miR-34 miRNAs Regulate Cellular Senescence in Type II Alveolar Epithelial Cells of Patients with Idiopathic Pulmonary Fibrosis

Abstract

Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

“…fl/fl mouse model of fibrosis recapitulates many pathologic findings in IPF including short telomeres in type II AECs (4,25), accumulation of senescent type II AECs (6,26), type II AEC hyperplasia (3), increased burden of alveolar macrophages (25), accumulation of α-SMA-immunoreactive mesenchymal cells (24,31), elevated levels of active TGF-β1 (32), and lung fibrosis (3). In addition to recapitulating features of IPF, the SPC-Cre TRF1…”

“…Molecular defects in IPF type II AECs include short telomeres (4,5) and expression of molecular markers of senescence (6,26). The findings summarized above show that telomere dysfunction isolated to type II AECs leads to the development of lung remodeling and fibrosis.…”

“…Consistent with the association with aging, telomere dysfunction has been implicated in the pathogenesis of IPF (2,3). Evidence includes the observation that telomeres are short in type II alveolar epithelial cells (AECs) of IPF patients (4,5), that type II AEC expression of senescence markers is unique to IPF lungs (6), and that peripheral blood leukocyte telomere length predicts survival in IPF patients (7). Variants in genes regulating telomere length including telomerase reverse transcriptase (TERT), RNA component of telomerase (TERC), and oligosaccharide-binding fold containing 1 (OBFC1) genes have been identified as susceptibility loci for development of sporadic IPF (8).…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…Studies in IPF lungs have identified significant pathogenic changes in the expression of miRNAs (44). Some of those changes are related to fibrotic response and TGF-β1 pathways, such as decreases in the miRNA let-7 (45), while others target senescence pathways (46). In high contrast, many of the miRNAs dysregulated in IPF recapitulate the fingerprint of developmental cell programming (47).…”

Licence to kill senescent cells in idiopathic pulmonary fibrosis?

“…Recent data, including the article by LEHMANN et al [18] published in this issue of the European Respiratory Journal, have linked cellular senescence with lung fibrosis development [19]. Indeed, IPF is characterised by increased epithelial [20][21][22] and mesenchymal/fibroblast [19] senescence. LEHMANN et al [18] focused on epithelial senescence in IPF, confirming that lung epithelial cells display senescence markers such as SAβG, P21, P16…”