American Journal of Respiratory Cell and Molecular Biology. Vol. 33, pp. 113-120, 2005
© 2005 American Thoracic Society
DOI: 10.1165/rcmb.F301
Back to the Future
Historical Perspective on the Pathogenesis of Idiopathic Pulmonary Fibrosis
Paul W. Noble and
Robert J. Homer
Department of Medicine, Section of Pulmonary and Critical Care Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
Correspondence and requests for reprints should be addressed to Paul W. Noble, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, TAC-441C, New Haven, CT 06520-8057. E-mail: paul.noble{at}yale.edu
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Introduction
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One of the more challenging areas of pulmonary medicine remains elucidating the pathogenesis of idiopathic pulmonary fibrosis (IPF). IPF is a devastating disease process with death occurring in the majority of patients within 5 years of diagnosis (1). A major reason for the difficulties in identifying pathogenic mechanisms has been related to the evolution in defining what IPF is. The diagnosis of IPF has been a moving target, and we are still without a gold standard. The generally accepted gold standard is a light microscopy viewing of a surgical lung biopsy revealing a pattern that has been termed "usual interstitial pneumonia" (UIP). To be "confident" of this pattern, it is usually expected that the pathologist be familiar with the range of patterns of acute and chronic lung injury originally described by Dr. Averill Liebow of Yale University, who is credited with the light microscopy recognition of this pattern on surgical lung biopsy or autopsy (1), and that is shown in Figure 1. It was termed "usual" because, of the interstitial pneumonias of unknown cause that he and his colleagues encountered, it was the most common and hence, usual form. The purpose of this historical perspective is to trace the evolution in the concepts of pathogenesis of IPF/UIP.
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Figure 1. Surgical lung biopsy specimen demonstrating the classic findings of UIP. These include temporal heterogeneity, fibrosis abutting the pleural surface, and minimal interstitial inflammation.
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THE HAMMAN AND RICH YEARS
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The discussion of pathogenesis of IPF must begin with the extraordinary clinical-radiographic-pathologic description of four patients who succumbed to respiratory insufficiency between 1931 and 1943 at the Johns Hopkins Hospital (2). This description was provided by Dr. Louis Hamman (an internist) and Dr. Arnold Rich (a pathologist) and is suggested reading for anyone with more than a passing interest in IPF. This case report permeated through the literature for the next 46 years (3–11) until the cases were revisited with the passage of time and refined classification of idiopathic interstitial pneumonias (12). The Hamman-Rich syndrome is now reclassified as acute interstitial pneumonia (AIP) rather than usual interstitial pneumonia. However, for several decades, the Hamman-Rich Syndrome was what most clinicians associated idiopathic pulmonary fibrosis with. The reason for this can be understood from the range of cases that were described and lung pathology that was presented at autopsy. Drs. Hamman and Rich observed three unusual cases of pulmonary disease in the Medical Wards of the Johns Hopkins Hospital. As they described:
The symptoms of each case differed somewhat from those of the others and yet bore a striking resemblance so that having seen two cases, the correct diagnosis was suggested when the third appeared. The pathological process in the lungs was identical in all and this lesion was so extraordinary and distinctive that there can be no doubt that the symptoms displayed by each case, different thought they were, arose from the same underlying morbid process, variations in symptoms depending upon the stage this process had reached at the time the patients came under observation (2).
Interestingly, the authors anticipated finding more cases readily, but the fourth case in the series was described 10 years later and they published their observations in 1944 (2). The duration of disease ranged from one to six months. This description illustrates a fundamental reason there has been so much uncertainty and debate regarding the diagnosis and ultimately the pathogenesis of idiopathic interstitial pneumonias. So much of the observations depend on time and sampling. These variables make for a heterogenous group of patterns and clinical presentations. In particular, it is the description of case four that led to the subsequent confusion between acute interstitial pneumonias and idiopathic interstitial pneumonias of subacute or chronic presentation. A 68-year-old white woman was admitted to the hospital service of Dr. Charles R. Austrian, February 16, 1943 complaining of shortness of breath, cough, and general malaise of four months duration. She had previously evaluated by her physician, who ascribed her symptoms to mild heart failure and advised "rest and digitalis." Her symptoms of breathlessness and cough persisted. The cough was described as "dry and harassing." Physical exam was noted for breath sounds that were "blowing in quality, in places tubular and numerous fine crepitant rales were heard over both lower lobes, also a few sonorous rales." She died after 59 d of hospitalization. At autopsy,
All sections from all lobes, showed a diffuse thickening of the alveolar walls, and there were also small scars which had obliterated the architecture entirely. It was clear that, in places, organization of intra-alveolar exudates had occurred. The thickened alveolar walls were edematous, and contained wandering cells, fibroblasts, collagen fibers and newly formed capillaries. The lining alveolar walls were greatly enlarged, and hyaline membranes were plentiful (3).
This is a description of what would presently be termed organizing diffuse alveolar damage. One additional insightful observation was included in describing the epithelium. "The bronchiolar epithelium was in places low and flattened, or squamous, and in places low cuboidal epithelium had proliferated from the bronchioles to line adjacent air sacs."
In 1957 Rubin and Lubiner reviewed the 39 cases described as Hamman-Rich Syndrome in the literature and 15 additional cases of their own (8). It is here that "variants" are described, as are the observations that the Hamman-Rich Syndrome is "not necessarily a limited pulmonary disease since a similar type of tissue reaction can be found in the lungs of patients with certain systemic disturbances, notably the rheumatoid group of collagen diseases" and "of particular importance is the fact that diffuse interstitial fibrosing pneumonia is not always an acute and fatal disease, as initially believed." In this report, the authors described that in long-standing disease the lungs may be "cirrhotic," "liver-like" in consistency, and present a "cobblestone" appearance (Figure 2). On section, such lungs are apt to reveal diffuse bronchiolectasis and gross bronchiectasis, which give the organs a "honeycomb" appearance. With the advent of the high-resolution chest CAT scan, this honeycombing can be recognized by a distinct pattern of reticulation with cystic changes in the lung periphery that appears to be of fundamental importance in both diagnostic accuracy and prognosis of IPF (13–15) (Figures 3A and 3B). Clues to the pathogenesis were provided by Hamman and Rich in their description of the pathology: (1) the presence of an extensive, diffuse, and progressive interstitial proliferation of fibrous tissue throughout both lungs; and (2) the striking proliferation of the lining alveolar cells. Additional, but more variable, components included: (1) necrosis of alveolar and bronchiolar epithelium, (2) the presence of a hyaline membrane lining the alveoli, (3) marked edema from fibrin deposition in the alveolar walls, (4) the presence of eosinophils, and (5) an absence of stainable bacteria. The cases presented by Rubin and Lubliner had a duration of illness that extended for as much as six years. It appears from the literature that as long as some aspect of the pathology that was described by Hamman and Rich was present in the context of profound interstitial pulmonary fibrosis, the Syndrome was diagnosed.
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Figure 2. Autopsy specimen of IPF demonstrating the manifestations of advanced fibrosis on the pleural surface.
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Figure 3. Classic high resolution CAT scan findings in IPF. Subpleural honeycombing, traction bronchiectasis, and thickened interlobular septae with a paucity of ground glass infiltrates.
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In 1964, Sheridan and colleagues described the evolution in the concept of idiopathic interstitial pulmonary fibrosis into something quite different from the acute (or subacute) and fulminating disease described by Hamman and Rich (16). They commented that many cases were more chronic in nature and that the average survival was 2–4 yr. Interestingly, a pathologic distinction between the more chronic cases and the fulminant Hamman-Rich cases was not made. Gaensler and coworkers further substantiated this, when they described a series of 105 patients with diffuse pulmonary disease that underwent open lung surgical biopsy between 1948 and 1963 (17). It was established that lung biopsy could be performed safely and that the diagnosis of interstitial pulmonary fibrosis, which was still called the Hamman-Rich Syndrome, could be established ante-mortem. In 1962 Gross published a conceptual essay on the acute versus chronic nature of Hamman-Rich syndrome (18). He appears to be among the first to raise idea that "acute diffuse interstitial fibrosis of the lungs" may in some cases be a chronic fibrosis with an acute, sumperimpsosed exacerbation that is either infectious or noninfectious. His concepts were developed on the basis of animal studies. Included in this discussion was the observation that chronic interstitial pneumonitis, which tends to obliterate airspaces as in the Hamman-Rich syndrome, begins as a proliferation of alveolar lining cells. In the author's words:
The proliferating alveolar cells produce an associated supporting reticulin stroma. The stroma may retain its reticulin character during the life of the individual or, depending upon the etiologic agent, in may "collagenize". Associated with collagenization, there is the cellularity of the tissue. It is interesting to note that, as long as the stroma remains reticulin in character, the lesion is reversible because reticulin fibers are labile and may undergo fragmentation and lysis. With the destruction of the reticulin stroma, the proliferated alveolar cells lose their structural support, desquamate and undergo degenerative change.
This appears to be the first description of the loss of integrity of epithelial basal lamina or baseement membrane and failure of successful re-epitheliazation in chronic interstitial pneumonitis.
Gracey and coworkers examined the alveolar capillary membrane by electron microscopy in 14 patients with idiopathic interstitial pulmonary fibrosis in 1967 (19). They made the interesting observation that abnormalities in patients with diffuse interstitial fibrosis can be related to the two main structures, the alveolar septum and the alveolar–capillary membrane. Two abnormalities were noted: "one was a pronounced decrease in the number of capillaries within the alveolar septae and the other was an asymmetric interposition of collagen and cells between part of the surface of a capillary and the nearby alveolar lining cell." Gracey and colleagues failed to find evidence to support the concept of a thickened alveolar capillary membrane as the pathogenic mechanism for impaired gas exchange, which had been made popular by Austrian and coworkers (20). In fact, they found evidence to suggest that hyperplastic alveolar epithelium was not in contact with the basement membrane. This was either due to destruction of the basement membrane, or else alveolar epithelial cells were proliferating on top of each other. This study was among the first to suggest by the description of the findings by electron microscopy that an important component of the pathogenesis of IPF may be related to abnormalities in epithelial proliferation.
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THE LIEBOW CLASSIFICATION
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In the mid and late 1960s, the "modern" era of interstitial lung disease began when Liebow and Carrington (1) described five histopathologic subgroups of chronic idiopathic interstitial pneumonia: the most common or "usual" interstitial pneumonia (UIP), bronchiolotis interstitial pneumonia (BIP), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), and giant cell interstitial pneumonia (GIP). It was their belief that "histologic characteristics may provide both clues to etiology and to pathogenesis." The holy grail of IPF has been the quest to understand the cellular and molecular events that explain the unique histologic pattern of UIP (Figure 2). Scadding from the United Kingdom proposed the term fibrosing alveolitis in 1964 (21), to which the adjective "cryptogenic" was added later; in view of the Liebow group's classification. The essential tenet of these authors' contribution was that the histologic pattern can portend prognosis. This has been the lasting contribution of the description of the UIP pattern.
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THE INFLAMMATION (ALVEOLITIS) HYPOTHESIS
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The work that influenced a decade of thoughts regarding pathogenesis of IPF was generated during the 1970s and 80s from the Pulmonary Branch of the National Heart, Lung and Blood Institute under the direction of Dr. Ron Crystal. This was an extraordinarily productive period of investigation based on samples from patients with interstitial lung diseases. A number of leaders in pulmonary medicine emerged from this period of time that have had an important influence on the development of academic pulmonary medicine. There were a number of important observations that were made not only on IPF, but sarcoidosis and other interstitial lung diseases (22, 23). The two that we will emphasize have been scrutinized over the passage of time. The most controversial has been called the "inflammation theory" of IPF. Much of the data that was obtained from patients with various interstitial lung diseases came through the use of the flexible fiberoptic bronchoscope and the technique of bronchoalveolar lavage. The history of bronchoscopy and bronchoalveolar lavage has recently been chronicled by Reynolds and coworkers (24). Patients with IPF underwent BAL, and differential cell counts were determined. Based on the observation that there were increased numbers of inflammatory cells recovered by BAL in patients with IPF, Crystal and colleagues generated the hypothesis that IPF began as an "alveolitis" and progressed to interstitial fibrosis. This theory was detailed in the 1976 publication from an NIH conference (25). The alveolitis in IPF was characterized by an excessive accumulation of neutrophils relative to normal individuals or patients with sarcoidosis, in whom lymphocytes predominated. In this publication, the authors purveyed the concept that DIP and UIP are "simply parts of the same disease rather than specific disease entities. DIP most likely represents early IPF, whereas UIP represents the later stages of the disease." The authors argued that several lines of evidence "strongly suggest that therapeutic intervention should be directed toward stopping the inflammatory and immune response rather than toward stopping the fibrotic process." Furthermore, "histologic observations clearly show that early aspects of the disease are highly cellular with alveolar inflammation predominating. This concurs with the suggestion by Scadding and Hinson (26) that patients with cellular biopsies respond better to corticosteroids... and the suggestion by Carrington and co-workers (27) that patients with DIP [that is, early IPF] also respond better to therapy." A major shortcoming of this era was that a randomized placebo-controlled clinical trial was never performed in patients with IPF. It remains unknown today if steroids are more effective than placebo in the treatment of IPF. The inflammatory hypothesis of the pathogenesis of IPF has fallen out of favor for several reasons. The main reason is that scrutiny of the UIP pattern in patients that do no appear to have advanced disease from the clinical standpoint fails to reveal evidence of significant interstitial or alveolar inflammation. This, coupled with the perceived lack of efficacy of corticosteroid treatment in patients with IPF/UIP, has led to a reinterpretation of the BAL data in IPF. It is now believed that that neutrophil accumulation in IPF/UIP, particularly in advanced stages of the disease, is due to the extensive tissue remodeling and traction bronchiectasis. That is, the neutrophil accumulation is a consequence and not a cause of IPF/UIP. However, it is important to point out that this is the latest "theory." History has taught us with IPF that revisions are not infrequent, and it may be premature to pronounce an end to the role of inflammation in the pathogensis of IPF (28).
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THE GROWTH FACTOR HYPOTHESIS
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The second major observation that we will discuss came in the 1980s and may yet still prove to be the most important discovery in pathogenesis of IPF. Proof of principle is still awaiting the unequivocal demonstration of therapeutic efficacy of a single agent in the treatment of IPF. In 1983, Bitterman and colleagues published the important observation that cultured media from alveolar macrophages isolated by BAL from patients with IPF was able to promote the proliferation of cultures of lung fibroblasts (29). The authors termed this factor "alveolar macrophage-derived growth factor." The concept that the alveolar macrophage became activated in IPF and secreted a growth factor or factors to promote fibroblast proliferation initiated a great interest in both growth factors and mechanisms that could regulate macrophage functions. Bitterman and coworkers, Rom and colleagues, Martinet and coworkers, Mortinet and colleagues, and Nagaoka and coworkers, among others all working in the Pulmonary Branch at the NIH, identified the AMDGFs as IGF-1 and PDGF-B (30–34). These pioneering studies paved the way for subsequent studies that have identified other growth factors present in lung tissue from patients with IPF, such as transforming growth factor-ß (35, 36). In addition, other studies have shown that alveolar epithelial cells may also be an important source of growth factors (37). Nevertheless, these observations represented a paradigm shift in the concept of pathogenesis of IPF. The idea that fibrosis may be a result of abnormal wound healing and inappropriate or unregulated production of growth factors that stimulate fibroblast growth and matrix production continues to be actively pursued with novel therapeutic approaches.
Carrington and colleagues published their prospective longitudinal findings on patients with UIP and DIP in 1978 (38). This study began in 1952 and followed patients with the different histologic patterns for up to 24 yr. Some patients were treated with corticosteroids and others were not. Fifty-three patients with a "confident" histologic diagnosis of UIP and 40 patients with a "confident" histologic diagnosis of DIP were included. At the end of 5 yr, the mortality for UIP was 44%, compared with only 5% in DIP. Twenty-six patients in each group were treated. Almost two thirds of those with DIP improved, compared with only three with UIP. Nineteen percent of the patients with UIP were unchanged with treatment, and 69% became worse. When compared with untreated patients, 15% were unchanged and 85% were worse. The shortest survival was 1 yr; six patients survived from 11–16 yr. Although additional observational studies on treatment of patients with IPF with corticosteroids have been published (39), little additional knowledge has been added to what Carrington and Gaensler demonstrated over 25 years ago.
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THE EPITHELIAL–MESENCHYMAL HYPOTHESIS
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The resonating question that has emerged since the 1970s has been: why is it that corticosteroids are so ineffective if the hallmark of IPF is lung inflammation? In 1980 Witschi and colleagues presented animal data with a model of alveolar epithelial injury and suggested that interstitial pulmonary fibrosis occurs if the epithelial surface layer is not successfully restored (40). If there is an impediment to "re-epithelialization," interstitial fibroblasts will proliferate in an unregulated manner. While the details of this potential mechanism were not elucidated, this work, along with others, has led to the emergence of epithelial–mesenchymal "cross-talk" as a pathogenic pathway in IPF. The studies that have contributed to this theory have been very elegantly reviewed by Selman and coworkers in a recent review (41). The potential role for the epithelial cell in the pathogenesis of IPF received support from the landmark electron microscopy studies performed by Dr. Anna Luisa Katzenstein and J. L. Myers in the 1980s (42, 43). These studies suggested that necrosis of alveolar epithelial cells can lead to alveolar collapse. Electron microscopy studies on lung tissue from patients with AIP and UIP were performed. As stated above, the Hamman-Rich cases have been reclassified as AIP. A common link between these distinct pathologic conditions was found to epithelial necrosis with denuding of the basement membrane and alveolar collapse. The epithelial necrosis is confined to small foci that are widely scattered and recognized histologically by the presence of loose aggregated interstitial fibroblasts (fibroblastic foci). Katzenstein used the term necrosis to denote absence of alveolar epithelial cells. Recent observations have suggested that rather than necrosis, the cells may undergo programmed cell death (apoptosis) (44). While the mechanism of cell death may be distinct, the fundamental issue is the consequence of the loss of the epithelial surface. Ultrastructurally, Katzenstein described that
Alveolar collapse is characterized by invagination of the denuded epithelial basal lamina into alveolar septae with the formation of deep clefts. Re-epitheliazation occurs over the luminal surface of basal lamina in these areas, leaving collapsed segments permanently apposed and incorporated into the interstitium. This mechanism helps to explain several aspects of parenchymal remodeling in UIP, including interstitial thickening, honeycomb changes and volume loss.
These observations proposed a common theme of acute lung injury in both AIP and UIP. The difference is that the injury is proposed to be microscopic and occurring at sites where fibroblastic foci are present (Figure 4). This concept of the pathogenesis of IPF as repeated episodes of microscopic lung injury was further supported by the immunohistochemical analysis of a variety of fibrotic lung disorders by Kuhn and colleagues (45, 46). Fibroblastic foci were identified in UIP biopsies as sites of invasion of airspaces by fibroblasts synthesizing extracellular matrix components (Figure 5). The conclusion was that "the subepithelial clusters of collagen-synthesizing fibroblasts signify that the fibrosis in IPF is quite analogous to the intraalveolar fibrosis following acute lung injury, but on a smaller and more protracted scale." In 1988, Katzenstein suggested that quantitating the fibroblastic foci in UIP biopsies might have prognostic value. Several groups have performed these studies, and the results support her hypothesis (47–49).
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Figure 4. Usual interstitial pneumonia. Light microscopy view of a fibroblastic focus on surgical lung biopsy.
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The current understanding of the pathogenesis of IPF consists of a jigsaw puzzle of intriguing observations. These observations have been reviewed recently (44, 50) and are depicted schematically in Figure 6. Currently, efforts are focused on trying to elucidate pathways by which epithelial cell injury leads to unremitting fibrosis and understanding the relationship between microscopic acute lung injury and abnormal wound repair (44). Although much information has been learned from both patient samples and animal studies, a unifying mechanism remains elusive. Most of what we have learned about the pathogenesis of IPF emanates from the careful and thoughtful observations of inquisitive pathologists working with clinician investigators to generate hypothesis to test. Because much of the history of IPF can be traced to two such individuals, it is fitting to recall the poignant summary of the cases presented by Louis Hamman and Arnold Rich in 1944:This report describes the clinical and pathological entity characterized by a peculiar, progressive, diffuse fibrosis of the pulmonary alveolar walls, leading to deficient aeration of the blood with resulting dyspnoea and cyanosis, ... The etiology of the condition is at present undetermined.
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Figure 6. Schematic representation of recent observations in animal models and patient specimens associated with progressive fibrosis.
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Footnotes
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Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Received in final form June 7, 2005
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D. Kass, R. S. Bridges, A. Borczuk, and S. Greenberg
Methionine Aminopeptidase-2 as a Selective Target of Myofibroblasts in Pulmonary Fibrosis
Am. J. Respir. Cell Mol. Biol.,
August 1, 2007;
37(2):
193 - 201.
[Abstract]
[Full Text]
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L. Richeldi and E. Abraham
Identifying Patients with Idiopathic Pulmonary Fibrosis: Quality or Quantity?
Am. J. Respir. Crit. Care Med.,
May 15, 2007;
175(10):
976 - 977.
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D. M. Brass, J. Tomfohr, I. V. Yang, and D. A. Schwartz
Using Mouse Genomics to Understand Idiopathic Interstitial Fibrosis
Proceedings of the ATS,
January 1, 2007;
4(1):
92 - 100.
[Abstract]
[Full Text]
[PDF]
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O.J. Dempsey, K.M. Kerr, L. Gomersall, H. Remmen, and G.P. Currie
Idiopathic pulmonary fibrosis: an update
QJM,
October 1, 2006;
99(10):
643 - 654.
[Abstract]
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S. D. Shapiro
Extracellular matrix in lung disease. Proceedings of the Twenty-First Transatlantic Airway Conference.
Proceedings of the ATS,
July 1, 2006;
3(5):
397 - 455.
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J. L. Chunn, A. Mohsenin, H. W. J. Young, C. G. Lee, J. A. Elias, R. E. Kellems, and M. R. Blackburn
Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations
Am J Physiol Lung Cell Mol Physiol,
March 1, 2006;
290(3):
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[Abstract]
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J. P. Bridges, Y. Xu, C.-L. Na, H. R. Wong, and T. E. Weaver
Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C
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January 30, 2006;
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Copyright © 2005 American Thoracic Society.
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Introduction
THE HAMMAN AND RICH...