Rationale: The molecular mechanisms underlying acute exacerbations of idiopathic pulmonary fibrosis (IPF) are poorly understood. We studied the global gene expression signature of acute exacerbations of IPF. Methods: RNA was extracted from 23 stable IPF lungs, and 8 IPF with acute exacerbation (IPF-AEx) and 15 control lungs and used for hybridization on Agilent gene expression microarrays. Functional analysis of genes was performed using Spotfire, Genomica, and NIH DAVID. Gene validations for MMP1, MMP7, AGER, DEFA1-3, COL1A2 and CCNA2 were performed by qRT-PCR. Immunohistochemistry and in situ TUNEL assays were performed on the same tissues used for the microarray. ELISA for -defensins was performed on plasma from control subjects, stable IPF, and IPF-AEx patients. Results: Gene expression patterns in IPF-AEx and IPF samples were similar in the genes that distinguish IPF from control lungs. 579 genes were differentially expressed (FDR<5%) between stable IPF and IPF-AEx. Functional analysis of these genes did not indicate any evidence for an infectious or overwhelming inflammatory etiology. CCNA2 and -defensins were among the most up-regulated genes. CCNA2 and -defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. -defensin protein levels were increased in the peripheral blood of patients with IPF-AEx. Conclusions: Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2, -defensins and apoptosis of epithelium. The concomitant increase in -defensins in peripheral blood and the lung may suggest their use as biomarkers for this disorder.