miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways.

Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs (miRs) can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several miRs have been shown to be associated with lung fibrosis, the mechanisms by which miRs modulate epithelial behavior in lung fibrosis are lacking. Here, we identified miR-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome (BOS) after lung transplantation, idiopathic pulmonary fibrosis (IPF), and murine bleomycin-induced fibrosis. Antagomirs for miR-323a-3p augment, and mimics suppress, murine lung fibrosis after bleomycin injury, indicating that this miR may govern profibrotic signals. We demonstrate that miR-323a-3p attenuates TGF-α and TGF-ß signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, miR-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of miR-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that miR-323a-3p has a central role in lung fibrosis that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.

Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients.

Acute cellular rejection (ACR) is a common complication in lung transplantation and associated with increased risk of chronic allograft dysfunction. MicroRNAs are critical controllers of cellular transcription whose expression can be altered in disease states. The purpose of this pilot study was to evaluate whether microRNA profiling of epithelial cells obtained from airway brushings can distinguish lung transplant patients with ACR from those without rejection. We studied 21 subjects (10 with ACR, 11 without ACR) and assessed the expression of over 700 microRNAs in their airway epithelium. We identified 117 differentially expressed microRNAs that robustly segregated the two groups, and were uniformly downregulated in patients with ACR. Leveraging experimentally verified microRNA targets, we systematically mapped pathways and processes regulated by ACR-induced microRNAs and noted enrichment of programs involved in development, proliferation, migration, and repair. Collectively, our study suggests that ACR is associated with a distinct epithelial microRNA signature that can provide insight into the pathogenesis of acute rejection and potentially serve as a sensitive, minimally invasive biomarker tool for diagnostic and prognostic stratification of lung transplant patients.