Cellular lung dosimetry for inhaled radon decay products as a base for radiation-induced lung cancer risk assessment

Summary Lung cancer induction is commonly regarded as the most important somatic risk arising from the inhalation of radon and its decay products. Relating carcinogenesis to radiation exposure needs a detailed knowledge of the cellular dose distribution in the human respiratory tract. Different dosimetric models have been developed for the determination of cellular doses, particularly for the basal cells of the bronchial epithelium which are considered as the critical cells for lung cancer induction. Part I of the paper describes the influence of various environmental as well as anatomical and physiological factors on the resulting dose. Significant inter- as well as intra-subject variabilities of structural components of the human lung, respiration characteristics and clearance mechanisms demonstrate the necessity of applying stochastic models in lung dosimetry.     

Reduced activity of the epithelial sodium channel in malaria-induced pulmonary oedema in mice

Lung complications during malaria infection can range from coughs and impairments in gas transfer to the development of acute respiratory distress syndrome (ARDS). Infecting C57BL/6 mice with Plasmodium berghei K173 strain (PbK) resulted in pulmonary oedema, capillaries congested with leukocytes and infected red blood cells (iRBCs), and leukocyte infiltration into the lungs. This new model of malaria-associated lung pathology, without any accompanying cerebral complications, allows the investigation of mechanisms leading to the lung disease. The activity of the amiloride-sensitive epithelial sodium channel (ENaC) in alveolar epithelial cells is decreased by several respiratory tract pathogens and this is suggested to contribute to pulmonary oedema. We show that PbK, a pathogen that remains in the circulation, also decreased the activity and expression of ENaC, suggesting that infectious agents can have indirect effects on ENaC activity in lung epithelial cells. The reduced ENaC activity may contribute to the pulmonary oedema induced by PbK malaria.     

NK cell lymphoma, nasal type, with massive lung involvement: a case report

Extranodal NK/T cell lymphoma, nasal type, is an Epstein–Barr virus-associated lymphoma that most commonly involves the nasal cavity and upper respiratory tract. Lung involvement by NK/T cell lymphoma is rare and seldom reported in the literature. We describe the unusual case of a 41-year-old male with NK cell lymphoma, nasal type, who presented with massive secondary lung involvement 2.5 years after the detection of a retroperitoneal mass. The diagnosis was made by open lung biopsy. Despite aggressive treatment, the patient died shortly after the initiation of therapy. Lung involvement by NK/T cell lymphoma occurs most commonly as part of widely disseminated disease and carries a poor prognosis for the patient. Novel agents and innovative therapies need to be developed for this aggressive lymphoma.     

Synthesis and cytotoxic activity of MOM-ether analogs of isosteviol

Lung cancer is one of the most common malignancies worldwide. In this Letter, novel MOM-ether analogs of isosteviol were designed and synthesized to be tested for anticancer activities against H1299 lung cancer cell lines. The effects of these derivatives were studied in H1299 human large cell lung carcinoma cells that are null for p53 and compared to normal counterparts NL-20 normal lung epithelial cells. The initial screening of twelve MOM-ether analogs of isosteviol derivatives on H1299 lung cancer cells by MTT assay revealed that two derivatives (an ester and a carbamate) were the most potent in reducing cell viability. The IC₅₀ values for these derivatives were determined to be 14 and 21 μM respectively. We compared the cytotoxicity of the best derivatives in H1299 lung cancer cells and NL-20 normal lung epithelial cells. Both derivatives showed lower cytotoxic effects on NL-20 normal lung epithelial cells. Moreover, both derivatives induced apoptosis in H1299 lung cancer cells more than NL-20 normal lung epithelial cells.     

急性呼吸窘迫综合征小鼠肺内源性干细胞表达水平的研究

目的探讨急性呼吸窘迫综合征（ARDS）小鼠肺组织中肺内源性干细胞的表达水平。 方法10只C57BL/6小鼠分成两组：实验组和对照组,实验组通过气管内注射脂多糖（LPS）构建小鼠ARDS模型,采用气管内注射PBS作为对照组;采用胶原酶、热消化法消化小鼠肺组织获取小鼠肺单细胞悬液;双重免疫荧光染色方法鉴定小鼠肺组织中sca-1⁺CD31^-CD45^-细胞;流式细胞术对肺sca-1⁺CD31^-CD45^-细胞进行分选。采用方差分析及独立t检验进行统计学分析。 结果通过气管内注入LPS成功制作小鼠急性ARDS模型;5只小鼠的全肺组织制备单细胞悬液总数目达5×10⁷个/ml,活细胞百分比为98﹪;肺内源性干细胞包括Ⅱ型肺泡上皮细胞、clara细胞以及支气管肺泡干细胞等,通过肺组织双重免疫荧光染色,验证小鼠肺组织Ⅱ型肺泡上皮细胞、clara细胞以及支气管肺泡干细胞;对照组及实验组各样本肺内源性干细胞数目占单细胞悬液细胞数比例呈正态分布,且实验组肺内源性干细胞数目水平（10.73±10.65）﹪较对照组水平（12.23±0.73）﹪降低（t = -3.405,P < 0.01）。 结论ARDS时,小鼠肺内源性干细胞（sca-1⁺CD31^-CD45^-）水平降低,减少的肺内源性干细胞具体去向尚不明确,其有可能参与机体急性炎症过程中气道上皮细胞的修复、再生过程。     

Epithelial-vascular cross talk mediated by VEGF-A and HGF signaling directs primary septae formation during distal lung morphogenesis

There is increasing evidence that epithelial-vascular interactions are essential for tissue patterning. Here we identified components of the molecular cross talk between respiratory epithelial cells and pulmonary capillaries necessary for the formation of the gas exchange surface of the lung. Selective inactivation of the Vegf-A gene in respiratory epithelium results in an almost complete absence of pulmonary capillaries, demonstrating the dependence of pulmonary capillary development on epithelium-derived Vegf-A. Deficient capillary formation in Vegf-A deficient lungs is associated with a defect in primary septae formation, a morphogenetic process critical for distal lung morphogenesis, coupled with suppression of epithelial cell proliferation and decreased hepatocyte growth factor (Hgf) expression. Lung endothelial cells express Hgf, and selective deletion of the Hgf receptor gene in respiratory epithelium phenocopies the malformation of septae, confirming the requirement for epithelial Hgf signaling in normal septae formation and suggesting that Hgf serves as an endothelium-derived factor that signals to the epithelium. Our findings support a mechanism for primary septae formation dependent on reciprocal interactions between respiratory epithelium and the underlying vasculature, establishing the dependence of pulmonary capillary development on epithelium-derived Vegf-A, and identify Hgf as a putative endothelium-derived factor that mediates the reciprocal signaling from the vasculature to the respiratory epithelium.     

血栓调节蛋白在胚胎肺及肺癌中的表达

目的研究血栓调节蛋白(thrombomodulin,TM)在胚胎肺、正常肺组织及肺癌组织中的表达。方法以不同周龄的胚胎肺组织、正常成人肺组织、肺癌组织为研究对象,应用免疫组织化学SP法检测TM的存在。结果8、15、18、21、24、27、29周人胎肺组织中,TM在气管纤毛柱状上皮细胞、I型和Ⅱ型肺泡上皮细胞及软骨、结缔组织均呈阴性表达,围绕肺泡上皮细胞团周围的血管内皮细胞阳性表达。正常成人支气管纤毛柱状上皮细胞、肺泡上皮细胞不表达,但在血管内皮细胞呈阳性表达。TM在鳞状上皮不典型增生的细胞膜和细胞问桥表达,在肺鳞癌表达,阳性率为97．3％(34／35),在癌细胞膜和细胞问桥阳性表达,但腺癌、小细胞癌癌细胞不表达。结论TM在胚胎肺以及成人肺仅见于血管内皮细胞,在支气管上皮、肺泡上皮不表达。与其它的血管内皮细胞标记物不同,TM的表达在肺鳞癌与腺癌表扶明显不同．右助于鉴别肺鳞癌与肺腺癌．     

MUC1-C influences cell survival in lung adenocarcinoma Calu-3 cells after SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces coronavirus disease 2019 (COVID-19) and may increase the risk of adverse outcomes in lung cancer patients. In this study, we investigated the expression and function of mucin 1 (MUC1) after SARS-CoV-2 infection in the lung epithelial cancer cell line Calu-3. MUC1 is a major constituent of the mucus layer in the respiratory tract and contributes to pathogen defense. SARS-CoV-2 infection induced MUC1 C-terminal subunit (MUC1-C) expression in a STAT3 activation-dependent manner. Inhibition of MUC1-C signaling increased apoptosis-related protein levels and reduced proliferation-related protein levels; however, SARS-CoV-2 replication was not affected. Together, these results suggest that increased MUC1-C expression in response to SARS-CoV-2 infection may trigger the growth of lung cancer cells, and COVID-19 may be a risk factor for lung cancer patients.     

Shining a light on metabolic vulnerabilities in non-small cell lung cancer

Metabolic reprogramming is a hallmark of cancer which contributes to essential processes required for cell survival, growth, and proliferation. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and its genomic classification has given rise to the design of therapies targeting tumors harboring specific gene alterations that cause aberrant signaling. Lung tumors are characterized with having high glucose and lactate use, and high heterogeneity in their metabolic pathways. Here we review how NSCLC cells with distinct mutations reprogram their metabolic pathways and highlight the potential metabolic vulnerabilities that might lead to the development of novel therapeutic strategies.     

Ultrastructural and morphometric study of the lung of the European salamander,Salamandra salamandra L.

Ultrastructural and morphometric investigations were performed on the lung of the European salamander, Salamandra salamandra L. Folds of first and second order are covered with a ciliated epithelium containing goblet cells. The respiratory surface of the lung is lined by a single type of cell which, in amphibians, combines features of type I and type II alveolar cells of the mammalian lung. In the salamander the respiratory and ciliated epithelial cells as well as goblet cells possess electron dense and lucent vesicles in their cytoplasm as well as lamellar bodies. A small amount of surfactant, composed most probably of phospholipids and mucopolysaccharides, was observed covering the entire inner surface of the lung. Morphometric methods were used to determine the dimensions of the perinuclear region of pneumocytes, the thickness of the air-blood barrier and lung wall, and also the diameter of capillaries. The thickness of the respiratory air-blood barrier was found to be considerably higher than that of the corresponding barrier in mammals.     

Neuregulin-ErbB4 signaling in the developing lung alveolus: a brief review

Lung immaturity is the major cause of morbidity and mortality in premature infants, especially those born <28 weeks gestation. Proper lung development from 23–28 weeks requires coordinated cell proliferation and differentiation. Infants born at this age are at high risk for respiratory distress syndrome (RDS), a lung disease characterized by insufficient surfactant production due to immaturity of the alveoli and its constituent cells in the lung. The ErbB4 receptor and its stimulation by neuregulin (NRG) plays a critical role in surfactant synthesis by alveolar type II epithelial cells. In this review, we first provide an introduction to normal human alveolar development, followed by a discussion of the neuregulin and ErbB4-mediated mechanisms regulating alveolar development and surfactant production.     

Very Long-Chain Acyl-CoA Synthetase 3: Overexpression and Growth Dependence in Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide. In the United States, only one in six lung cancer patients survives five years after diagnosis. These statistics may improve if new therapeutic targets are identified. We previously reported that an enzyme of fatty acid metabolism, very long-chain acyl-CoA synthetase 3 (ACSVL3), is overexpressed in malignant glioma, and that depleting glioblastoma cells of ACSVL3 diminishes their malignant properties. To determine whether ACSVL3 expression was also increased in lung cancer, we studied tumor histologic sections and lung cancer cell lines. Immunohistochemical analysis of normal human lung showed moderate ACSVL3 expression only in bronchial epithelial cells. In contrast, all of 69 different lung tumors tested, including adeno-, squamous cell, large cell, and small cell carcinomas, had robustly elevated ACSVL3 levels. Western blot analysis of lung cancer cell lines derived from these tumor types also had significantly increased ACSVL3 protein compared to normal bronchial epithelial cells. Decreasing the growth rate of lung cancer cell lines did not change ACSVL3 expression. However, knocking down ACSVL3 expression by RNA interference reduced cell growth rates in culture by 65–76%, and the ability of tumor cells to form colonies in soft agar suspension by 65–80%. We also conducted studies to gain a better understanding of the biochemical properties of human ACSVL3. ACSVL3 mRNA was detected in many human tissues, but the expression pattern differed somewhat from that of the mouse. The enzyme activated long- and very long-chain saturated fatty acid substrates, as well as long-chain mono- and polyunsaturated fatty acids to their respective coenzyme A derivatives. Endogenous human ACSVL3 protein was found in a punctate subcellular compartment that partially colocalized with mitochondria as determined by immunofluorescence microscopy and subcellular fractionation. From these studies, we conclude that ACSVL3 is a promising new therapeutic target in lung cancer.     

The diagnostic accuracy of sputum and urine cytology

The diagnostic accuracies of sputum and urinary cytology were examined in series spanning more than 20 years. The sensitivity and respiratory tract cytology in 1,289 patients with subsequently proven lung cancer was 69% while that or urine cytology in 860 patients with urinary tract cancer was 77%. The specificities were 96% for lung cancer and 97% for urinary tract cancer. Neither procedure was widely used for routine screening, but diagnostic cytology played an important part in providing a definite morphologic diagnosis in many of these cases. Urinary cytology was also very effective in the follow-up of patients with treated bladder cancer because of its high sensitivity for detecting carcinoma in situ.     

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

Lung cancer is the most deadly type of cancer in humans, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer showing high resistance to radiation and chemotherapy. Despite the outstanding progress made in anti-tumor therapy, discovering effective anti-tumor drugs is still a challenging task. Here we describe a new semisynthetic derivative of cucurbitacin B (DACE) as a potent inhibitor of NSCLC cell proliferation. DACE arrested the cell cycle of lung epithelial cells at the G2/M phase and induced cell apoptosis by interfering with EGFR activation and its downstream signaling, including AKT, ERK, and STAT3. Consistent with our in vitro studies, intraperitoneal application of DACE significantly suppressed the growth of mouse NSCLC that arises from type II alveolar pneumocytes due to constitutive expression of a human oncogenic c-RAF kinase (c-RAF-1-BxB) transgene in these cells. Taken together, these findings suggest that DACE is a promising lead compound for the development of an anti-lung-cancer drug.     

Silencing lncRNA DUXAP8 inhibits lung adenocarcinoma progression by targeting miR-26b-5p

Lung adenocarcinoma (LUAD), a common type of lung cancer, has become a popularly aggressive cancer. Long noncoding RNAs (lncRNAs) play a critical role in the pathogenesis of human cancers, while the function of double homeobox A pseudogene 8 (DUXAP8) in LUAD remains to be fully inquired. Therefore, our study was conducted to elucidate the DUXAP8 expression in LUAD and its mechanism on the biological features of LUAD cells. Loss-of-function experiments were performed to assess the function of DUXAP8 proliferation and apoptosis of H1975 and A549 cells. Functionally, silencing DUXAP8 inhibited proliferation and induced apoptosis of LUAD cells. Mechanistically, further correlation assay indicated a negative association between miR-26b-5p and DUXAP8 expression. Subsequently, we testified that DUXAP8 exerted its role in the progression and development of LUAD through targeting miR-26b-5p. In summary, our results elucidated that that DUXAP8 promoted tumor progression in LUAD by targeting miR-26b-5p, which provide a novel therapeutic target for diagnosis and therapy of LUAD.     

转基因肺癌动物模型研究进展

肺癌是世界各国常见的恶性肿瘤,肺癌动物模型在人类肺癌病因、诊断、治疗等方面发挥重要的作用。其中转基因肺癌模型能够更好的模拟肺癌,更有利于肺癌病因及发病过程的研究。本文介绍了近年来转基因肺癌模型的研究进展。