Clinical outcomes of interstitial lung abnormalities: a systematic review and meta-analysis.

Interstitial lung abnormalities (ILA), incidental findings on computed tomography scans, have raised concerns due to their association with worse clinical outcomes. Our meta-analysis, which included studies up to April 2023 from PubMed/MEDLINE, Embase, and Cochrane Library, aimed to clarify the impact of ILA on mortality, lung cancer development, and complications from lung cancer treatments. Risk ratios (RR) with 95% confidence intervals (CI) were calculated for outcomes. Analyzing 10 studies on ILA prognosis and 9 on cancer treatment complications, we found that ILA significantly increases the risk of overall mortality (RR 2.62, 95% CI 1.94-3.54; I2 = 90%) and lung cancer development (RR 3.85, 95% CI 2.64-5.62; I2 = 22%). Additionally, cancer patients with ILA had higher risks of grade 2 radiation pneumonitis (RR 2.28, 95% CI 1.71-3.03; I2 = 0%) and immune checkpoint inhibitor-related interstitial lung disease (RR 3.05, 95% CI 1.37-6.77; I2 = 83%) compared with those without ILA. In conclusion, ILA significantly associates with increased mortality, lung cancer risk, and cancer treatment-related complications, highlighting the necessity for vigilant patient management and monitoring.

Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-ß1 activity.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-ß1 (TGF)-ß1 activity and TGF-ß1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-ß1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

Overexpression of fatty acid synthase attenuates bleomycin induced lung fibrosis by restoring mitochondrial dysfunction in mice.

Proper lipid metabolism is crucial to maintain alveolar epithelial cell (AEC) function, and excessive AEC death plays a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The mRNA expression of fatty acid synthase (FASN), a key enzyme in the production of palmitate and other fatty acids, is downregulated in the lungs of IPF patients. However, the precise role of FASN in IPF and its mechanism of action remain unclear. In this study, we showed that FASN expression is significantly reduced in the lungs of IPF patients and bleomycin (BLM)-treated mice. Overexpression of FASN significantly inhibited BLM-induced AEC death, which was significantly potentiated by FASN knockdown. Moreover, FASN overexpression reduced BLM-induced loss of mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). Oleic acid, a fatty acid component increased by FASN overexpression, inhibited BLM-induced cell death in primary murine AECs and rescue BLM induced mouse lung injury/fibrosis. FASN transgenic mice exposed to BLM exhibited attenuated lung inflammation and collagen deposition compared to controls. Our findings suggest that defects in FASN production may be associated with the pathogenesis of IPF, especially mitochondrial dysfunction, and augmentation of FASN in the lung may have therapeutic potential in preventing lung fibrosis.

N-acetylcysteine decreases lung inflammation and fibrosis by modulating ROS and Nrf2 in mice model exposed to particulate matter.

Background and Objectives: Air pollutants can induce and incite airway diseases such as asthma. N-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how NAC change redox-regulated gene expression in asthma mouse model exposed to particulate matter (PM). To investigate the effects of NAC on asthma mice exposed to PM through Reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), and mucin 5 (Muc5).Methods: To investigate the effects of NAC (100 mg/kg) on redox-regulated gene expression and lung fibrosis in a mouse model of asthma exposed to PM. A mice model of asthma induced by ovalbumin (OVA) or OVA plus titanium dioxide (OVA + TiO2) was established using wild-type BALB/c female mice, and the levels of Nrf2 and mucin 5AC (Muc5ac) proteins following NAC treatment were examined by Western blotting and immunostaining. In addition, the protein levels of ROS were checked.Results: Airway hyperresponsiveness and inflammation, goblet cell hyperplasia, and lung fibrosis were higher in OVA, OVA + TiO2 mice than in control mice. NAC diminished OVA + TiO2-induced airway hyperresponsiveness and inflammation, goblet cell hyperplasia, and lung fibrosis. Levels of ROS, Nrf2, and Muc5ac protein were higher in lung tissue from OVA + TiO2 mice than that from control mice and were decreased by treatment with NAC.Conclusions: NAC reduce airway inflammation and responsiveness, goblet cell hyperplasia, and lung fibrosis by modulating ROS and Nrf2.

Clinical Applications of Liquid Biopsy in Non-Small Cell Lung Cancer Patients: Current Status and Recent Advances in Clinical Practice.

Recent advances in targeted and immune therapies have enabled tailored treatment strategies for advanced lung cancer. Identifying and understanding the genomic alterations that arise in the course of tumor evolution has become hugely valuable, but tissue biopsies are often insufficient for representing the whole cancer genome due to tumor heterogeneity. A liquid biopsy refers to the isolation and analysis of any tumor-derived material in the blood, and recent studies of this material have mostly focused on cell-free tumor DNA (ctDNA) in plasma. Indeed, liquid biopsy analysis is now expected to expand in utility and scope in clinical practice. In this review, we assess the biology and technical aspects of ctDNA analysis and discuss how it is currently applied in the clinic. Key points: Liquid biopsy is a potentially powerful tool in the era of personalized medicine for guiding targeted therapies in non-small cell lung cancer.

KMBARC registry: protocol for a multicentre observational cohort study on non-cystic fibrosis bronchiectasis in Korea.

INTRODUCTION: Despite the significant disease burden of bronchiectasis in Korea, no large-scale, representative prospective cohort studies have been conducted to evaluate the clinical characteristics of Korean patients with bronchiectasis, indicating an urgent need for cohort studies on bronchiectasis. METHODS AND ANALYSIS: The Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) is a prospective, non-interventional observational cohort study on bronchiectasis in Korea. The inclusion criteria of this registry are as follows: (1) adult patients (aged ≥18 years) with or without respiratory symptoms (cough, chronic sputum and/or recurrent respiratory infection) and chest computed tomography revealing bronchiectasis affecting one or more lobes and (2) stable status at the time of registration: patients with bronchiectasis who were admitted for a respiratory aetiology can be enrolled at least 4 weeks after hospital discharge. The exclusion criteria are as follows: (1) bronchiectasis due to cystic fibrosis; (2) traction bronchiectasis associated with interstitial lung disease; (3) patients actively being treated for pneumonia, pulmonary tuberculosis or non-tuberculous mycobacterial infection; (4) patients who are unable or unwilling to provide informed consent; and (5) pregnant patients. Although the KMBARC questionnaires for baseline and annual follow-up data are similar to the European Multicentre Bronchiectasis Audit and Research Collaboration questionnaires, KMBARC has distinctive features such as use of Bronchiectasis Health Questionnaires, measurement with fatigue and depression scales, blood tests, use of consensus definition of exacerbations and information on emergency room or hospitalisation.We aim to recruit at least 1200 patients over the study period from more than 26 hospitals in South Korea. Patients will undergo a detailed baseline and yearly assessment for up to 5 years. The study objectives of the KMBARC registry are as follows: (1) uncovering the natural course of bronchiectasis; (2) aiding in establishing evidence-based bronchiectasis guidelines in Korea; and (3) encouraging and facilitating studies on bronchiectasis in Korea. ETHICS AND DISSEMINATION: This study received necessary approval from the Institutional Review Boards of all participating institutions. The Asan Medical Center Institutional Review Board gave overall approval for the study. Results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: KCT0003088.

Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine.

Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type and Car-/- mice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice, Car mRNA was down-regulated by TCPOBOP in liver and duodenum. Car-/- mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs (Cyp2b10, Cyp3a11, Aldh1a1, Aldh1a7, Gsta1, Gsta4, Gstm1-m4, Gstt1, Ugt1a1, Ugt2b34, Ugt2b36, and Mrp2-4) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.

Endobronchial mass formation after endobronchial ultrasound-transbronchial needle aspiration mimicking implantation metastasis.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosing intrathoracic lymphadenopathy. Here, we present two cases of endobronchial polyp formation after an EBUS-TBNA for suspicious malignant lymph nodes. An inflammatory polyp should be considered as a possible differential diagnosis for a newly developed mass after an EBUS-TBNA.