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.

Pulmonary accumulation of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IFP/UIP) has been linked to (1) increased migration of a circulating pool of fibrocytes, (2) cell proliferation, and (3) resistance to apoptosis. The mechanism of physiologic apoptosis of lung fibroblasts is poorly understood. Using normal and fibrotic human lung fibroblasts and the human lung fibroblast cell line, MRC-5, we examined the regulation of Fas-induced apoptosis by the proinflammatory cytokines TNF-alpha and IFN-gamma. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-alpha. IFN-gamma did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-alpha. Sensitization by TNF-alpha was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung, suggesting that this represents a conserved mechanism to engage Fas-induced apoptosis. The mechanism of sensitization was localized at the level of recruitment of the adapter protein, FADD, to the cytoplasmic domain of Fas. Collectively, these findings suggest that fibroblast apoptosis involves two steps, sensitization and induction, and that inadequate pulmonary inflammation in IPF/UIP may favor fibroblast accumulation by reducing sensitization to apoptosis.

Background: Data concerning the rate of pulmonary embolism (PE) in Asian patients with chronic obstructive pulmonary disease (COPD) exacerbation are sparse, and no study has shown predictors of PE in these patients. Objectives: The purpose of the present study was to investigate the prevalence and predictors of PE in Korean patients with COPD exacerbation. Methods: Hospitalized patients with COPD exacerbations were prospectively enrolled into this study and underwent computed tomography (CT) pulmonary angiography and indirect CT venography. Results: The most common cause of COPD exacerbation was lower respiratory tract infection (82%; n = 84), followed by PE (5%; n = 5). Eight patients (8%) had venous thromboembolism, and deep vein thrombosis (DVT) was seen in 6%, with proximal DVT in 4%. On multivariate analysis, the absence of symptoms of respiratory infection and plasma D-dimer elevation (≥500 µg/l) were significant factors predicting PE in patients with COPD exacerbations (odds ratio 31, 95% confidence interval 2-563, p = 0.02, and odds ratio 25, 95% confidence interval 1-464, p = 0.03, respectively). Conclusions: PE comprises approximately 5% of the etiologies of COPD exacerbations in Koreans. The absence of symptoms suggestive of respiratory infection and elevated plasma D-dimer levels were significant predictors of PE in this population.