A Fas pathway to pulmonary fibrosis.

ened, and useless alveolar walls of patients with lung fibrosis led investigators to think that the basic process leading to fibrosis was a sustained interstitial pneumonitis. Careful studies of animal models and humans over the last 15 years have revealed that, in fact, most pulmonary fibrosis begins in the alveolus and develops in definable stages over time (Figure 1): (a) epithelial cell injury and alveolar inflammation; (b) organization of the resultant alveolar exudate; and (c) incorporation of the alveolar fibroproliferative process into alveolar walls. Repeating cycles of this series leads to the characteristic signature of distorted and dysfunctional lung parenchyma (1, 2). However, an explanation for the earliest recognizable event in this process — loss of alveolar epithelial cells — has remained ob-scure. The emergence of the field of programmed cell death (apoptosis) and the realization that lung alveolar epithelial cells, like cells in many tissues, express the Fas death receptor have stimulated new thinking about these early events. Ligation and clustering of Fas receptors by Fas ligand (expressed on inflammatory cells in Figure 1) results in the assembly of a cytoplasmic protein scaffold containing activated caspase-8, the first in a cascade of proteases whose full activation culminates in irreversible cell injury and apoptosis (3). Because apoptotic cells are rapidly cleared by phagocytes, this was thought to be a mechanism of cell death that avoided inflammation. This scenario is best played out in the developing immune system, where fewer than 1% of T-cell precursors entering the thymus survive selection, many succumbing to a Fasmediated apoptotic death without discernible secondary inflammation (4). However, it is increasingly apparent that under some circumstances ligation of Fas leads to release of proinflammatory cytokines, indicating that, whatever its homeostatic role, Fas ligation can also lead to inflammation and tissue injury (5, 6). In this issue of the JCI, an injurious role for the Fas pathway in the pathogenesis of pulmonary fibrosis is reported (7). In a model of bleomycininduced pulmonary injury and fibrosis, developing 7–14 days after intratracheal injection of bleomycin, mice deficient in either Fas (lpr mutants) or Fas ligand (gld mutants) were found to be protected from fibrosis (as judged by accumulation of lung hydroxyproline). Epithelial cell apoptosis (as judged by DNA strand breaks) was also attenuated. Similar results were seen when an antagonistic soluble Fas receptor was given intravenously or by inhalation. These observations extend prior work demonstrating that agonist Fas antibodies promote pulmonary fibrosis in mice and that DNA strand breaks consistent with apoptosis are seen in increased numbers of alveolar epithelial cells, both in bleomycin-injured mice and in hu-mans with idiopathic