(Chest. 2005;128:526S-532S.)
© 2005
American College of Chest Physicians
Pathogenesis and Natural History of Usual Interstitial Pneumonia*
The Whole Story or the Last Chapter of a Long Novel
Robert M. Strieter, MD, FCCP
* From the Division of Pulmonary and Critical Care Medicine, Department of Medicine and Hospitalist Programs, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Correspondence to: Robert M. Strieter, MD, FCCP, 900 Veteran Ave, 14–154 Warren Hall, Los Angeles, CA 90095-1786; e-mail: rstrieter{at}mednet.ucla.edu
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Abstract
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Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is not well-understood. Current explanations of the natural history and pathogenesis of IPF/UIP are controversial, and ongoing research continues to investigate multiple hypotheses. A complete understanding of the natural history of IPF could potentially help to identify different mechanisms that are operative at the early, intermediate, and end stages of the disease. This knowledge could lead to the development of more effective therapeutic interventions that target stage-specific aberrant pathways involved in IPF/UIP pathogenesis.
Key Words: idiopathic pulmonary fibrosis • natural history • pathogenesis • usual interstitial pneumonia • vascular remodeling
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Introduction
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Idiopathic interstitial pneumonias are a heterogeneous group of diffuse parenchymal lung disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis.1 In 2002, the American Thoracic Society/European Respiratory Society classified1 idiopathic interstitial pneumonias into seven distinct entities based on clinical manifestations, pathology, and radiologic features (Table 1
). One of these entities, idiopathic pulmonary fibrosis (IPF), is a progressive, fatal disease. IPF has been defined in an American Thoracic Society/European Respiratory Society consensus statement1 as a type of chronic fibrosing interstitial pneumonia of unknown etiology that is limited to the lungs and is associated with surgical biopsy specimens showing a histologic pattern of usual interstitial pneumonia (UIP). UIP histopathology is not unique to IPF, and has been reported in asbestosis, chronic hypersensitivity pneumonitis, and collagen vascular disorders with associated interstitial lung disease.1
While ongoing research continues to investigate multiple hypotheses of UIP pathogenesis, neither the natural history nor the pathogenesis of UIP is currently well understood. To determine whether UIP represents the end stage of IPF, it is important to elucidate the complete natural history and pathogenesis of IPF, which would allow the investigation of potentially different mechanisms that may be operative at the early, intermediate, and end stages of the disease. This knowledge could lead to the implementation of targeted therapeutic interventions at specific stages of the disease process.
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Pathology of IPF
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Ultrastructural analyses of IPF lung tissue obtained from biopsies in the 1980s and early 1990s provided important knowledge about the pathogenesis of the disease. These studies demonstrated marked abnormalities in the basement membrane of the capillary endothelium. In most cases, the endothelial basement membrane showed thickening or reduplication, with cytoplasmic swelling or blebbing, indicating degeneration. These studies also demonstrated a striking loss of type I alveolar pneumocytes leading to exposure of the underlying basement membrane.2
At an anatomic level, it is hypothesized that the lung lobule is the target of multiple attacks by disease over time. A normal alveolus undergoes an insult of unknown origin that leads to injury of the epithelium, endothelium, and basement membrane, resulting in the obliteration of the alveolus. The loss of normal basement membrane integrity results in the inability of the injured alveoli to reendothelialize and reepithelialize the basement membrane. In response to that injury, an intraalveolar exudative process takes place with infiltration of macrophages, fibroblasts, and other inflammatory cells. Intraalveolar neovascularization, which is similar to wound granulation tissue, also occurs. The resulting formation of intraluminal buds progresses to the obliteration of the alveolus. Despite ongoing type II pneumocyte hyperplasia, this process ultimately leads to fusion of the adjacent alveolar structures by connective tissue components, the loss of alveolar architecture, and the formation of fibroblastic foci composed of parallel-arranged fibroblasts/myofibroblasts enmeshed in an extracellular matrix (ECM) that is primarily composed of collagen and fibronectin. These foci of organized and fibrotic exudates form within the alveolar airspace and the interstitium (Fig 1
).23
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Multiple Hit Hypotheses for the Pathogenesis of IPF
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The exact mechanisms underlying the development of IPF remain unknown. The ultrastructural findings discussed above underlie the long-prevailing belief that chronic inflammation plays an essential role in the pathogenesis of IPF. This hypothesis is based on the idea that injury/inflammation of the alveolar-capillary constituents and basement membrane leads to the loss of type I epithelial and endothelial cells, the proliferation of type II pneumocytes, the loss of alveolar space integrity, the recruitment and proliferation of stromal cells, and the deposition of the ECM. The cycle of dysregulated repair involving an initial injury or inflammatory event is purported to lead to the perpetuation of chronic inflammation, with deposition of the ECM progressing inevitably to end-stage pulmonary fibrosis.
Alternative hypotheses regarding the pathogenesis of IPF have recently emerged.4 One hypothesis postulates that pulmonary fibrosis results from epithelial injury and abnormal wound repair in the absence of preceding chronic inflammation. There is currently little evidence to substantiate this hypothesis, which does not take into account the natural history of the disease but rather reflects a single "snapshot" view, disregarding the fact that injury to any tissue is always followed by an inflammatory response and subsequent repair. While a poor response to conventional antiinflammatory therapy at the end stage of fibrosis has been cited in support of this hypothesis, this negative finding should not rule out the possibility of a pathogenic role for early-stage inflammation.
Recent data from Zuo and colleagues5 have suggested that the pathogenesis of IPF may be much more complex than was previously believed. That study5 used oligonucleotide microarray analysis to compare gene expression patterns in lung samples from patients with histologically proven IPF to those of healthy control subjects. The expression of four categories of genes was markedly increased. These included genes that were associated with cell contraction, including those that encode smooth muscle proteins. Particular up-regulated contractility genes included actin, myosin, and tropomyosin. The expression of genes that encode proteins involved in signaling (cell adhesion kinase ß), ECM formation (collagen I and III, fibronectin, and filamin), and ECM degradation (matrix metalloproteinase [MMP]-1, MMP-2, MMP-7, and MMP-9) was also increased.5 Surprisingly, in light of the presumed lack of inflammation preceding fibrosis, a third set of genes demonstrated the expression of a number of proinflammatory cytokines, chemokines, and antioxidants.5 The expression of a fourth set of genes encoding amyloid and Igs has suggested the presence of a potential "antigen" within the lung to which the host responded with B-cell differentiation and, ultimately, Ig formation. Furthermore, the finding of the expression of the third and fourth set of genes in patients with UIP would normally be associated with chronic inflammatory disorders.
Another study by Hunninghake and colleagues,6 which was designed to identify clinical and radiologic findings associated with a pathologic diagnosis of UIP, found that chest radiographic findings consistent with UIP and two high-resolution CT scan findings (ie, lower lobe honeycombing and irregular lines in the upper lobes) were positively associated with a diagnosis of UIP.6 Unexpectedly, there was significant mediastinal adenopathy in the majority (55%) of patients with a diagnosis of IPF.6 This finding suggested that the majority of IPF patients had an ongoing immune lymphoproliferative process, presumably in response to some unknown antigen. Taken together, the studies of Zuo et al5 and Hunninghake et al6 indicate that genes (ie, Ig genes) are up-regulated and that the host responds with immune-mediated lymphoproliferation. These findings do not support the notion that pulmonary fibrosis results from epithelial injury and abnormal wound repair in the absence of preceding inflammation.
A third hypothesis has recently emerged that provides a unifying theory for the evolution of IPF. This modification of the first two hypotheses postulates that inflammation is subsequent to injury and that IPF occurs as a result of a polarization of the immune response of the body to repeated injury (ie, "multiple hits") to the lung. According to this hypothesis, recurrent exposure to injury and/or antigens leads to an imbalance that favors T-helper type 2 immunity, contributing to a failure of reendothelialization and reepithelialization, and leading to the release of profibrotic growth factors into the region of injury. These profibrotic cytokines initiate fibroblast migration to the site of injury and promote their proliferation and differentiation into myofibroblasts. In IPF, myofibroblasts secrete an overabundance of ECM proteins, including collagens and proteoglycans. These fibroblasts and myofibroblasts may not undergo normal apoptosis, and begin to occupy the alveolar airspace while continuing to exhibit enhanced ECM deposition and secreting factors that promote fibrogenesis and angiogenesis. This results in the development of granulation-like tissue, making further resolution impossible. Finally, hyperplastic type II epithelial cells attempt to repair the damaged basement membrane but cannot reestablish normal alveolar function. The abnormal healing progresses in a temporally heterogeneous pattern, in which healthy lung tissue is interspersed with a gradually increasing collection of fibroblastic foci, honeycomb cysts, and interstitial inflammation, which are the characteristic features of UIP of IPF. The process leading to fibrosis can be thought of as a series of overlapping sequential events, with the initial injury of unknown origin followed by coagulation, inflammation, aberrant granulation tissue generation, the failure of reepithelialization and reendothelialization, and fibrosis with loss of lung architecture.
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Natural History of the Clinical Progression of IPF
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The natural history and complete pathologic process of a disease must be understood in order for it to be designated as a clinical, pathologic entity, and not simply as a histopathologic process. The task of elucidating the pathogenesis of IPF is made difficult by the absence of longitudinal studies of biopsy specimens from IPF patients. It remains unclear whether this pathology begins as UIP and remains unchanged with disease progression or begins as a cellular pattern that progresses to UIP over time. An important diagnostic criterion of UIP is clear evidence of temporally heterogeneous areas of normal lung, active fibrosis, and end-stage honeycomb fibrosis. This aspect of the disease suggests that events occurring at different points in time lead to dysregulated repair that is associated with aberrant vascular remodeling, increased fibroproliferation, and marked deposition of ECM leading to fibrosis.
The traditional view of IPF progression holds that a slow and steady decline in respiratory function ultimately leads to respiratory failure and death. Emerging evidence, however, has suggested that multiple injuries, or hits, to the lung occur over a period of time, and these hits lead to acute exacerbations that result in periods of more rapid decline in lung function, which can ultimately result in death. Evidence shows temporally heterogeneous areas of normal lung, active fibrosis, and end-stage honeycomb fibrosis in patients with UIP, suggesting that UIP is not an early lesion, may possibly characterize an intermediate stage, and may represent the end stage of the disease.
A study by Flaherty et al7 sheds light on the natural history of UIP. This prospective study evaluated multiple open lung biopsies involving more than one lobe of the lung in 109 patients with UIP. Forty-seven percent of patients (mean age, 63.3 years) exhibited histopathology of UIP in all lobes. Twenty-six percent of patients (mean age, 56.9 years) showed nonspecific interstitial pneumonia (NSIP) in at least one lobe and UIP in at least one lobe, indicating the presence of two different idiopathic pulmonary processes in the lung at the same time. In the remaining 26% of patients (mean age, 53.1 years), NSIP was found in all lobes. Ten percent of patients had two or more biopsy specimens obtained from the same lobe; among these patients, 73% of the lobes had coexistent NSIP with UIP.6 The mean ages of the patients in each group indicated the presence of a disease process that occurred over an entire decade. These results demonstrated that interlobar and intralobar histologic heterogeneity occurs frequently in patients with idiopathic interstitial pneumonia.
Recent evidence,7 although controversial, suggests that the disease process may begin with a predominantly cellular pattern, as seen in patients with NSIP, and progresses to end-stage fibrosis as seen in patients with IPF, with an intermediate stage that is characterized by a mixed pattern comprising both cellular and fibrotic components (consistent with a fibrotic NSIP pattern) [Fig 2
].
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Vascular Remodeling in Pulmonary Fibrosis
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Under normal homeostatic conditions, there is a balance between angiostatic and angiogenic stimuli within the microenvironment. However, most, if not all, fibroproliferative disorders are associated with aberrant angiogenesis related to vascular remodeling.
Vascular remodeling in patients with IPF was originally demonstrated in the 1960s.8 These early studies showed vascular remodeling within areas of fibrosis leading to anastomoses between the systemic and pulmonary microvasculature. A postmortem examination of the lung of an IPF patient showed extensive aberrant neovascularization. A more recent study9 using immunohistochemistry for factor VIII-related antigen (von Willebrand factor [vWF]) showed the development of a very aberrant vascular network in areas of fibrosis. In another recent study,10 CD34 immunoreactivity was used as a marker of capillary endothelium, and vWF immunoreactivity was used as a marker of endothelial cells in other vessels. Dual immunohistochemistry revealed that vWF-positive venules connected CD34-positive capillaries within the fibrotic lesions.
The vascular remodeling phenomenon has been recapitulated in an animal model of pulmonary fibrosis.11 Rats were subjected to the intratracheal instillation of bleomycin, an anticancer drug known to cause lung fibrosis as a side effect of chemotherapy.11 Analyses of lung tissue showed the formation of a new peribronchial system of blood vessels located in areas of heavy collagen and connective tissue deposition, and further demonstrated that the interstitial fibrosis induced by bleomycin was associated with aberrant vascular remodeling.
The impact of vascular remodeling in pulmonary fibrosis may be significant. Remodeling in areas of fibrosis may contribute to fibrogenesis in a manner analogous to the way that aberrant neovascularization contributes to tumor growth. In addition, the formation of anastomoses between the systemic and pulmonary microvasculature can increase right-to-left shunting under conditions of pulmonary hypertension and can contribute to hypoxemia in IPF patients.
Evidence for a role of vascular remodeling in hypoxemia comes from a study12 of vasodilators in patients with pulmonary hypertension secondary to lung fibrosis. Patients received nitric oxide by inhalation and were then randomized to receive either IV epoprostenol or oral sildenafil. Patients receiving epoprostenol showed an increase in baseline shunting from < 5 to 16%, which was associated with significant hypoxemia. This result suggests that, in response to alterations resulting from treatment with vasodilators, dynamic vascular beds can be recruited and perfused in the absence of ventilation, amplifying the magnitude of the shunt and the resulting hypoxemia.
Vascular remodeling in pulmonary fibrosis is regulated by both positive factors that promote angiogenesis, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and angiogenic nonconserved amino acid (CXC) chemokines, as well as by negative factors that inhibit angiogenesis, such as angiostatin and interferon (IFN)-inducible angiostatic CXC chemokines (Table 2
).12
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Chemokines
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CXC chemokines are a family of cytokines that comprise an amino acid sequence motif consisting of two cysteines separated by a CXC. The CXC chemokines regulate angiogenesis in a disparate fashion based on structural/functional differences. Those CXC members that contain a glutamic acid-leucine-arginine (ELR) motif promote angiogenesis, while those that lack the ELR motif are, in general, potent inhibitors of angiogenesis.13 An important aspect of the regulation of angiogenesis is its induction by specific stimuli in the microenvironment. For example, lipopolysaccharide, tumor necrosis factor-
, and interleukin (IL)-1ß are very strong promoters of angiogenic factor secretion, while IFN-
inhibits angiogenesis. Moreover, IFN-, IFN-, and IFN-ß have a significant role in the up-regulation of IFN-inducible (ELR-negative) CXC chemokines that are very potent and dominant inhibitors, not only of ELR-positive (angiogenic) CXC chemokines, but also of VEGF and bFGF as well.
A current hypothesis proposes that the aberrant neovascularization that occurs in pulmonary fibrosis results from an imbalance of angiogenic vs angiostatic CXC chemokines. Specifically, it postulates that there is overexpression of ELR-positive angiogenic CXC chemokines in the local microenvironment. A proposed treatment strategy might, therefore, involve the administration of immune factors such as IFN to change the milieu from a predominance of type 2 cytokines (which promote humoral immunity and signal fibroblast proliferation and fibrosis) to Th1 cytokines (which promote cell-mediated immunity, decrease fibroblast proliferation and angiogenesis, and promote restoration). This change would effect an induction of angiostatic, IFN-inducible, ELR-negative CXC chemokines and a reduction in the expression of angiogenic, ELR-positive chemokines, thereby returning the balance to normal.
The role of chemokine imbalance in pulmonary fibrosis was evaluated in a study9 that examined lung biopsy specimens from IPF or control patients. Keane et al9 showed that expression of the angiogenic ELR-positive CXC chemokine IL-8 was markedly higher in specimens from IPF patients than in control subjects, whereas the expression of the IFN-inducible angiostatic CXC chemokine IP-10 was higher in the lungs of control subjects than in those of IPF patients. Immunohistochemical localization of IL-8 was highly associated with pulmonary fibroblasts and ECM.9 These results support the notion that an imbalance of CXC chemokines favors angiogenic activity in IPF lung.
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Biology and Clinical Effects of IFN--1b Relevant to IPF
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The findings discussed above provided the basis for a recent randomized, double-blind, placebo-controlled study14 that examined the expression of specific biomarkers in response to IFN--1b administration in 32 patients with IPF. Patients who received subcutaneous IFN--1b for 6 months showed a marked increase in a specific ELR-negative, IFN-inducible T-cell- chemoattractant (ITAC) that is referred to as ITAC/CXCL11. This CXC chemokine is a potent inhibitor of angiogenesis, and has important immunomodulatory and antimicrobial activity. A significant reduction of another proangiogenic molecule, epithelial-derived neutrophil activating peptide-78 kD (also called CXCL5), was also observed.14 The findings showed a trend toward the reduction of profibrotic biomarkers and the up-regulation of molecules associated with antimicrobial defense and antiangiogenesis. These results suggested that systemic administration of IFN- could favorably affect multiple biological pathways in IPF patients and implicated these pathways as potential targets for therapeutic intervention.
Based on the observation that IFN- induces ITAC/CXCL11 expression in the lungs of patients, ITAC/CXCL11 was used as a research tool in an animal model of bleomycin-induced pulmonary fibrosis.15 The lungs of mice that had been treated with bleomycin showed an increase in the expression of both type I and type III collagen deposition, which are key markers of fibrosis. In mice that had been treated systemically with ITAC/CXCL11, pulmonary collagen deposition was significantly reduced compared to control animals, and pulmonary fibrosis was significantly attenuated.15 A study of mice that were deficient in CXCR3, a receptor for IFN- inducible cytokines, found increased mortality and progressive interstitial fibrosis in CXCR3-deficient mice compared to controls. The fibrotic phenotype was reversed following the administration of exogenous IFN-.16 These results support the suggestion that IFN- up-regulates intrapulmonary molecules that may be important in down-regulating pulmonary fibrosis.
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Origin of Fibroblasts During the Pathogenesis of Pulmonary Fibrosis
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Several theories exist regarding the origin of fibroblasts/myofibroblasts that contribute to the pathogenesis of pulmonary fibrosis. A classic theory holds that fibroblasts/myofibroblasts are resident cells that are activated and induced to proliferate and deposit ECM constituents in response to injury. A current theory suggests that tissue injury induces epithelial cells to transition to a mesenchymal phenotype, the fibroblast/myofibroblast, which subsequently contributes to fibroproliferation. Another contemporary theory postulates that circulating fibrocytes, which are derived from bone marrow, behave like mesenchymal stem cells, extravasate into sites of tissue injury, and contribute to pulmonary fibrosis.
Fibrocytes are cells isolated from peripheral blood that develop a spindle-shaped morphology in culture. This cell type expresses collagen I and is therefore not a typical leukocyte.17 Circulating fibrocytes express the chemokine receptor CXCR4, the receptor for CXCL12 and an important mediator of chemotaxis to wounds. In addition, fibrocytes express -smooth muscle actin, a hallmark of myofibroblasts.16 Human fibrocytes injected into SCID mice previously exposed to bleomycin were found to migrate to the lung, which was the site of injury.17 In this mouse model of bleomycin-induced injury,17 there was a significant infiltration of the lungs, with fibrocytes expressing the markers CD45+Col I+CXCR4+. Bone marrow of bleomycin-challenged animals showed similar up-regulation of these markers, suggesting that bone marrow is at least one source of circulating fibrocytes.17 When the active recruitment of these circulating fibrocytes/mesenchymal stem cells to the lung was blocked with an antibody to the CXCL12 cytokine, a significant attenuation in bleomycin-induced fibrosis was observed.17 These results provide evidence that circulating fibrocytes may contribute to the pathogenesis of pulmonary fibrosis.
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Conclusions
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Although controversies remain regarding the pathogenesis and natural history of IPF, our knowledge of the mechanisms that contribute to this disease process has been greatly enhanced by a number of studies. Research has demonstrated that IPF represents a type of abnormal wound healing involving the aberrant polarization of the immune response, the persistence of fibroblasts and myofibroblasts, and the breakdown of reepithelialization and reendothelialization. A better understanding of the complete natural history and pathogenesis of IPF will require the use of novel techniques to investigate the operative mechanisms at the early, intermediate, and end stages of the disease. Potential new therapies are being actively investigated with the goal of developing more effective therapeutic interventions that target specific aberrant biological pathways underlying IPF pathogenesis.
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Footnotes
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Abbreviations: bFGF = basic fibroblast growth factor; CXC = nonconserved amino acid; ECM = extracellular matrix; ELR = glutamic acid-leucine-arginine; IFN = interferon; IL = interleukin; IPF = idiopathic pulmonary fibrosis; ITAC = interferon-inducible T-cell -chemoattractant; MMP = matrix metalloproteinase; NSIP = nonspecific interstitial pneumonia; UIP = usual interstitial pneumonia; VEGF = vascular endothelial growth factor; vWF = von Willebrand factor
Dr. Strieter has given lectures on the pathogenesis of IPF, and these honoraria have been paid for by InterMune.
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References
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- Corrin, B, Dewar, A, Rodriguez-Roisin, R, et al Fine structural changes in cryptogenic alveolitis and asbestosis. J Pathol 1985;147,107-119[CrossRef][ISI][Medline]
- Basset, F, Ferrans, VJ, Soler, P, et al Intraluminal fibrosis in interstitial lung disorders. Am J Pathol 1986;122,433-461[Abstract]
- Selman, M, Pardo, A The epithelial/fibroblastic pathway in the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2003;29,S93-S97
- Zuo, F, Kaminski, N, Eugui, E, et al Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A 2002;99,6292-6297[Abstract/Free Full Text]
- Hunninghake, GW, Lynch, DA, Galvin, JR, et al Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124,1215-1223[Abstract/Free Full Text]
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- Turner-Warwick, M Precapillary systemic-pulmonary anastomoses. Thorax 1963;18,225-237[Medline]
- Keane, MP, Arenberg, DA, Lynch, JP, III, et al The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 1997;159,1437-1443[Abstract]
- Ebina, M, Shimizukawa, M, Shibata, N, et al Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004;169,1203-1208[Abstract/Free Full Text]
- Peão, MN, Aguas, AP, de Sa, CM, et al Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin. Anat Rec 1994;238,57-67[CrossRef][Medline]
- Ghofrani, HA, Wiedemann, R, Rose, F, et al Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomized controlled trial. Lancet 2002;360,895-900[CrossRef][ISI][Medline]
- Strieter, RM, Belperio, JA, Phillips, RJ, et al CXC chemokines in angiogenesis of cancer. Semin Cancer Biol 2004;14,195-200[CrossRef][Medline]
- Strieter, RM, Starko, KM, Enelow, RI, et al Effects of interferon-gamma 1b on biomarker expression in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004;170,133-140[Abstract/Free Full Text]
- Burdick, MD, Murray, LA, Keane, MP, et al CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. Am J Respir Crit Care Med 2005;171,261-268[Abstract/Free Full Text]
- Jiang, D, Liang, J, Hodge, J, et al Regulation of pulmonary fibrosis by chemokine receptor CXCR3. J Clin Invest 2004;114,291-299[CrossRef][ISI][Medline]
- Phillips, RJ, Burdick, MD, Hong, K, et al Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004;114,438-446[CrossRef][ISI][Medline]
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Abstract
Introduction
