© 2004 American Thoracic Society
Respiratory Epithelium in Usual Interstitial Pneumonia/Idiopathic Pulmonary FibrosisSpark or Destructive Flame?
a Mayo Clinic Rochester, Minnesota Alveolitis, as historically defined, cannot suffice as an explanation for the characteristic pattern of fibrosis and disordered lung architecture that define usual interstitial pneumonia (UIP), the morphologic counterpart of idiopathic pulmonary fibrosis (IPF). UIP/IPF remains a relentlessly progressive lung disorder despite four decades of interest in its pathogenesis and treatment. In an ATS-sponsored consensus statement it was concluded that, "we lack sufficient clinical evidence that any treatment improves survival or the quality of life for patients with IPF" (1). Despite this discouraging conclusion, the authors acknowledged the use of immunosuppressive agents as an entrenched standard of care. The rationale for immunosuppressive therapy, mainly corticosteroids, was rooted in the prevailing hypothesis that inflammation (alveolitis) was key to initiation and maintenance of lung fibrosis linked to empirical observations made at a time that precise diagnostic distinctions did not exist between IPF and its better behaved mimics. A growing body of evidence indicates that epithelial injury and activation rather than alveolitis are almost certainly the spark responsible for a cascade of events that march inexorably toward fibrosis and honeycomb change in IPF (2). The precise steps that lie between epithelial injury and fibrosis represent a challenging puzzle into which a number of pieces have fallen. Investigators in the 1980s demonstrated features common to seemingly disparate forms of acute and chronic fibrosing lung diseases that could not easily be explained as the consequences of alveolitis (3–6). These features included epithelial necrosis, denudation and collapse of damaged epithelial basement membranes, migration of fibroblasts/myofibroblasts into air spaces, and accumulation of extracellular matrix resulting in reorganized—and in some patients restored—interstitial/intraalveolar compartments. These events were demonstrated at sites of acute lung injury in UIP/IPF (fibroblast foci), the organizing phase of diffuse alveolar damage in patients with acute interstitial pneumonia, and the intraluminal plugs of fibroblastic tissue (Masson bodies) in cryptogenic organizing pneumonia. The presence of these common events was somewhat surprising given the very different clinical contexts in which they occurred. The conclusion that reparative pathways might dictate differences in the pathogenesis of these conditions was inevitable. Epithelial cells are key participants in the early and late events that follow acute lung injury. A recent review summarizes abnormal wound repair as a model for understanding IPF (2). Following epithelial injury, surviving and regenerating respiratory epithelium contributes to abnormal antifibrinolytic activity at sites of injury and also elaborates various fibrogenic cytokines/growth factors important in recruitment and phenotypic modulation of fibroblasts and myofibroblasts (2, 7). Fibroblasts, in turn, may amplify alveolar damage by inducing epithelial cell apoptosis (8) and modulating epithelial phenotype through the complex interactions attributed to the "epithelial-mesenchymal trophic unit" (9, 10). Despite the morphologic overlap, we now know that the fibroblast foci of UIP/IPF differ from the Masson bodies of organizing pneumonia in several important ways including fibroblast/myofibroblast phenotype, rates of fibroblast/myofibroblast apoptosis, modulation of extracellular matrix deposition, and extent of neovascularization (2). Differences in the character and extent of reepithelialization may play a pivotal role in determining why "fibroblast foci" of UIP/IPF resolve into a scar while the Masson bodies of organizing pneumonia disappear without a trace. Disordered reepithelialization in UIP/IPF has previously been linked to upregulation of epithelial cell apoptosis and impaired adhesion to damaged basement membranes (2, 8, 11). In this issue of the Journal (pp. 27–33), Lappi-Blanco and colleagues contrast and compare reepithelialization at sites of acute injury in lung biopsies from patients with UIP/IPF and cryptogenic organizing pneumonia, lending further support to a model of abnormal wound repair in UIP/IPF (12). Using immunohistochemical techniques, fewer epithelial cells were demonstrated as a percentage of affected surface area in fibroblast foci compared with Masson bodies. The differences were statistically significant, but there was a wide range in each group indicating that key differences are as likely to be qualitative as they are quantitative. Indeed they identified greater degrees of epithelial "disarray" in the population of hyperplastic epithelial cells in UIP/IPF as evidenced by variation in cytomorphology, layering of cells at the leading edge of regeneration, exfoliation of epithelial cells, and a greater degree of heterogeneity within and between acute lung injury sites. Furthermore, immunoreactivity for surfactant associated protein A was limited to hyperplastic epithelium associated with fibroblast foci in UIP/IPF, suggesting that pneumocytes are the primary players in UIP/IPF while bronchiolar epithelium or more primitive stem cells participate in cryptogenic organizing pneumonia. This difference is intuitively attractive given that UIP/IPF affects the distal pulmonary acinus and cryptogenic organizing pneumonia is distinctly bronchiolocentric.
Despite quantitative and qualitative differences between populations of "reparative" epithelial cells in UIP/IPF and cryptogenic organizing pneumonia, Lappi-Blanco and coworkers demonstrate no differences in synthesis or expression of the The role of respiratory epithelium in initiating and maintaining abnormal wound repair remains an elusive but promising area of study with the potential to impact future treatment strategies. Discovery of novel therapies may hinge on a greater understanding of genetically determined differences in recovery rather than identifying a specific trigger (etiology) for epithelial injury/activation. After all, a fire requires not only an inciting spark but also a flammable substrate before it can prove destructive. In IPF, respiratory epithelium may function as both. FOOTNOTES Conflict of Interest Statement: J.L.M. has no declared conflict of interest; M.S. has no declared conflict of interest. REFERENCES
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2 chain of laminin-5 (
3ß1 plays an important role in determining the incorporation of laminin-5 into its proper higher order structure within the extracellular matrix, and its activation is critical for epithelial cell spreading/migration on laminin-5 (
