ADPGK-AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth.

Long noncoding RNAs (lncRNAs) influence the transcription of gene networks in many cell types, but their role in tumor-associated macrophages (TAMs) is still largely unknown. We found that the lncRNA ADPGK-AS1 was substantially upregulated in artificially induced M2-like human macrophages, macrophages exposed to lung cancer cells in vitro, and TAMs from human lung cancer tissue. ADPGK-AS1 is partly located within mitochondria and binds to the mitochondrial ribosomal protein MRPL35. Overexpression of ADPGK-AS1 in macrophages upregulates the tricarboxylic acid cycle and promotes mitochondrial fission, suggesting a phenotypic switch toward an M2-like, tumor-promoting cytokine release profile. Macrophage-specific knockdown of ADPGK-AS1 induces a metabolic and phenotypic switch (as judged by cytokine profile and production of reactive oxygen species) to a pro-inflammatory tumor-suppressive M1-like state, inhibiting lung tumor growth in vitro in tumor cell-macrophage cocultures, ex vivo in human tumor precision-cut lung slices, and in vivo in mice. Silencing ADPGK-AS1 in TAMs may thus offer a novel therapeutic strategy for lung cancer.

CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Rationale: Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. Objectives: To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Methods: Four cohorts were investigated: 1) sputum samples (healthy, n = 4; COPD, n = 37), 2) lung tissue samples (healthy, n = 13; smokers without COPD, n = 10; smoker+COPD, n = 17), 3) pulmonary lobectomy tissue samples (no/mild emphysema, n = 6), and 4) blood samples (healthy, n = 6; COPD, n = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. Measurements and Main Results: 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.

Management of a solitary pulmonary arteriovenous malformation by video-assisted thoracoscopic surgery and anatomic lingula resection: video and review.

BACKGROUND: Pulmonary arteriovenous malformations are abnormal communications between the pulmonary arterial and venous vasculature leading to a right-to-left blood shunt. Based on possible complications, including hypoxemia, hemorrhage, infection and paradoxical embolism, deactivation of the malformation from the circulation is the treatment option of choice, either by interventional embolization or by surgery. Embolization is less invasive and has widely replaced surgery, but bears the risk of revascularization, recanalization and downstream migration of the device with paradoxical embolism. METHODS: We report on the case of a 76-year-old male patient suffering from a complex, plexiform pulmonary arteriovenous malformation in the lingula, which was treated by video-assisted thoracoscopic surgery and anatomic lingula resection. Patient's medical history, clinical examination and imaging studies did not reveal any evidence of hereditary hemorrhagic telangiectasia. RESULTS: Left-sided anterior three-port video-assisted thoracoscopic surgery (VATS) approach was used. Instead of only wedge resecting the very peripherally located pulmonary arteriovenous malformation, the lingular vessels were controlled centrally and an anatomic lingula resection was performed in order to prevent a more central re-malformation. To prevent rupture of the aneurysm sac through pressure overload, the feeding arteries were controlled before the draining vein. Duration of the total procedure was 151 min, the single chest tube was removed on the postoperative day 3, and the patient was discharged on the postoperative day 6. CONCLUSION: Although interventional embolism of the feeding artery of a pulmonary arteriovenous malformation is the current therapeutic gold standard, minimally invasive anatomic lung resection by video-assisted thoracoscopic surgery can be considered, especially for the treatment of solitary large arteriovenous malformations. By anatomic lung resection, the risk of recanalization, collateralization and peri-interventional paradoxical embolism may be reduced.