© 2002 American Thoracic Society
Rebuttal from Dr. GauldieThe case made by Streiter for involvement of inflammation at the initiation of usual interstitial pneumonia/idiopathic pulmonary fibrosis assumes that there are no other mechanisms whereby epithelial cells and mesenchymal cells interact and influence their behavior and context of extracellular matrix that surrounds the cells. Interaction in the developing lung shows that these cells are easily influenced by each other without inflammation through mediators such as fibroblast growth factor and TGF-ß. In idiopathic pulmonary fibrosis tissue, epithelial cells are a primary source of TGF-ß (1), a factor known to block apoptosis of myofibroblasts (2), leading to progression. True, a number of interstitial pneumonias are directly associated with identifiable inflammation, as are most experimental models of pulmonary fibrosis, including bleomycin. However, Adamson and colleagues' studies showing that fibrogenesis proceeds in the absence of inflammatory cells from peripheral blood (3) and our own study of overexpression of interleukin-1ß, where fibrosis only becomes apparent long after the initiating event of interleukin-1ß expression has ceased (4), argue for progression mechanisms involving resident tissue cells and extracellular matrix without systemic involvement of inflammation. Streiter refers to a clinical study to support inflammation needed for propagation, but the data are also restricted to "snapshots" of pathology with no longitudinal data to support inflammation as an initiating event (5). Moreover, the survival curves shown for usual interstitial pneumonia alone and usual interstitial pneumonia with scattered inflammation are similar, which argues against inflammation as a necessary precursor to idiopathic pulmonary fibrosis. Others report that inflammation, if seen, is usually associated with areas of matrix deposition and honeycomb structure, an association that is consistent with altered extracellular matrix and mesenchymal cells, creating a microenvironment that can enhance the secondary accumulation of inflammatory cells through release of chemokines or maturation factors such as stem cell factor. Streiter argues that physiologically relevant expression of TGF-ß may not necessarily lead to fibrosis. We agree that it is the "context in which TGF-ß is expressed" that ultimately leads to pulmonary fibrosis, but the "context" is the altered microenvironment of extracellular matrix, including proteoglycans and integrins, and growth factors, such as TGF-ß, adjacent to the fibroblastic foci (1) that provides a pathway of prolonged stimulation and fibrogenesis rather than healing. REFERENCES
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