© 2003 American Thoracic Society
Inflammation in idiopathic pulmonary fibrosisTo the Editor:In a recent editorial, Gauldie argued against a role of inflammation in the evolution of idiopathic pulmonary fibrosis (IPF), one of the main arguments being the failure of steroid to markedly (and favorably) influence the course of IPF (1). This might suggest that IPF is fundamentally different from the other chronic inflammatory (most likely auto-immune) diseases such as rheumatoid arthritis, Scleroderma, or Crohn disease, which are generally responding to steroids. The steroid argument is based upon the assumption that steroids act only by repressing and/or limiting the life span of leukocytes, the effector of inflammation, while leaving the cells of the alveolar septa as "innocent bystanders." There is, however, increasing evidence that this assumption is not correct, and consequently the steroid argument an invalid one. Steroids are indeed documented to repress the replication of bronchial and alveolar epithelium during development, and thus to interfere with alveolar septation (2). In adults, steroids also turn off the replication of alveolar epithelial cells (3), and/or increase the incidence of apoptosis in the pulmonary epithelia (4). In a model of alveolar injury mediated by the exposure of mice to oxygen, essentially an alveolar cell death with little contribution of "inflammation," Barazzone and colleagues recently demonstrated that steroids (endogenous or administered) aggravate the alveolar injury (5). These observations indicate that even in adults, steroids are not neutral regarding the alveolar septa, and even worse, synergize with agents that harm the alveolar epithelium. Thus, the absence of a global effect of steroids suggests that the beneficial repression of inflammation is neutralized by an enhancement alveolar damage, one of the effects of inflammation. Alveolar cell death and increased alveolar replication are a constant observation in active IPF, and there is evidence that it might contribute to enhance fibroblast proliferation and collagen deposition. It is therefore likely that agents that increase alveolar epithelial cell death will also aggravate the fibrotic process. Thus, the objective of therapy should be to repress inflammation without harming the alveolar epithelium or ideally to prevent alveolar damage. If steroids do not fit these criteria, there are currently other options. Tumor necrosis factor antagonists are currently successful in the treatment of rheumatoid arthritis and Crohn disease in humans (6) and are also effective for the treatment of the experimental fibrosis in mice, perhaps by blocking the main effector of alveolar damage, tumor necrosis factor. It is thus surprising and regrettable they have not yet been tried in IPF.
Centre Medical Universitaire Geneva, Switzerland REFERENCES
From the Author:In my recent editorial, I have not stated that inflammation has no role in the evolution of IPF, rather I argue that inflammation may not play a role in the progression of established IPF (1). Most IPF patients present with active established disease, different from the experimental models of bleomycin or silica-induced pulmonary fibrosis, which are associated with early episodes of injury and inflammation after administration of the injurious stimuli, and have varied aspects of chronic fibrosis over the experimental time. I would suggest that established IPF is different from a chronic disease such as rheumatoid arthritis with regard to the clinical response to steroid administration and failure of such treatment to stop or reverse the fibrotic changes seen in IPF.We agree with Piguet that steroids can have both a beneficial (antiinflammatory) effect as well as a deleterious (epithelial cell replication inhibition) effect and this could contribute to the lack of efficacy in IPF. However, we argue that inflammation is dampened through this treatment. This, coupled with our observations in cytokine gene transfer animal models, that progressive fibrosis can be induced and propagated in apparent absence of ongoing inflammation, implies that inflammation plays a minor role in the progressive nature of established IPF.
As for the suggestion that tumor necrosis factor-
McMaster University Hamilton, Ontario, Canada REFERENCES
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