In addition, investigation of the potential role
of DNA viruses in the pathogenesis of these diseases is warranted.
Although no viral particles are observed in electron micrographs
of biopsies of patients with IPF, a systematic evaluation
for viral DNA has not been reported.
Several plausible schemes for the pathogenesis of IPF
have been proposed (7-9, 30). These schemes are not mutually
exclusive. For simplicity and focusing research questions
and new therapeutic options, these diagrams commonly depict
inflammatory cells acting directly on fibroblasts through
a variety of inflammatory mediators, cytokines, and growth
factors (Figure 1). However, the interaction of the inflammatory
cascade with parenchymal lung cells is also important. Because
this pathologic process occurs within the microenvironment
of the distal gas exchange units of the lung, i.e., alveoli
and terminal bronchioles, there are also important interactions
of inflammatory cells with pulmonary epithelial cells and
endothelial cells. It should be noted that not only inflammatory
and parenchymal cells affect fibroblasts, but fibroblasts
also alter inflammatory and parenchymal cells. Hypotheses
about specific cell types and mediators in pulmonary fibrosis
have been reviewed previously and will not be presented in
this report because it was not a major focus of this workshop.
Figure 1. Pathogenesis
of pulmonary fibrosis. There are numerous pathways that
can lead to pulmonary fibrosis and none are mutually
exclusive. In this diagram, important cell-cell interactions
that do not involve fibroblasts are not shown in order
to focus attention on the role of fibroblasts. This
scheme poses a problem in that specific targeted therapy
would be ineffective because of the redundancy of pathways
toward fibrosis. However, it is highly likely that only
a few of these pathways are critical in human IPF. Studies
with KGF in rats and gene deletion studies in mice indicate
that a single growth factor or receptor might be highly
effective. Therapy need not be directed at the whole
inflammatory response as is the current rationale for
corticosteroids and cytotoxic agents. Abbreviations:
IL-4 5 interleukin-4; FGF-2 5 fibroblast growth
factor-2, basic FGF; TGF-b 5 transforming growth factor-beta;
TNF-a 5 tumor necrosis factor; PDGF 5 platelet-derived
growth factor; IL-1 5 interleukin-1; IGF-1 5 insulin-like
growth factor-1; HB-EGF 5 heparin binding epidermal-like
growth factor; gIFN 5 gamma interferon; PGE2 5 prostaglandin
In the normal lung, the interstitium of the alveolar
wall is thin and the number of fibroblasts is limited. Most
fibroblasts and collagen fibers occur along blood vessels
and conducting airways. The balance of fibrogenic and antifibrogenic
factors must be toward suppression of fibroblast proliferation
and matrix production. However, we know little about the antifibrogenic
factors that are present in the normal lung. The identification
of these antifibrogenic factors as well as those that occur
in the late-term fetal lung when the mesenchyme decreases
might provide new insight and novel approaches to the treatment
of pulmonary fibrosis.
The major targets of therapy have focused on the inflammatory
cells, and this has led to the use of anti-inflammatory agents.
However, corticosteroids and cytotoxic drugs are minimally
effective in IPF. Newer approaches should include agents that
directly affect fibroblasts, agents that alter specific classes
of inflammatory cells such as macrophages or T cells and their
inflammatory products, and agents that alter epithelial/ fibroblast
or endothelial/ fibroblast interactions. The regulation of
the fibrotic process in the lung will be enhanced by the development
of transgenic mice with genetic deletions of specific
growth factors, mediators, or cytokine and their cognate receptors.
In addition, current molecular techniques afford the opportunity
of producing recombinant soluble growth factors and cytokine
receptors for treatment protocols.
One important pathologic feature of UIP, the underlying histopathology
of IPF, is the fibroproliferative plaque which is the focal
area of active fibrogenesis (31-33). The cell-cell interactions,
inflammatory mediators, and growth factors in these foci need
to be defined and may provide important avenues for therapy.
Many investigators believe that regulation of injury, repair,
and fibrogenesis in these specific areas might hold the clue
to new treatments for IPF. Pulmonary hypertension is a complication
of pulmonary fibrosis that merits additional attention and
might benefit from more aggressive therapy. Pulmonary hypertension
is one of the rate-limiting factors in the dyspnea and exercise
limitation of patients with IPF and a contributor to mortality.
In addition to supplemental oxygen, patients may benefit from
vasodilators such as prostacyclin and treatment directed at
POTENTIAL THERAPEUTIC INTERVENTIONS
As noted previously, current therapy has minimal beneficial
effects on patients with IPF. Thus, future studies should
focus on newer forms of therapy and, if possible, early in
the course of the disease. The selection of agents for treatment
trials should be guided by our current knowledge of the pathogenesis
of IPF and preclinical data on experimental pulmonary fibrosis
in rodents and in vitro experiments. The following
list contains agents that the participants discussed and recommended
for consideration in clinical trials. Some of the agents are
ready to be examined now in a Phase II or Phase III clinical
trial. However, others on the list, while promising, will
require additional evaluation prior to a trial.
Pirfenidone, an antifibrotic agent, showed promise in
IPF patients in an open label study (34). There was limited
toxicity and improvement in some patients, but a larger prospective
double-blind study is required to establish efficacy. In this
study most patients had failed immunosuppressive and cyto-toxic
therapy and had advanced disease. Pirfenidone ameliorates
bleomycin-induced pulmonary fibrosis in hamsters (35). In
vitro, pirfenidone decreases IPF lung fibroblast proliferation,
extracellular matrix production, transforming growth factor-beta
(TGF-b)-stimulated collagen synthesis, and mitogenic effects
of platelet-derived growth factor (PDGF) (36).
Interferon Gamma (IFN-g)
IFN-g is an attractive therapeutic candidate because it regulates
both macrophage and fibroblast functions. The theoretical
benefits would include diminished expression of insulin-like
growth factor 1 (IGF-1), a profibrogenic growth factor produced
by macrophages, and suppression of fibroblast proliferation
and collagen synthesis. In addition, IFN-g inhibits a fibrogenic
growth factor produced by mast cells, fibroblast growth factor-2
(FGF-2, basic FGF) (37), and a variety of neutrophil- derived
Interferon Beta (IFN-b)
IFN-b is widely used for the treatment of chronic hepatitis
C and multiple sclerosis and has anti-inflammatory properties.
In mice, IFN-b inhibits irradiation-induced pulmonary fibrosis
(39). There is currently an ongoing prospective clinical trial
on the effect of IFN-b in the treatment of patients with IPF.
Suramin is a sulfonated naphthylurea that has been used
clinically for many years to treat onchocerciasis. It also
has been shown to have in vitro antiretroviral activity
and was used in some clinical trials in acquired immunodeficiency
syndrome (AIDS) in the 1980s. The main clinical use of suramin
has been in the treatment of prostate cancer. Suramin has
the unusual in vitro property of antagonizing the effects
of a number of growth factors including TGF-b, IGF-1, PDGF,
epidermal-like growth factor (EGF), and FGF. The mechanism
has not been completely identified, but there appears to be
inhibition at the level of ligand binding. The attractive
property of suramin is the relatively promiscuous nature of
its growth factor binding. It is likely that a number of growth
factors mediate fibroblast proliferation and collagen deposition
and that the potential effect against many different growth
appealing. Suramin has been shown to delay wound healing.
A less attractive quality is that suramin must be administered
intravenously. One reversible toxic effect of suramin is the
inhibition of mineralocorticoid release. For this reason,
low doses of prednisone are required with the administration.
Suramin offers a novel approach to treating IPF by targeting
some of the effector molecules, namely growth factors.
Relaxin is a secreted protein thought to be responsible
for structural remodeling of the interpubic ligament and cervix
during the later phases of pregnancy. Relaxin inhibits TGF-b-induced
collagen and fibronectin production by human lung fibroblasts
and increases expression of matrix metalloproteinase 1 (procollagenase)
and decreases the production of a tissue inhibitor of metalloproteinases
(40). In vivo, relaxin inhibits pulmonary fibrosis
produced by bleomycin and fibrosis associated with implanted
polyvinyl sponges (41).
The prostaglandin PGE2 is a potent inhibitor of fibroblast
proliferation and matrix production in vitro, and,
therefore, administration of PGE2 may ameliorate the fibrotic
process. An oral analogue of PGE2 is a potential candidate
for therapeutic intervention. Exogenous PGE2 has not been
evaluated in vivo in animal models of pulmonary fibrosis
to our knowledge. However, in an animal model of pulmonary
fibrosis produced by bleomycin, indomethacin, an inhibitor
of cyclooxygenase, decreased pulmonary fibrosis (42) Leukotriene
B4 (LTB4 ), a potent chemotactic factor for neutrophils, is
increased in lavage and lung homogenates of patients with
IPF, and macrophages from IPF patients secrete more LTB4 than
control macrophages (43, 44). There are high concentrations
of constitutive 5-lipoxygenase activation in IPF lungs (44).
Leukotrienes have a broad spectrum of biologic responses and
in general are proinflammatory. Leukotrienes also stimulate
collagen synthesis and fibroblast chemotaxis, proliferation,
and collagen synthesis. Inhibition of leukotriene production
may be an effective adjuvant therapy, and drugs are now available
to block leukotriene synthesis.
Angiotensin-converting Enzyme Inhibitors/ Angiotensin
II Receptor Antagonists
The angiotensin-converting enzyme inhibitor, captopril,
has been shown to reduce fibroblast proliferation and pulmonary
fibrosis due to irradiation in rats (45, 46). Angiotensin
II stimulates matrix production by fibroblasts, and angiotensin
II receptor blockers have been reported to inhibit pulmonary
fibrosis resulting from irradiation and bleomycin. Because
these drugs are available for human studies and can be given
orally, further evaluation seems warranted.
Keratinocyte Growth Factor
Keratinocyte growth factor (KGF) greatly stimulates type
II cell proliferation in vivo and in vitro (47,
48). KGF represents a class of growth factors that stimulate
epithelial cells but have no direct effect on mesenchymal
cells and fibroblasts. The KGF receptor is expressed only
on epithelial cells. In addition, KGF causes a pleotropic
cytoprotective effect on pulmonary epithelial cells and increases
surfactant protein gene expression and sodium/ potassium ATPase
(49, 50). These properties would be beneficial in altering
the response to lung injury. Animals pretreated with KGF are
protected from injury and the subsequent development of fibrosis
caused by bleomycin, irradiation, acid instillation, oxygen
toxicity, and a-naphthylthio-urea (51-55). Because IPF is
thought to be a chronic fibrotic disease resulting from focal
active inflammation and fibrogen-esis, administration of KGF
might be very beneficial. However, although animal studies
with KGF are impressive and reproducible, in most studies
KGF must be given before injury and long-term therapy would
require systemic administration. Many investigators believe
that type II cell hyperplasia is an important response to
limit fibroblast migration, proliferation, and matrix production.
However, as shown in Figure 1, type II cells are also candidates
for production of fibrogenic cytokines and growth factors
and could contribute to the fibroproliferative response.
Other Potential Therapeutic Agents
Other potential agents discussed include cyclosporin,
N-acetyl cysteine and other antioxidants, thalidomide
(56, 57), endothelin receptor antagonists (58, 59), the human
soluble tumor necrosis factor (TNF) receptor fusion protein
interleukin-10 (IL-10), and anticoagulants. In addition, it
is highly likely that other promising agents will emerge in
the next few years.
The workshop did not attempt to rank potential interventions
and the aforementioned list should not be considered any attempt
at prioritization. The consensus of the conference was that
the time was right to evaluate the efficacy of new agents
in the treatment of IPF.
The current availability of several novel therapeutic
agents and the emergence of additional agents from laboratory
and clinical studies of pulmonary fibrosis indicate that it
is appropriate to begin systemic evaluation of different treatment
regimens in IPF.
Improvement in the treatment of patients with IPF will require
rigorous controlled clinical trials to compare different treatment
options. Although the incidence of IPF is greater than previously
thought, multicenter trials will still be required, because
it is very unlikely that any single center will have sufficient
numbers of suitable patients to provide results in a timely
Prospective studies should be designed to provide valuable
information on causes, genetic predisposition, and pathogenesis
of IPF. This is especially true for providing DNA samples
for genetic studies, e. g., genetic markers of susceptibility.
There is also a need for additional prospective case-controlled
epidemiologic studies to identify potential contributing environmental
Additional surrogate markers of disease activity are needed.
Because the duration of disease is long and progression is
slow, current outcomes need to be based on mortality or significant
changes in physiology or HRCT scores. It would be useful to
develop surrogate markers of disease activity such that if
a particular marker changed within 1 to 2 mo of therapy, one
could predict a long-term favorable response or failure of
The diagnosis of IPF and IPF-related diseases must be made
with a very high level of confidence so that the results can
be readily interpreted. It is anticipated that there will
be some responders and some nonresponders to therapy. The
future care of patients with IPF and IPF-related diseases
precise identification of the responders for interpretation
of results and for designing subsequent prospective studies.
In general, diagnosis usually requires a surgical biopsy usually
provided by video-assisted thorascopic surgery (VATS) in order
to provide sufficient tissue for pathologic diagnosis. Assessment
should be made by an expert panel of pathologists who communicate
regularly to provide consistent interpretations.
Clinical trials would benefit from broad inclusion criteria
so that patients with IPF-related diseases, who are more likely
to respond to therapy are included. However, the diagnosis
of individual cases must be as specific and definite as possible
so that the anticipated responders can be defined as precisely
as possible. For example, there may be separate parallel studies
for patients with the pathologic diagnosis of BOOP, NSIP,
UIP, and those with connective tissue disease.
Additional studies of the reproducibility of HRCT scoring
systems and pathology interpretations are warranted.
Measurement of quality of life is an important outcome variable
and the current questionnaires should be made as disease-specific
as possible and validated for use in future studies.
There is a need for animal models of lung inflammation and
fibrosis. Studies of transonic and knockout mice with targeted
alterations in cytokines, growth factors, and their receptors
are important and will be critical for defining the role of
certain inflammatory and fibrogenic factors in the response
to injury and the development of pulmonary fibrosis.
There is a pressing need to continue research to investigate
the regulation of injury, repair, and fibrogenesis in the
unique microenvironment of the lung. These studies will provide
insight for development of the next generation of therapeutic
options for IPF.
The authors wish to thank the participants of the conference
who provided important ideas embodied in this report. These
Robert Baughman, Cincinnati, OH; Reuben Cherniack, Denver,
CO; Thomas V. Colby, Scottsdale, AZ; Bernadette Gochuico,
Bethesda, MD; Jeffrey Golden, San Francisco, CA; Ronald Gold-stein,
Boston, MA; Gary W. Hunninghake, Iowa City, IA; Anna Katzenstein,
Syracuse, NY; Talmadge E. King, San Francisco, CA; Charles
Kuhn, Bethesda, MD; David Lynch, Denver, CO; Robert J. Mason,
Denver, CO, Chair; Robert A. Musson, Bethesda, MD; Paul W.
Nobel, New Haven, CT; Ganesh Raghu, Seattle, WA; Marvin I.
Schwarz, Denver, CO; Cecilia M. Smith, San Diego, CA.
1. Coultas, D. B., R. E. Zumwalt, W. C. Black, and R.
E. Sobonya. 1994. The epidemiology of interstitial lung disease.
Am. J. Respir. Crit. Care Med. 150: 967-972.
2. Cherniack, R. M., R. G. Crystal, and A. R. Kalica. 1991.
NHLBI Workshop summary. Current concepts in idiopathic pulmonary
fibrosis: a road map for the future. Am. Rev. Respir. Dis.
3. Hunninghake, G., and A. R. Kalica. 1995. Approaches to
the treatment of pulmonary fibrosis. Am. J. Respir. Crit.
Care Med. 151: 915-918.
4. Ryu, J. H., T. V. Colby, and T. E. Hartman. 1998. Idiopathic
pulmonary fibrosis: current concepts. Mayo Clin. Proc.
5. Bjoraker, J. A., J. H. Ryu, M. K. Edwin, J. L. Meyers,
H. D. Tazelaar, D. R. Schroeder, and K. P. Offord. 1998. Prognostic
significance of histopathologic subsets in idiopathic pulmonary
fibrosis. Am. J. Respir. Crit. Care Med. 157: 199-203.
6. Katzenstein, A. A., and J. L. Myers. 1998. Idiopathic pulmonary
fibrosis: clinical relevance of pathologic classification.
Am. J. Respir. Crit. Care Med. 157: 1301-1315.
7. Goldstein, R. H., and A. Fine. 1995. Potential therapeutic
initiatives for fibrogenic lung disease. Chest 108:
8. Hogaboam, C. M., R. E. Smith, and S. L. Kunkel. 1998. Dynamic
interactions between lung fibroblasts and leukocytes: implications
for fibrotic lung disease. Proc. Assoc. Am. Phys. 110:
9. Kasper, M., and G. Haroske. 1996. Alterations in the alveolar
epithelium after injury leading to pulmonary fibrosis. Histol.
Histopathol. 11: 463-483.
10. Kuhn, C. 1993. The pathogenesis of pulmonary fibrosis.
Monogr. Pathol. 36: 78-92.
11. Fukuda, Y., M. Ishizaki, S. Kudoh, M. Kitaichi, and N.
Yamanaka. 1998. 5 Localization of matrix metalloproteinases-1,
-2, and -9 and tissue inhibitor of metalloproteinase-2 in
interstitial lung disease. Lab. Invest. 7: 687-698.
12. Hunninghake, G., D. Schwartz, T. King, J. Lynch, J. Hogg,
J. Waldren, T. Colby, N. Muller, D. Lynch, J. Galvin, B. Gross,
G. Toews, R. Helmers, J. Cooper, R. Baughman, S. Sahn, M.
Millard, and J. Stutzman. 1998. IPF Open Lung Biopsy Study
Group: open lung biopsy in IPF (abstract). Am. J. Respir.
Crit. Care Med. 157: A277.
13. Turner-Warwick, M., B. Burrows, and A. Johnson. 1980.
Cryptogenic fibrosing alveolitis: response to corticosteroid
treatment and its effect on survival. Thorax 35: 593-599.
14. Turner-Warwick, M., B. Burrows, and A. Johnson. 1980.
Cryptogenic fi-brosing alveolitis: clinical features and their
influence on survival. Thorax 35: 171-180.
15. Rudd, R. M., P. L. Haslam, and M. Turner-Warwick. 1981.
Cryptogenic fibrosing alveolitis: relationship of pulmonary
physiology and bronchoalveolar lavage to response to treatment
and prognosis. Am. Rev. Respir. Dis. 124: 1-8.
16. Johnson, M. A., S. Kwan, N. J. C. Snell, A. J. Nunn, J.
H. Darbyshire, and M. Turner-Warwick. 1989. Randomised controlled
trial comparing prednisolone alone with cyclophosphamide and
low dose prednisolone in combination in cryptogenic fibrosing
alveolitis. Thorax 44: 280-288.
17. Winterbauer, R. H., S. P. Hammar, K. O. Hallman, J. E.
Hays, N. E. Par-dee, E. H. Morgan, J. D. Allen, K. D. Moores,
W. Bush, and J. H. Walker. 1989. Diffuse interstitial pneumonitis:
clinicopathologic correlations of 20 patients treated with
prednisone/ azathioprine. Am. J. Med. 65: 661-672.
18. Raghu, G., W. J. Depaso, K. Cain, P. Hammar, C. E. Wetzel,
D. F. Dries, J. Hutchinson, N. E. Pardee, and R. H. Winterbauer.
1991. Azathioprine combined with prednisone in the treatment
of idiopathic pulmonary fibrosis: a prospective double-blind,
randomized, placebo-controlled trial. Am. Rev. Respir.
Dis. 144: 291-296.
19. Douglas, W. W., J. H. Ryu, J. Swensen, P. Offord, D. R.
Schroeder, G. M. Caron, and R. A. DeRemee. 1998. Colchicine
versus prednisone in the treatment of idiopathic pulmonary
fibrosis: a randomized prospective study. Am. J. Respir.
Crit. Care Med. 158: 220-225.
20. Hubbard, R., I. Johnson, and J. Britton. 1998. Survival
in patients with cryptogenic fibrosing alveolitis: a population-based
cohort study. Chest 113: 396-400.
21. Johnston, I. D. A., R. J. Prescott, J. C. Chalmers, and
R. M. Rudd. 1997. British Thoracic Society study of cryptogenic
fibrosing alveolitis: current presentation and initial management.
Thorax 52: 38-44.
22. Dayton, C. S., D. A. Schwartz, R. A. Helmers, P. J. Puerringer,
S. R. Gilbert, R. K. Merchant, and G. W. Hunninghake. 1993.
Outcome of subjects with idiopathic pulmonary fibrosis who
fail corticosteroid therapy: implications for future studies.
Chest 103: 69-73.
23. Schwartz, D. A., R. A. Helmers, J. R. Galvin, S. Van Fossen,
D. L. Frees, C. S. Dayton, L. F. Burmeister, and G. W. Hunninghake.
1994. Determinants of survival in idiopathic pulmonary fibrosis.
Am. J. Respir. Crit. Care Med. 149: 450-455.
24. Stack, B. H. R., Y. F. J. Choo-Kang, and B. E. Heard.
1972. The prognosis of cryptogenic fibrosing alveolitis. Thorax
25. Baughman, R. P., and E. E. Lower. 1992. Use of intermittent,
intravenous cyclophosphamide for idiopathic pulmonary fibrosis.
Chest 102: 1090-1094.
26. Katzenstein, A. A., and J. L. Meyers. 1998. Idiopathic
pulmonary fibrosis: clinical relevance of pathologic classification.
State of the Art. Am. J. Respir. Crit. Care Med. 157:
27. Lynch, J. P., and W. J. McCune. 1997. Immunosuppressive
and cytotoxic pharmacotherapy for pulmonary disorders. Am.
J. Respir. Crit. Care Med. 155: 395-420.
28. Mapel, D. W., J. M. Samet, and D. B. Coultas. 1996. Corticosteroids
and the treatment of idiopathic pulmonary fibrosis: past,
present and future. Chest 110: 1058-1067.
29. Selman, M., G. Carrillo, J. Salas, R. P. Padilla, R. Perez-Chavira,
R. Sansores, and R. Chapela. 1998. Colchicine, D-penicillamine,
and prednisone in the treatment of idiopathic pulmonary fibrosis:
a controlled clinical trial. Chest 114: 507-512.
30. Phan, S. H. 1994. New strategies for treatment of pulmonary
fibrosis. Thorax 50: 415-421.
31. Broekelmann, T. J., A. H. Limper, T. V. Colby, and J.
A. McDonald. 1991. Transforming growth factor beta 1 is present
at sites of extracellular matrix gene expression in human
pulmonary fibrosis. Proc. Natl. Acad. Sci. U. S. A. 88:
32. Kuhn, C., and J. A. McDonald. 1991. The roles of the myofibroblast
in idiopathic pulmonary fibrosis: ultrastructural and immunohistochemical
features of sites of active extracellular matrix synthesis.
Am. J. Pathol. 138: 1257-1265.
33. Kuhn, C., III, J. Boldt, J. T. E. King, Jr., E. Crouch,
T. Vartio, and J. A. McDonald. 1989. An immunohistochemical
study of architectural remodeling and connective tissue synthesis
in pulmonary fibrosis. Am. Rev. Respir. Dis. 140: 1693-1703.
34. Raghu, G., C. Johnson, D. Lockhart, and Y. Mageto. 1999.
Treatment of idiopathic pulmonary fibrosis with a new antifibrotic
agent, pirfenidone: results of a prospective open label study.
Am. J. Respir. Crit. Care Med. (In press)
35. Swarnalatha, N. I., S. B. Margolin, D. M. Hyde, and S.
N. Giri. 1998. Lung fibrosis is ameliorated by pirfenidone
fed in diet after the second dose in a three-dose bleomycin-hamster
model. Exp. Lung Res. 24: 119-132.
36. Lurton, J. M., T. Trejo, A. S. Narayaman, and G. Raghu.
1996. Pirfenidone inhibits the stimulatory effects of profibrotic
cytokines on human lung fibroblasts in vitro (abstract).
Am. J. Respir. Crit. Care Med. 153: A403.
37. Inoue, Y., T. E. J. King, S. S. Tinkle, K. Dockstader,
and L. S. Newman. 1996. Human mast cell basic fibroblast growth
factor in pulmonary fibrotic disorders. Am. J. Pathol.
38. Kasama, T., R. M. Strieter, N. W. Lukacs, P. M. Lincoln,
M. D. Burdick, and S. L. Kunkel. 1995. Interferon gamma modulates
the expression of neutrophil-derived chemokines. J. Investig.
Med. 43: 58-67.
39. McDonald, S., P. Rubin, A. Y. Chang, D. P. Peney, J. N.
Finkelstein, S. Grossberg, R. Feins, and P. K. Gregory. 1993.
Pulmonary changes induced by combined mouse beta-interferon
(rMuIFN-beta) and irradiation in normal miceÑ toxic
versus protective effects. Radiother. On-col. 26: 212-218.
40. Unemori, E. N., L. B. Pickford, A. L. Salles, C. E. Piercy,
B. H. Grove, M. E. Erikson, and E. P. Amento. 1996. Relaxin
induces an extracellular matrix- degrading phenotype in human
lung fibroblasts in vitro and inhibits lung fibrosis in a
murine model in vivo. J. Clin. Invest. 98: 2739-2745.
41. Unemori, E. N., L. S. Beck, W. P. Lee, Y. Xu, M. Siegel,
G. Keller, H. D. Liggitt, E. A. Bauer, and E. P. Amento. 1993.
Human relaxin decreases collagen accumulation in vivo in
two rodent models of fibrosis. J. Invest. Dermatol. 101:
42. Thrall, R. S., J. R. McCormick, R. M. Jack, R. A. McReynolds,
and P. A. Ward. 1979. Bleomycin-induced pulmonary fibrosis
in the rat: inhibition by indomethacin. Am. J. Pathol.
43. Ozaki, O., H. Hayashi, K. Tani, F. Ogushi, U. Yasuoka,
and T. Ogura. 1992. Neutrophil chemotactic factor in the respiratory
tract of patients with chronic airway diseases or idiopathic
pulmonary fibrosis. Am. Rev. Respir. Dis. 145: 85-91.
44. Wilborn, J., M. Bailie, M. Coffey, M. Burdick, R. Strieter,
and M. Peters Golden. 1996. Constitutive activation of 5-lipoxygenase
in the lungs of patients with idiopathic pulmonary fibrosis.
J. Clin. Invest. 97: 1827-1836.
45. Ward, W. F., A. Molteni, C. H. Ts'ao, Y. T. Kim, and J.
M. Hinz. 1992. Radiation pneumotoxicity in rats: modification
by inhibitors of angiotensin converting enzyme. Int. J.
Radiat. Oncol. Biol. Phys. 22: 623-625.
46. Nguyen, L., W. F. Ward, C. H. Ts'ao, and A. Molteni. 1994.
Captopril inhibits proliferation of human lung fibroblasts
in culture: a potential antifibrotic mechanism. Proc. Soc.
Exp. Biol. Med. 205: 80-84.
47. Ulich, T. R., E. S. Yi, K. Longmuir, S. Yin, R. Blitz,
C. F. Morris, R. M. Housley, and G. F. Pierce. 1994. Keratinocyte
growth factor is a growth factor for type II pneumocytes in
vivo. J. Clin. Invest. 93: 1298-1306.
48. Panos, R. J., J. S. Rubin, S. A. Aaronson, and R. J. Mason.
1993. Keratinocyte growth factors and hepatocyte growth factor/
scatter factor are heparin-binding growth factors for alveolar
type II cells in fibroblast-conditioned medium. J. Clin.
Invest. 92: 969-977.
49. Yano, T., R. R. Deterding, L. D. Nielsen, C. Jacoby, J.
M. Shannon, and R. J. Mason. 1997. Surfactant protein and
CC-10 expression in acute lung injury and in response to keratinocyte
growth factor. Chest 111: 137S-138S.
50. Sugahara, K., J. S. Rubin, R. J. Mason, E. L. Aronsen,
and J. M. Shannon. 1995. Keratinocyte growth factor increases
mRNAs for SP-A and SP-B in adult rat alveolar type II cells
in culture. Am. J. Physiol. 269: L344-L350.
51. Panos, R. J., P. Bak, W. S. Simonet, S. L. Aukerman, J.
S. Rubin, and L. J. Smith. 1995. Keratinocyte growth factor
(KGF) prevents hyperoxia induced mortality in rats (abstract).
Am. J. Respir. Crit. Care Med. 151: A181.
52. Deterding, R. R., A. M. Havill, T. Yano, C. R. Jacoby,
J. M. Shannon, W. S. Simonet, and R. J. Mason. 1997. Keratinocyte
growth factor prevents bleomycin lung injury in rats. Proc.
Assoc. Am. Phys. 109: 254-268.
53. Yano, T., R. R. Deterding, W. S. Simonet, J. M. Shannon
and R. J. Mason. 1996. Keratinocyte growth factor reduces
lung damage due to acid instillation in rats. Am. J. Respir.
Cell Mol. Biol. 15: 433-442. 6
54. Guo, J., E. S. Yi, A. M. Havill, I. Sarosi, L. Whitcomb,
S. Yin, S. C. Middleton, P. Piguet, and T. R. Ulich. 1998.
Intravenous keratinocyte growth factor protects against experimental
pulmonary injury. Am. J. Physiol. 275: L800-L805.
55. Mason, C. M., B. P. H. Guery, W. R. Summer, and S. Nelson.
1996. Keratinocyte growth factor attenuates long leak induced
by a-naphthyl-thiourea in rats. Crit. Care Med. 24:
56. Moller, D. R., M. Wysocka, B. M. Greenlee, X. Ma, L. Wahl,
D. A. Flockhart, G. Trinchieri, and C. L. Karp. 1997. Inhibition
of IL-12 production of thalidomide. J. Immunol. 159:
57. Tavares, J. L., A. Wangoo, P. Dilworth, B. Marshall, S.
Kotecha, and R. J. Shaw. 1997. Thalidomide reduces tumour
necrosis factor-alpha production by human alveolar macrophages.
Respir. Med. 91: 31-39.
58. Park, S. H., D. Saleh, A. Giaid, and R. P. Michel. 1997.
Increased endothelin-1 in bleomycin-induced pulmonary fibrosis
and the effect of an endothelin receptor antagonist. Am.
J. Respir. Crit. Care Med. 156: 600-608.
59. Saleh, D., K. Furukawa, M. S. Tsao, A. Maghazachi, B.
Corrin, M. Yanagisawa, P. J. Barnes, and A. Giaid. 1997. Elevated
expression of endothelin-1 and endothelin-converting enzyme-1
in idiopathic pulmonary fibrosis: possible involvement of
proinflammatory cytokines. Am. J. Respir. Cell Mol. Biol.
60. Anthonisen, N. R. 1989. Prognosis in chronic obstructive
pulmonary disease: results from multicenter clinical trials.
Am. Rev. Respir. Dis. 140: S95-S99.
61. Oswald-Mammosser, M., E. Weitzenblum, E. Quoix, G. Moser,
A. Chaouat, C. Charpentier, and R. Kessler. 1995. Prognostic
factors in COPD patients receiving long-term oxygen therapy:
importance of pulmonary artery pressure. Chest 107:
62. Herlitz, J., B. W. Karlson, J. Lindqvist, and M. Sjolin.
1997. Long term prognosis in men and women coming to the emergency
department with chest pain or other symptoms suggestive of
acute myocardial infarction. Eur. J. Emerg. Med. 4:
63. Mock, M. B., I. Ringqvist, L. D. Fisher, K. B. Davis,
B. R. Chaitman, N. T. Kouchoukos, G. C. Kaiser, E. Alderman,
T. J. Ryan, R. O. Russell, S. Mullin, D. Fray, and T. Killip.
1982. Survival of medically treated patients in the coronary
artery surgery study (CASS) registry. Circulation 66:
64. NCI. 1997. National Cancer Institute Factbook. National
Cancer Institute, Bethesda, MD.
65. Balanzo, J., J. Such, S. Sainz, D. Gonzalez, C. Guarner,
L. Allende, J. P. Lacalle, and F. Vilardell. 1990. Long-term
survival and severe rebleeding after variceal sclerotherapy.
Surg. Gynecol. Obstet. 171: 489-492. 7
(Received in original form March 1, 1999 and in revised
form June 1, 1999)
Workshop sponsored by the National Heart, Lung, and Blood
Institute and the Office of Rare Diseases, National Institutes
of Health, Bethesda, Maryland and held in Bethesda, Maryland
on September 9-10, 1998.
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 Centre, Suite
10018, 6701 Rockledge Drive, MSC 7952, Bethesda, MD 20892.