While studies have examined gene expression in lung tissue, gene regulatory processes underlying emphysema are not well understood. We obtained lung tissue RNA-seq and clinical data for 456 samples from COPD subjects in the Lung Tissue Research Consortium (LTRC). We assessed the associations of emphysema (Hounsfield units (HU) at the 15th percentile of chest CT densitometry at full inspiration (Perc15)) with differential expression of genes and differential usage of isoforms and exons using voom/limma, adjusting for select covariates. Differential expression refers to the change in absolute expression levels of a feature, whereas differential usage captures alternative splicing and refers to the change in relative expression levels of isoforms/exons that correspond to a given gene. 1,055 differentially expressed genes (DEGs) were significantly associated with emphysema (FDR 10%). We identified 730 differently used isoforms (DUIs) and 285 differentially used exons (DUEs), mapping to 598 and 216 genes respectively. Similar analyses were run in 2,370 blood samples from the COPDGene study. When comparing lung tissue and blood, 251 DEGs, 25 DUIs, and 2 DUEs were shared. Gene set enrichment analysis revealed 29 dysregulated pathways associated with emphysema in the lung, including decreased pathway activity related to oxidative phosphorylation and ribosomal function, and increased activity in TGF-Î² and FOXO signaling. Thirteen significant pathways were identified in bloodâ€”two were shared with lung (oxidative phosphorylation and ribosomal function). We identified emphysema-related changes in total gene expression and alternative splicing, and instances of shared pathway dysregulation between blood and lung tissue.