Idiopathic interstitial pneumoniasIdiopathic 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. 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.

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.

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.

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. Intraalveo-lar 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 pneu-mocyte 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).

endotheliumMultiple Hit Hypotheses for the Pathogenesis of IPF

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 pneu-mocytes, the loss of alveolar space integrity, the recruitment and proliferation of stromal cells, and the deposition of the ECM. The cycle of dysregu-lated 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. 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 colleagues have suggested that the pathogenesis of IPF may be much more complex than was previously believed. That study 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 (3), 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. Surprisingly, in light of the presumed lack of inflammation preceding fibrosis, a third set of genes demonstrated the expression of a number of proinflam-matory cytokines, chemokines, and antioxidants. 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.

IPF patients Another study by Hunninghake and colleagues, 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. Unexpectedly, there was significant mediastinal adenopathy in the majority (55%) of patients with a diagnosis of IPF. 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 reendothe-lialization 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 re-endothelialization, and fibrosis with loss of lung architecture.

Fig1
Figure 1. Loss of the lobule: formation of the fibroblastic focus (FF).

Table 1—Histologic and Clinical Classification of Idiopathic Interstitial Pneumonias

Histologic Pattern Clinical-Radiologic-PathologicDiagnosis
UIP IPF/cryptogenic fibrosing alveolitis
NSIP NSIP
Organizing pneumonia Cryptogenic organizing pneumonia
Diffuse alveolar damage Acute interstitial pneumonia
Respiratory bronchiolitis Respiratory bronchiolitis
interstitial lung disease
Desquamative interstitial pneumonia Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia Lymphoid interstitial pneumonia
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