Truly emerging--a new disease caused by a novel virus.

n engl j med 364;16 nejm.org april 21, 2011 1561 ing, in part, the heterogeneity of distribution of inhaled toxicants. Microaspiration and viral infection also typically produce heterogeneous lung disease. Indeed, there is strong evidence that microaspiration contributes to the risk of pulmonary fibrosis and produces heterogeneous injury in bronchiolar—alveolar units.9 Similarly, viral infections may trigger the pulmonary fibrosis phenotype in patients with defined underlying genetic causes of pulmonary fibrosis (e.g., mutations in SPC).6 Intriguingly, viruses produce unfolded-protein responses in healthy cells, and viral infection of cells expressing SPC variants associated with pulmonary fibrosis produced synergistic unfolded-protein–apoptotic responses, suggesting that viruses trigger an unfolded-protein response that crosses the threshold required to produce the pulmonary fibrosis phenotype.10 Like many successful genomewide linkage studies, the report by Seibold et al. provides a provocative stimulus for broadening our understanding of the pathogenesis of pulmonary fibrosis. It is likely that the “two-hit” hypothesis — one from genetic variation and one from environmental stressors — is generally correct but not complete. It must be modified to account for additional genetic and environmental influences. A better understanding of the pathogenesis of pulmonary fibrosis now may also require an understanding of the normal commerce between alveolar and bronchiolar surfaces. This study will stimulate investigations of the effects of the MUC5B variant on secretion rates of MUC5B in quantitative cell systems, the ectopic expression of MUC5B in alveolar epithelia in patients with this genetic variation, goblet-cell unfolded-protein responses in patients with and without this polymorphism, and other genes or environmental stressors that produce pulmonary fibrosis phenotypes in patients who do not express the variant SNP. In addition, the study dictates that we broaden our vision of pulmonary fibrosis therapeutics, particularly given the absence of satisfactory clinical responses to immunosuppressants and corticosteroids. Thus, agents in clinical development that may regulate the unfolded-protein response may be worthy of early trials in pulmonary fibrosis. Similarly, agents that reduce MUC5B transcriptional activity in vitro should be tested for activity in vivo, including in subjects expressing the variant genotype. Thus, the study by Seibold et al. may have “unstuck” our thought processes with respect to a disease that has frustrated both patients and their physicians. Disclosure forms provided by the author are available with the full text of this article at NEJM.org.