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Interferon- Toxicity in Idiopathic Pulmonary Fibrosis

We were most interested in the article by Honoré and colleagues (1) describing acute respiratory failure after interferon- therapy of end-stage idiopathic pulmonary fibrosis and we share the authors concerns. In an accompanying editorial, Selman (2) suggests possible molecular mechanisms, including interferon-–induced reductions in expression of epithelial and endothelial junction integrity and barrier function, and increases in endothelial permeability. We suggest that interferon- may also potentiate lung epithelial apoptosis in patients with idiopathic pulmonary fibrosis.

Lung epithelial apoptosis contributes to the pathophysiology of asthma, idiopathic pulmonary fibrosis, and acute lung injury. In idiopathic pulmonary fibrosis, proliferating fibroblasts replace apoptotic type 2 alveolar epithelial cells. Fas ligand, a soluble and cell-associated molecule, binds to its receptor, the Fas antigen, and initiates programmed cell death. Fas is constitutively expressed on alveolar epithelial type II cells and Fas/Fas ligand expression is increased in lung epithelial cells from patients with idiopathic pulmonary fibrosis (3). Elevation of soluble Fas ligand in bronchoalveolar lavage fluid predicts disease severity in adults with acute respiratory distress syndrome (4). Interferon- increases surface Fas expression on human type 2 alveolar epithelial cells and increases caspase activation and apoptosis (5). In experiments exploring the antiapoptotic effects of substance P, we pretreat human pulmonary type II alveolar epithelial cells with interferon- to potentiate Fas-induced apoptosis. Pretreatment with interferon- leads to apoptosis in 79.7% of cells, compared with 38% of cells treated with Fas alone. The Fas/Fas ligand pathway not only mediates apoptosis but also plays a proinflammatory role. Activation of the Fas/Fas ligand pathway leads to IL-8 secretion in many cells, including lung epithelial cells (6). Apoptosis-associated IL-8 secretion may promote neutrophil chemotaxis and may amplify the inflammatory cascade in pulmonary fibrosis.

Thus, interferon- upregulates alveolar epithelial Fas receptor expression and potentiates apoptosis. This upregulated apoptosis may promote IL-8 release, amplifying the inflammatory cascade by recruiting leukocytes to the site of apoptotic epithelial damage. We believe that interferon- may, through this molecular mechanism, have a deleterious effect in idiopathic pulmonary fibrosis and that this may explain, in part, the adverse outcome of the patients in Honoré and colleagues' interesting and important report.

Terence M. O'Connor^a and Charles P. Bredin^b

^a McMaster University Health Sciences Center Cardiorespiratory Research Unit Hamilton, Ontario, Canada
^b Cork University Hospital Cork, Ireland

FOOTNOTES

Dr. Crestani and Dr. Selman were given the opportunity to respond to this letter but declined to do so.

REFERENCES

1. Honoré I, Nunes H, Groussard O, Kambouchner M, Chambellan A, Aubier M, Valeyre D, Crestani B. Acute respiratory failure after interferon- therapy of end-stage pulmonary fibrosis. Am J Respir Crit Care Med 2003;167:953–957.[Abstract/Free Full Text]
2. Selman M. A dark side of interferon- in the treatment of idiopathic pulmonary fibrosis? Am J Respir Crit Care Med 2003;167:945–946.[Free Full Text]
3. Maeyama T, Kuwano K, Kawasaki M, Kunitake R, Hagimoto N, Matsuba T, Yoshimi M, Inoshima I, Yoshida K, Hara N. Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis. Eur Respir J 2001;17:180–189.[Abstract/Free Full Text]
4. Matute-Bello G, Liles WC, Steinberg KP, Kiener PA, Mongovin S, Chi EY, Jonas M, Martin TR. Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). J Immunol 1999;163:2217–2225.[Abstract/Free Full Text]
5. Coulter KR, Doseff A, Sweeney P, Wang Y, Marsh CB, Wewers MD, Knoell DL. Opposing effect by cytokines on Fas-mediated apoptosis in A549 lung epithelial cells. Am J Respir Cell Mol Biol 2002;26:58–66.[Abstract/Free Full Text]
6. Hagimoto N, Kuwano K, Kawasaki M, Yoshimi M, Kaneko Y, Kunitake R, Maeyama T, Tanaka T, Hara N. Induction of interleukin-8 secretion and apoptosis in bronchiolar epithelial cells by Fas ligation. Am J Respir Cell Mol Biol 1999;21:436–445.[Abstract/Free Full Text]

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