Figure 5

Potential role for miR-638 in the pathogenesis of emphysema. GSEA identified multiple pathways dysregulated in the aging response to oxidative stress that were enriched both in fibroblasts after miR-638 inhibition and anti-correlated with miR-638 expression in emphysema. The oxidative stress response to chronic tobacco smoke exposure leads to: (1) DNA damage and telomere shortening that stimulates cellular senescence in fibroblasts - senescent fibroblasts can no longer proliferate, and thus cannot effectively repair damaged ECM, and senescent cells also stimulate chronic inflammation leading to increased proteolysis and tissue damage; (2) mitochondrial dysfunction, leading to further production of reactive oxygen species and chronic oxidative stress; and (3) accumulation of degraded proteins and organelles with dysregulation in removal processes (autophagy and proteosomal), leading to further tissue damage and cellular senescence. We propose that miR-638 is involved in fine-tuning these processes and as its expression is increased with emphysema it contributes to increased cellular senescence, decreased tissue repair and increased tissue damage. Enriched pathways were found in all of these dysregulated processes. Predicted miR-638 targets that participate in these functions and are over-expressed with miR-638 knock-down and anti-correlated with miR-638 in emphysema are listed in blue.