Shohei Mori

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

Abstract Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869). Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D–binding protein (DBP) and survival were also examined. Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment. Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089–97. ©2018 AACR.

BACKGROUND: Minimally invasive thoracoscopic lobectomy is the recommended surgery for clinical stage I non-small cell lung cancer (NSCLC). The purpose of this study was to identify the risk factors, including sarcopenia, for postoperative complications in patients undergoing a complete single-lobe thoracoscopic lobectomy for clinical stage I NSCLC, as well as the impact of complications on disease-free survival. METHODS: We retrospectively investigated 173 patients with pathologically-diagnosed NSCLC who underwent curative thoracoscopic lobectomies between April 2013 and March 2018. Sarcopenia was assessed using the psoas muscle index calculated from preoperative computed tomography images at the third lumbar vertebral level. RESULTS: Complications developed in 38 (22%) patients, including 21 with prolonged air leak. In univariate analysis, the significant risk factors for complications were advanced age, male sex, higher Charlson Comorbidity Index (CCI) score, lower cholinesterase, lower albumin, higher creatinine level, pleural adhesion, operative time ≥ five hours, nonadenocarcinoma cancer, and larger tumor size. Multivariate analysis showed that age ≥ 75 years (P = 0.002) and pleural adhesion (P = 0.026) were significant independent risk factors for complications. Compared with the patient group without complications, postoperative complications were independently associated with shorter disease-free survival (P = 0.01). CONCLUSIONS: Advanced age and pleural adhesion were independent risk factors for complications after complete single-lobe thoracoscopic lobectomies for clinical stage I NSCLC, and postoperative complications were statistically associated with poor prognosis. Surgical teams should ensure an experienced surgeon leads the operation for patients at higher risk to avoid prolonged postoperative hospitalization and a possible poor prognosis.

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.