Case report of QT interval prolongation induced by anamorelin in an obese patient with non-small cell lung cancer.

BACKGROUND: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer. CASE PRESENTATION: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child-Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided. CONCLUSIONS: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.

Effects of polymorphisms in pregnane X receptor and ABC transporters on afatinib in Japanese patients with non-small cell lung cancer: pharmacogenomic-pharmacokinetic and exposure-response analysis.

PURPOSE: Because of the large interindividual variability of afatinib pharmacokinetics and adverse events, we evaluated the effects of polymorphisms in pregnane X receptor (NR1I2) and ABC transporters (ABCB1, ABCG2, and ABCC2) on the pharmacokinetics of afatinib. METHODS: The steady-state area under the concentration-time curve (AUC)0-24 of afatinib was analyzed using blood sampling just prior to and at 1, 2, 4, 6, 8, 12, and 24 h on day 15 after administration. RESULTS: The median oral clearance (CL/F) of afatinib in patients with the NR1I2 7635A allele was significantly lower than those in patients with the 7635G/G genotype (42.0 and 60.0 L/h, respectively, P = 0.025). There were no significant differences in afatinib CL/F between genotypes for NR1I2 8055C > T, -25385C > T, ABCB1, ABCG2, and ABCC2 polymorphisms. Based on the area under the receiver-operating characteristic curve, the threshold afatinib AUC0-24 value for prediction of dose reduction or withdrawal was 689 ng·h/mL at the best sensitivity (81.0%) and specificity (72.7%). In multivariate logistic regression analysis, an afatinib AUC0-24 above 689 ng·h/mL was independently associated with increased risk of dose reduction or withdrawal (OR: 11.66, P = 0.012). CONCLUSIONS: The NR1I2 7635A allele was related to a lower afatinib CL/F. Based on the AUC of 689 ng h/mL and CL/F, the optimal doses for patients with the NR1I2 7635G/G genotype and 7635A allele were recommended to be set at 40 and 30 mg/day, respectively, and subsequent adjustment of the maintenance dose based on the plasma concentrations of afatinib may be necessary to avoid afatinib-related adverse events.

Impact of the COVID-19 pandemic on the primary lung cancer screening program in Akita Prefecture, a region with the fastest aging population in Japan.

AIM: Akita Prefecture has the largest proportion of older inhabitants and the highest cancer mortality rate in Japan. Lung cancer is one of the biggest killers, and early detection is critical. Chest X-ray examinations are the main screening method for lung cancer; however, the COVID-19 pandemic has affected the screening system. Here, we evaluate how COVID-19 has affected lung cancer screening in Akita Prefecture. METHODS: Using the Akita General Health Corporation database, the average annual number of chest X-ray screening tests, close examinations and lung cancer diagnoses (stratified by sex and age) was evaluated during 2016-2019, and compared with the 2020 values. Furthermore, data on lung cancer registrations from 2018 to 2020 were obtained from the Collaborative Akita Prefecture Hospital-Based Cancer Registration System and analyzed. RESULTS: The average annual number of screening tests, close examinations and lung cancer diagnoses declined (by >50%) between 2016 to 2019 and 2020, especially among older people (aged ≥65 years). Furthermore, by stage, the number of patients with early-stage lung cancer (stage 0-I) decreased, and the number with advanced-stage cancer (stage IV) increased. CONCLUSIONS: The COVID-19 pandemic reduced lung cancer screening participation, especially among the older adult population in Akita Prefecture, resulting in a decrease in lung cancer diagnoses through screening. This might have reduced the number of early-stage cancer registrations. It is necessary to improve health education among the public regarding the importance of chest X-ray screening. Geriatr Gerontol Int 2023; 23: 622-627.

Inferior pulmonary ligament division during left upper lobectomy causes pulmonary dysfunction.

OBJECTIVES: The division of inferior pulmonary ligament (IPL) during upper lobectomy (UL) was believed to be mandatory to dilate the remaining lung sufficiently. However, the benefits, especially postoperative pulmonary function, remain controversial. This study aimed to evaluate whether IPL division leads to pulmonary dysfunction. METHODS: This retrospective study included 213 patients who underwent UL between 2005 and 2018. They were categorized into an IPL division group (D group, n = 106) and a preservation group (P group, n = 107). Postoperative dead space at the lung apex, pulmonary function and complications were assessed using chest X-rays and spirometry. Changes in bronchial angle, cross-sectional area and circumference of the narrowed bronchus on the excised side were measured on three-dimensional computed tomography. RESULTS: There was no significant difference in the postoperative complication rate, the dead space area, forced vital capacity (FVC), or forced expiratory volume in 1 s (FEV1) between the 2 groups after right UL (FVC; P = 0.838, FEV1; P = 0.693). By contrast, after left UL pulmonary function was significantly better in the P than in the D group (FVC; P = 0.038, FEV1; P = 0.027). Changes in bronchial angle did not significantly differ between the 2 groups. The narrowed bronchus's cross-sectional area (P = 0.021) and circumference (P = 0.009) were significantly smaller in the D group than in the P group after left UL. CONCLUSIONS: IPL division during left UL caused postoperative pulmonary dysfunction and airflow limitation due to bronchial kinking. IPL preservation may have a beneficial impact on postoperative pulmonary function.

Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer.

The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration-time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.

Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer.

We evaluated the area under the plasma concentration-time curve (AUC) of afatinib required to avoid the onset of grade 2 or higher diarrhea. The C0 and AUC0-24 of afatinib were significant higher in patients with grade 2 diarrhea than in those with grade 0-1 diarrhea. The areas under the receiver operator curves were 0.795 with the highest sensitivity (89%) and specificity (74%) at an AUC0-24 threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C0 threshold of 28.5 ng/mL. In Kaplan-Meier analysis based on these cut-off AUC0-24 and C0 values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC0-24 of afatinib from the single point of C6 showed the highest correlation with the measured AUC0-24 (r2 = 0.840); however, a significant correlation between the AUC0-24 and C0 was also observed (r2 = 0.761). C0 could be used as a marker of therapeutic drug monitoring because afatinib C0 was related to AUC0-24. Therefore, afatinib C0 should be monitored on day 8 after beginning therapy, and the daily dose of afatinib should be adjusted as an index with a cut-off value of 28.5 ng/mL.

Impaired TRIM16-Mediated Lysophagy in Chronic Obstructive Pulmonary Disease Pathogenesis.

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Clinical benefits of adjuvant chemotherapy with carboplatin and gemcitabine in patients with non-small cell lung cancer: a single-center retrospective study.

PURPOSE: In cases of non-small cell lung cancer (NSCLC), surgery remains the best option for cure, but surgery is of benefit only when the disease is localized. Although adjuvant chemotherapy reportedly has a significant beneficial effect on survival, the benefit of a carboplatin (CBDCA) regimen is unclear. We therefore investigated the efficacy and tolerability of CBDCA (area under the curve 5) plus gemcitabine (GEM, 1000 mg/m2) as adjuvant chemotherapy. METHODS: A total of 82 pStage IB-IIIA NSCLC patients who had undergone complete resection and received adjuvant chemotherapy were analyzed retrospectively. Among them, 65 patients received CBDCA + GEM and 17 received CDDP + VNR. Propensity score analysis generated 17 matched pairs of both groups. RESULTS: Sixty-five patients received CBDCA + GEM. Their 5-year relapse-free survival (RFS) and overall survival were 47.8% (median, 52.5 months) and 76.9% (median, 90.1 months), respectively. Toxicities, which included neutropenia, nausea/anorexia, fatigue, and vasculitis, were significantly milder than with CDDP + VNR. There were no significant differences in RFS between CBDCA + GEM and CDDP + VNR (p = 0.079) after matching for age, performance status, and pStage. CONCLUSION: CBDCA + GEM was effective and well tolerated as adjuvant chemotherapy, with a manageable toxicity profile.

Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis.

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.

Effects of STAT3 polymorphisms and pharmacokinetics on the clinical outcomes of gefitinib treatment in patients with EGFR-mutation positive non-small cell lung cancer.

WHAT IS KNOWN AND OBJECTIVE: We investigated the correlations among signal transducer and activator of transcription 3 (STAT3) rs4796793C >G polymorphism, gefitinib pharmacokinetics and clinical responses in Japanese patients with non-small cell lung cancer receiving gefitinib therapy. METHODS: Forty-five patients were enrolled in this study. Plasma trough concentrations (C0 ) of gefitinib at the steady-state were measured by high-performance liquid chromatography. RESULTS AND DISCUSSION: Patients having a gefitinib C0 of at least ≥200 ng/mL had significantly longer PFS than patients having a C0 of <200 ng/mL (median [95% confidence interval (CI)] PFS: 11.0 [8.2-13.7] and 5.3 [0.0-12.0] months, respectively, P = .042). There were no significant differences in PFS between patients with STAT3 rs4796793C/C and G alleles; however, patients with STAT3 rs4796793C/C having a gefitinib C0 of ≥ 200 ng/mL had significantly longer progression-free survival (PFS) and overall survival (OS) than those with a C0 of <200 ng/mL (median [95% CI] PFS: 11.4 [4.1-18.6] and 3.0 [0.0-7.0] months, respectively, P = .008; median [95% CI] OS: 20.6 [7.4-33.7] and 12.6 [10.1-15.1] months, respectively, P = .042). In patients with the STAT3 rs4796793G allele, there were no significant differences in PFS and OS between the two gefitinib C0 groups. In addition, there were no significant differences in PFS or OS according to smoking, presence of proton pump inhibitor combination, or onset of side effects. WHAT IS NEW AND CONCLUSION: Clinical outcomes of gefitinib in patients with the STAT3 rs4796793C/C genotype depended on plasma concentrations of gefitinib. In addition to information regarding EGFR mutations, the STAT3 rs4796793C >G polymorphism and gefitinib C0 may be potential predictors of clinical outcomes after beginning of gefitinib therapy.

ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib.

ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5 ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4 ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5 ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.

Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis.

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-ß-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-ß-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-ß signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.

Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis.

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.

An autopsy case of anaplastic lymphoma kinase-positive lung cancer exacerbated in a short period of time: a case report.

BACKGROUND: Anaplastic lymphoma kinase-positive lung cancer is a form of lung cancer that accounts for approximately 5% of non-small cell lung cancers. Recently, anaplastic lymphoma kinase inhibitors have been used for treatment of anaplastic lymphoma kinase-positive lung cancer, and their high clinical effect has also been demonstrated in cases of advanced stage lung cancer. Alectinib is an anaplastic lymphoma kinase inhibitor that it is recognized as a standard drug for primary therapy because of its superiority to crizotinib. CASE PRESENTATION: A 37-year-old Japanese man was admitted to our hospital due to multiple brain metastases. An autopsy report revealed that the cause of death was anaplastic lymphoma kinase-positive lung cancer, exacerbated in a short period despite treatment with alectinib. Necropsy revealed anaplastic lymphoma kinase-positive adenosquamous carcinoma of the lung, suggesting that it was involved in the prognosis of this patient. Based on the autopsy results, we reviewed the pathological tissue from transbronchial lung biopsy at the time of clinical diagnosis. The tissue specimen for clinical diagnosis in this case was a papillary adenocarcinoma. However, when this tissue was immunostained, thyroid transcription factor 1-negative and cytokeratin 5/6-positive parts were recognized. This result indicates that we could diagnose this patient as having had adenosquamous carcinoma of the lung. CONCLUSION: In cases of anaplastic lymphoma kinase-positive lung cancer poorly responsive to anaplastic lymphoma kinase inhibitors, re-examination of the tissue should be considered because there is a possibility of anaplastic lymphoma kinase-positive adenosquamous carcinoma.

Phase II trial of induction chemotherapy with carboplatin and paclitaxel plus bevacizumab in patients with stage IIIA to IV nonsquamous non-small cell lung cancer.

PURPOSE: Surgery remains the best curative treatment option for non-small cell lung cancer (NSCLC), but is of benefit only to patients with localized disease. A meta-analysis showed a significant beneficial effect of induction chemotherapy on survival, but there is still no clear evidence. This phase II study was conducted to establish whether induction chemotherapy with carboplatin (CBDCA) and paclitaxel (PTX) plus bevacizumab prior to surgery reduces the risk of progression. METHODS: The subjects of this study were 29 patients with treatment-naive nonsquamous NSCLC (clinical stages IIIA to IV). Patients received PTX (200 mg/m2), CBDCA (area under the curve, 5), and bevacizumab (15 mg/kg) followed by surgery. Chemotherapy was repeated every 3 weeks for up to six cycles. RESULTS: The overall response rate was 72.4%. Of the 29 patients, ten underwent surgery after the induction chemotherapy and complete resection was achieved in 7 (70%). The median progression-free-survival (PFS) time and the 3-year PFS rate were 0.92 years and 16.2%, respectively. The median overall survival (OS) time and the 3-year OS rate were 1.96 years and 44.9%, respectively. CONCLUSION: Combined modality therapy with surgery after induction chemotherapy with CBDCA and PTX plus bevacizumab is clinically feasible and tolerable for patients with unknown or negative molecular profiles.

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1ß-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis.

Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/ß-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor.

Risk factors of postoperative pulmonary complications in patients with asthma and COPD.

BACKGROUND: Postoperative pulmonary complications (PPC) in patients with pulmonary diseases remain to be resolved clinical issue. However, most evidence regarding PPC has been established more than 10 years ago. Therefore, it is necessary to evaluate perioperative management using new inhalant drugs in patients with obstructive pulmonary diseases. METHODS: April 2014 through March 2015, 346 adult patients with pulmonary diseases (257 asthma, 89 chronic obstructive pulmonary disease (COPD)) underwent non-pulmonary surgery except cataract surgery in our university hospital. To analyze the risk factors for PPC, we retrospectively evaluated physiological backgrounds, surgical factors and perioperative specific treatment for asthma and COPD. RESULTS: Finally, 29 patients with pulmonary diseases (22 asthma, 7 COPD) had PPC. In patients with asthma, smoking index (≥ 20 pack-years), peripheral blood eosinophil count (≥ 200/mm3) and severity (Global INitiative for Asthma(GINA) STEP ≥ 3) were significantly associated with PPC in the multivariate logistic regression analysis [odds ratio (95% confidence interval) = 5.4(1.4-20.8), 0.31 (0.11-0.84) and 3.2 (1.04-9.9), respectively]. In patients with COPD, age, introducing treatment for COPD, upper abdominal surgery and operation time (≥ 5 h) were significantly associated with PPC [1.18 (1.00-1.40), 0.09 (0.01-0.81), 21.2 (1.3-349) and 9.5 (1.2-77.4), respectively]. CONCLUSIONS: History of smoking or severe asthma is a risk factor of PPC in patients with asthma, and age, upper abdominal surgery, or long operation time is a risk factor of PPC in patients with COPD. Adequate inhaled corticosteroids treatment in patients with eosinophilic asthma and introducing treatment for COPD in patients with COPD could reduce PPCs.

Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4.

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor ß) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy.

BACKGROUND: Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-ß (TGF-ß)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-ß. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.