See related article, pages 1529–1536. that a central feature is a network of reciprocal inductive and inhibitory signals involving at least mesenchymal cells, pulmonary epithelial cells, and components of the ECM (Figure 1)(12). During development, tight spatial and temporal regulation of this cellular conversation is essential, and the balance of inputs from mesenchyme and epithelium is crucial. Thus, either overexpression or inhibition of some of the critical products of either cell type—eg, members of the TGF-β (13), Hedgehog (14), or FGF families (15)—can dramatically disrupt lung development. In this context, the role of IL-1β in the model described by Kolb et al.(3) could be principally to induce sufficiently severe acute inflammation to cause complete or disproportionate loss of epithelial or mesenchymal cells or of the ECM proteins required to induce normal repair. Indeed, with the exception of TGF-β1, each of the stimuli known to cause dramatic and progressive pulmonary fibrosis in rodent models (bleomycin, fas ligation, and IL-1β overexpression) appears to share the ability to cause cell death and loss of structural integrity of alveoli. The remarkable ability of the adult lung to repair itself suggests that substantial loss of alveolar integrity can still allow the normal developmental reciprocal inductive program to proceed. However, this program presumably depends on some threshold or a combination of surviving mesenchymal cells, epithelial cells, and perhaps ECM components. Either death of cells or destruction of the matrix of sufficient scale is likely to perturb this cellular conversation and result in the dysfunctional repair process that characterizes pulmonary fibrosis. As we evolve a more detailed understanding of which features of normal development are required for normal lung repair, more sophisticated models will emerge. For example, factors that enhance production and/or activation of TGF-β1 could tip the balance toward inhibition of epithelial proliferation and enhancement of both fibroblast proliferation and matrix production. In the absence of counterbalancing signals from the epithelium, a positive feedback loop could ensue. This loop would be reinforced both by TGF-β inducing its own expression (16) and by its ability to upregulate expression of the αvβ6 integrin (17), thereby enhancing its own activation. A better understanding of how normal development is regulated and the existence of models of dysregulated development, such as the one described by Kolb et al.(3), are likely to provide fruitful opportunities to improve our understanding of the largely untreatable group of disorders characterized by progressive pulmonary fibrosis.