© 2002 American Thoracic Society
Inflammatory Mechanisms Are Not a Minor Component of the Pathogenesis of Idiopathic Pulmonary FibrosisThe pathogenesis of usual interstitial pneumonia (UIP) is due to inflammation/injury to the alveolar-capillary wall (ACW)/basement membrane (BM), leading to a loss of type I epithelial and endothelial cells, proliferation of type II cells, a loss of alveolar integrity, recruitment and proliferation of stromal cells, and deposition of extracellular matrix and end-stage fibrosis (1–3). These events require the interplay between immune/nonimmune cells, cellular constituents of the ACW/interstitium, and deposition of extracellular matrix (1–3). However, the initial inflammation/injury or the mechanisms responsible for the perpetuation of chronic inflammation and extracellular matrix deposition are not known. Continual exposure to environmental "antigens" may promote exaggerated inflammation/injury with loss of ACW/BM integrity and failure of normal re-epithelialization and re-endothelialization leading to dysregulated repair (i.e., fibroblast proliferation and extracellular matrix deposition within alveoli and interstitium) and end-stage fibrosis (1–3). A challenge has been made to the hypothesis that chronic inflammation is an important contributing factor to the pathogenesis of pulmonary fibrosis. In fact, it has been postulated that chronic inflammation plays little or no role in the pathogenesis of UIP (4–6). This concept has led a movement to embrace the alternative hypothesis: pulmonary fibrosis results from epithelial injury and abnormal wound repair in the absence of preceding inflammation (6). However, it is based on a "snapshot" view of UIP, superphysiologic expression of cytokines in animal models, and a poor response to conventional antiinflammatory therapy (6–9). In addition, the hypothesis fails to take into account mechanism(s) that contributes to injury and dysregulated repair. Furthermore, the notion would imply that we comprehend the natural history of the pathogenesis of UIP.
Recently, the first prospective study has been reported on the histopathologic variability of surgical lung biopsies of patients with idiopathic interstitial pneumonia (10). Forty-seven percent of the patients exhibited the histopathology of UIP in all lobes (mean age, 63.3 years). However, UIP coexisted in 26% of patients with nonspecific interstitial pneumonia (NSIP) (mean age, 57 years) (10). In the remaining 28%, NSIP was found alone (mean age, 53.1 years) (10). Moreover, 10% had two or more surgical lung biopsies obtained from one lobe. Seventy-three percent of these lobes had coexistent NSIP with UIP (10). These findings demonstrate interlobar and intralobar variability of idiopathic interstitial pneumonia and the coexistence of chronic inflammation with fibrosis. Does this mean that we have different "disease" processes within the same patient, or does this support that UIP is a continuum of the natural history of untreated NSIP Although there is no model that recapitulates the pathogenesis of UIP, the majority of animal models of fibrosis start with inflammation that progresses to chronic inflammation and fibrogenesis (11, 12). There are exceptions to the association of inflammation and fibrosis. For example, there are animal models in which the profibrotic cytokine transforming growth factor-ß (TGF-ß) is superphysiologically expressed by adenoviral vector in the lung, thereby bypassing inflammation-induced expression of TGF-ß (13). Although TGF-ß remains the most potent cytokine for the induction of extracellular matrix, the shear presence of TGF-ß alone does not dictate progression to fibrosis. In fact, the expression of TGF-ß is necessary during the resolution of inflammation, which leads to normal re-epithelialization in the absence of overwhelming fibrosis (14). Therefore, expression of physiologically relevant TGF-ß may not necessarily lead to fibrosis; however, it is the context in which TGF-ß is expressed that ultimately leads to pulmonary fibrosis. Injury to the ACW/BM ultimately leads to failure of re-epithelialization and re-endothelialization and loss of alveoli with coalescence and fibrosis. In this context, the expression of TGF-ß contributes to dysregulated repair and fibrosis. In contrast, if inflammation occurs concomitantly with preservation of the ACW/BM, then re-epithelialization and re-endothelialization proceeds with protection of alveoli. TGF-ß expression under these conditions is necessary for normal resolution of inflammation without overt fibrosis. Transient overexpression of interleukin-1ß, as compared with tumor necrosis factor, has a greater effect in promoting fibrosis (5, 15). Both interleukin-1ß and tumor necrosis factor lead to acute/subacute and chronic inflammation that evolves into pulmonary fibrosis (5, 15). TGF-ß is expressed in conjunction with these cytokines, and the presence of TGF-ß is associated with fibrosis (5, 15). Why would the effect of interleukin-1ß be greater than tumor necrosis factor in the promotion of pulmonary fibrosis? The persistent expression of TGF-ß occurs in the context of interleukin-1ß-induced inflammation and marked ACW/BM destruction (5). Disrupting the integrity of the ACW/BM leads to the following: (1) failure of normal re-epithelialization and re-endothelialization and (2) a loss of alveoli and fibrosis. The concomitant and subsequent expression of TGF-ß in this context results in the fibrogenic response with failure of normal resolution.
A cogent argument is that clinical measurements of inflammation fail to correlate with stage or outcome in UIP and that conventional antiinflammatory therapy does not improve outcome (6). However, this would imply that UIP is a unique disease, as compared with the end stage of idiopathic interstitial pneumonia. The compelling findings mentioned previously here support that UIP is not a disease but a manifestation of prolonged chronic inflammation and evolving fibrosis (10). In fact, the temporal heterogeneity of UIP makes it difficult to describe early versus late UIP that would support the concept of an early or late "stage of disease" for UIP. Moreover, the findings for the histopathologic variability in idiopathic interstitial pneumonia would support that if stages exist, then they represent NSIP Before discarding the role of chronic inflammation in mediating the pathogenesis of pulmonary fibrosis and accepting pulmonary fibrosis results from epithelial injury and abnormal wound repair in the absence of preceding inflammation, we need to understand further the natural history of UIP. The finding that UIP can coexist with NSIP supports the notion that indeed chronic inflammation is integral to the pathogenesis of UIP. ROBERT M. STRIETER Department of Medicine, Division of Pulmonary and Critical Care Medicine and Department of Pathology and Laboratory Medicine, University of California, Los Angeles School of Medicine Los Angeles, California FOOTNOTES This work was funded by the National Institutes of Health grants CA87879, HL66027, P50CA90388, and PO1HL67665 (R. M. S.). REFERENCES
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UIP? The differences in age of these patients suggests that the natural history of UIP may actually represent the pathogenesis of untreated NSIP to UIP over a decade. Furthermore, this supports the notion that chronic inflammation is a significant contributing factor in the pathogenesis of UIP. 
