A component of high-grade fetal lung adenocarcinoma diagnosed as the cause of lymph node metastasis.

High-grade fetal lung adenocarcinoma (H-FLAC) is a rare type of tumor. There have been no reports demonstrating the degree of metastatic susceptibility of this tumor type. In this report, we describe a case in which 15% of the adenocarcinoma components were H-FLAC diagnosed as the cause of lymph node metastasis. A 75-year-old man presented with suspected primary lung cancer (clinical stage IIA, T2bN0M0) and underwent left upper lobectomy and superior mediastinal lymph node dissection. Postoperative histopathology revealed lung cancer with only lobar bronchial lymph node (#11) metastasis. Approximately 60% of the invasive adenocarcinoma showed a papillary morphology, 25% showed a lepidic morphology, and 15% showed a fetal morphology. The histomorphological and immunohistological features of #11 metastasis were similar to those of H-FLAC. Herein, we report a rare and important case of H-FLAC with proven lymph node metastasis, showing that even a small amount of H-FLAC tissue can cause metastasis.

Arginase 1 does not affect RNA m6A methylation in mouse fetal lung.

BACKGROUND: Arginase 1 (Arg1) encodes a key enzyme that catalyzes the metabolism of arginine to ornithine and urea. In our recent study, we found that knockdown of Arg1 in the lungs of fetal mice induces apoptosis of epithelial cells and dramatically delays initiation of labor. As the most abundant internal mRNA modification, N6 -methyladenosine (m6 A) has been found to play important roles in lung development and cellular differentiation. However, if the knockdown of Arg1 affects the RNA m6A modification in fetal lungs remains unknown. METHODS: In the current study, the RNA m6A levels and the expression of RNA m6A related enzymes were validated in 13.0 dpc fetal lungs that Arg1 was knocked down by adeno-associated virus carrying Arg1-shRNA, using western blot, immunofluorescence, and RT-qPCR. RESULTS: No statistical differences were found in the expression of methyltransferase, demethylases, and binding proteins in the fetal lungs between AAV-shArg1-injected mice and AAV-2/9-injected mice. Besides, there is no significant change of overall RNA m6A level in fetal lungs from AAV-shArg1-injected mice, compared with that from AAV-2/9-injected mice. CONCLUSIONS: These results indicate that arginase 1 does not affect RNA m6A methylation in mouse fetal lung, and the mechanisms other than RNA m6A modification underlying the effects of Arg1 knockdown on the fetal lung development and their interaction with labor initiation need to be further explored.

Fetal Lung Interstitial Tumor: A Comprehensive Case Study with an Emphasis on Next-Generation Sequencing.

Fetal lung interstitial tumor (FLIT), which is characterized by immature interstitial cells resembling the fetal lung parenchyma of 20 to 24 weeks of gestation, is a rare respiratory neoplasm. This study presents the first reported FLIT in Korea. It also aims to refine the diagnostic method of FLIT and increase the accuracy of prognostic assessment by using next-generation sequencing to check for anaplastic lymphoma receptor tyrosine kinase (anaplastic lymphoma kinase) gene rearrangement. Although the initial prognosis for FLIT has been promising since its first report in 2010, certain pathological features are associated with poorer outcomes. Therefore, achieving an accurate diagnosis of FLIT is crucial for avoiding unnecessary treatments beyond surgical resection.

Transplacental infection by bovine alphaherpesvirus type 1 induces protein expression of COX-2, iNOS and inflammatory cytokines in fetal lungs and placentas.

Bovine alphaherpesvirus type 1 (BoAHV-1) is associated with respiratory and reproductive syndromes. Until present the immunologic mechanisms involved in BoAHV-1 abortion are partially known. We studied key elements of the innate immune response in the placentas and fetal lungs from cattle experimentally-inoculated with BoAHV-1. These tissues were analyzed by histopathology. Furthermore, virus identification was performed by qPCR and the expression of the inflammatory cytokines such as tumor necrosis factor-alpha, interleukin 1-alpha and inflammatory mediators like inducible nitric oxide synthase and cyclooxeganse-2 was evaluated by immunohistochemistry. The viral transplacental infection was confirmed by the detection of BoAHV-1 by qPCR in the placenta and fetal organs, which revealed mild inflammatory lesions. Inducible nitric oxide synthase immunolabelling was high in the lungs of infected fetuses and placentas, as well as for tumor necrosis factor-alpha in the pulmonary parenchyma and cyclooxeganse-2 in fetal annexes. However, the expression of interleukin 1-alpha was weak in these organs. To our knowledge, this is the first study that provides strong evidence of an early immune response to BoAHV-1 infection in the conceptus. Advances in the knowledge of the complex immunological interactions at the feto-maternal unit during BoAHV-1 infection are needed to clarify the pathogenesis of abortion.

Spontaneous Partial Regression of Fetal Lung Interstitial Tumor With A2M::ALK Rearrangement in a Neonate.

The differential diagnosis for neonatal primary lung masses includes developmental anomalies and congenital lung tumors. Fetal lung interstitial tumor (FLIT) is a rare benign mesenchymal lesion which presents either antenatally or within the first 3 months of age. FLIT is a circumscribed solid-cystic mass which histologically resembles the fetal lung during the canalicular stage at 20-24 weeks of gestation. It is composed of immature mesenchymal cells expanding the interstitium and irregular airspace-like structures. Of all published cases, only 1 identified an α2-macroglobulin (A2M)::anaplastic lymphoma kinase (ALK) fusion and all cases underwent surgical resection in the neonatal or infancy period. We present the second case of FLIT with an A2M::ALK fusion diagnosed postnatally in a neonate which partially regressed spontaneously during conservative management with interim resection at 39 months of age, and provide a review of the literature.

Gestational Diabetes Mellitus Impedes Fetal Lung Development Through Exosome-Dependent Crosstalk Between Trophoblasts and Lung Epithelial Cells.

Background: Fetal lung underdevelopment (FLUD) is associated with neonatal and childhood severe respiratory diseases, among which gestational diabetes mellitus (GDM) play crucial roles as revealed by recent prevalence studies, yet mechanism underlying GDM-induced FLUD, especially the role of trophoblasts, is not all known. Methods: From the perspective of trophoblast-derived exosomes, we established in vitro, ex vivo, in vivo and GDM trophoblast models. Utilizing placenta-derived exosomes (NUB-exos and GDMUB-exos) isolated from normal and GDM umbilical cord blood plasma and trophoblast-derived exosomes (NC-exos and HG-exos) isolated from HTR8/SVneo trophoblasts medium with/without high glucose treatment, we examined their effects on fetal lung development and biological functions. Results: We found that, compared with the NUB-exos group, the exosome concentration increased in GDMUB-exos group, and the content of exosomes also changed evidenced by 61 dysregulated miRNAs. After applying these exosomes to A549 alveolar type II epithelial cells, the proliferation and biological functions were suppressed while the proportion of apoptotic cells was increased as compared to the control. In ex vivo studies, we found that GDMUB-exos showed significant suppression on the growth of the fetal lung explants, where the number of terminal buds and the area of explant surface decreased and shrank. Besides, the expression of Fgf10, Vegfa, Flt-1, Kdr and surfactant proteins A, B, C, and D was downregulated in GDMUB-exos group, whilst Sox9 was upregulated. For in vivo studies, we found significant suppression of fetal lung development in GDMUB-exos group. Importantly, we found consistent alterations when we used NC-exos and HG-exos, suggesting a dominant role of trophoblasts in placenta-derived exosome-induced FLUD. Conclusion: In conclusion, GDM can adversely affect trophoblasts and alter exosome contents, causing crosstalk disorder between trophoblasts and fetal lung epithelial cells and finally leading to FLUD. Findings of this study will shine insight into the theoretical explanation for the pathogenesis of FLUD.

Prenatal ultrasound-and MRI-based imaging predictors of respiratory symptoms at birth for congenital lung malformations.

BACKGROUND: Congenital lung malformations (CLM) are rare developmental anomalies of the fetal lung with a minority of patients exhibiting symptoms around the time of birth. Although ultrasound remains the gold standard, fetal MRI has recently been incorporated as an adjunct imaging modality in the workup and prenatal counseling of patients with CLM as it is thought to more accurately delineate lesion boundaries and diagnose lesion type. We evaluate what prenatal variables correlate with postnatal respiratory symptoms. METHODS: We performed a retrospective review of patients with prenatal diagnosis of CLM treated at our institution between 2006-2020. Fetal ultrasound and magnetic resonance imaging (MRI) parameters including maximal congenital pulmonary airway malformation volume ratio (CVR), absolute cyst volume, and observed to expected normal fetal lung volume (O/E NFLV) were correlated with outcomes including postnatal respiratory symptoms, need for supplementary oxygen or mechanical ventilation, delay in tolerating full feeds, resection in the neonatal period. RESULTS: Our study included 111 patients, all of whom underwent fetal ultrasound with 64 patients additionally undergoing fetal MRI. Postnatal respiratory symptoms were noted in 22.5% of patients, 19.8% required supplemental oxygen, 2.7% mechanical ventilation and two patients requiring urgent resection. Ultrasound parameters including absolute cyst volume and maximal CVR correlated with need for mechanical ventilation (p=0.034 and p=0.024, respectively) and for urgent resection (p=0.018 and p=0.023, respectively) and had a marginal association with postnatal respiratory symptoms (p=0.050 and p=0.052). Absolute cyst volume became associated with postnatal respiratory symptoms (p=0.017) after multivariable analysis controlling for maternal steroid administration and gestational age. O/E NFLV did not correlate with perinatal outcomes. CONCLUSION: We have found that ultrasound-based measurements correlate with postnatal respiratory symptoms, while MRI derived O/E NFLV does not. Further studies are needed to elucidate the role of MRI in the prenatal workup of congenital lung malformations. TYPE OF STUDY: Study of Diagnostic Test. LEVEL OF EVIDENCE: Level I.

Successful treatment with atezolizumab combination chemotherapy in a patient with high-grade fetal adenocarcinoma of the lung: A case report.

High-grade fetal lung adenocarcinoma (H-FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56-year-old man with stage IV H-FLAC who was successfully treated with carboplatin plus nab-paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.

Can we predict the need for postnatal surgery in patients with prenatal fetal lung masses detected by CVR value?

AIM: The purpose of this study is to evaluate whether CPAM-volume ratio (CVR) can predict postnatal management (follow up for resolution and surgical treatment) in fetuses with fetal lung masses in the prenatal period. MATERIALS AND METHODS: 44 patients who presented at our center with prenatally diagnosed CPAM (Congenital Pulmonary Airway Malformation) and BPS (Bronchopulmonary Sequestration) were analyzed. Obstetric history and outcomes, karyotype results, CVR, additional sonographic findings, characteristics of masses were recorded. CVR was calculated for all cases. In the study we sought to identify a CVR threshold and did not use the thresholds classically used in the literature. RESULTS: 20 fetal BPS and 24 CPAM cases were analyzed. After excluding 5 patients, 46% of the patients were diagnosed with BPS and 54% with CPAM. In this study the cut off < 0,53 for CVR is taken, it predicts the no need for postnatal surgery with a sensitivity of 85% and a specificity of 88%. When we take the > 0,76 cut-off value for patients who will require emergency surgery within the first 10 days, it predicts the need for surgery with 90% sensitivity and 89% specificity. In addition, it was determined that all patients with mediastinal shift were operated. CONCLUSION: We believe that the CVR value and the presence of mediastinal shift should be evaluated in all cases of CPAM and BPS for prediction of the surgery. Proper counseling about the prognosis could be given to the family in cases with mediastinal shift and CVR value above 0,76.

Understanding the role of placental pathophysiology in the development of bronchopulmonary dysplasia.

The associations between bronchopulmonary dysplasia (BPD) and the gestational pathologies of chorioamnionitis (CA) and hypertensive disorders of pregnancy (HDP) have become increasingly well recognized. However, the mechanisms through which these antenatal conditions cause increased risk of BPD remain less well characterized. The objective of this review is to discuss the role of the placenta in BPD predisposition as a primary driver of intrauterine alterations adversely impacting fetal lung development. We hypothesize that due to similarities in structure and function, placental disorders during pregnancy can uniquely impact the developing fetal lung, creating a unique placental-pulmonary connection. In the current review, we explore this hypothesis through analysis of clinical literature and preclinical model systems evaluating BPD predisposition, discussion of BPD phenotypes, and an overview on strategies to incorporate placental investigation into research on fetal lung development. We also discuss important concepts learned from research on antenatal steroids as a modulator fetal lung development. Finally, we propose that the appropriate selection of animal models and establishment of in vitro lung developmental model systems incorporating primary human placental components are key in continuing to understand and address antenatal predisposition to BPD.

Prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia: a systematic review and meta-analysis.

PURPOSE: This study aimed to evaluate prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia (CDH). METHODS: A systematic literature search was performed to identify relevant observational studies that evaluated the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e-LHR), observed-to-expected total fetal lung volume (o/e-TFLV), lung-to-thorax transverse area ratio (L/T ratio), intrathoracic herniation of the liver and the stomach, and side of diaphragmatic hernia, using a threshold for the prediction of mortality in fetuses with CDH. Study quality was assessed using the QUADAS-2 tool. Hierarchical summary receiver operating characteristic curves were constructed. RESULTS: A total of 50 articles were included in this meta-analysis. The QUADAS-2 tool identified a high risk of bias in more than one domain scored in all parameters. Among those parameters, the diagnostic odds ratio of mortality with o/e-LHR < 25%, o/e-TFLV < 25%, and L/T ratio < 0.08 were 11.98 [95% confidence interval (CI) 4.65-30.89], 11.14 (95% CI 5.19-23.89), and 10.28 (95% CI 3.38-31.31), respectively. The predictive values for mortality were similar between the presence of liver herniation and retrocardiac fetal stomach position. CONCLUSIONS: This systematic review suggests that o/e-LHR, o/e-TFLV, and L/T ratio are equally good predictors of neonatal mortality in fetuses with isolated CDH.

Maduración pulmonar fetal en diabetes mellitus pregestacional y complicaciones crónicas / Fetal lung maturation in pregestational diabetes mellitus and chronic complications

Las pacientes embarazadas con diabetes mellitus (DM) pregestacional y complicaciones micro y macroangiopáticas tienen mayor riesgo de empeoramiento de las mismas y de presentar otros trastornos asociados al embarazo. La progresión de la retinopatía diabética ocurre durante el embarazo y el posparto. La nefropatía se asocia con un mayor riesgo de preeclampsia, parto prematuro, restricción del crecimiento fetal y mortalidad perinatal. Cuando hay enfermedad de arterias coronarias o gastroparesia se observa un aumento de la morbilidad materna y fetal. El parto prematuro es una condición prevalente en pacientes con DM. La maduración pulmonar fetal con corticosteroides fue extensamente estudiada, con numerosas pruebas controladas, hasta convertirse en una de las más importantes terapias prenatales basadas en evidencias para reducir la mortalidad perinatal y el síndrome de dificultad respiratoria, la hemorragia intraventricular y la enterocolitis necrosante en los niños prematuros. Sin embargo, en dicha evidencia no se han incluido a embarazadas con DM, por lo cual no se conocen resultados perinatales en este grupo de pacientes.

Pregnant patients with pregestational diabetes mellitus (DM) and micro and macroangiopathic complications have a higher risk of their worsening and of presenting other pregnancyassociated disorders. The progression of diabetic retinopathy occurs during pregnancy and postpartum. Nephropathy is associated with an increased risk of preeclampsia, preterm delivery, fetal growth restriction, and perinatal mortality. When there is coronary artery disease or gastroparesis, an increase in maternal and fetal morbidity is observed Preterm delivery is a prevalent condition in diabetic patients. Corticosteroid fetal lung maturation has been extensively studied, with numerous controlled trials, to become one of the most important evidence-based prenatal therapies to reduce perinatal mortality and decrease respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, in premature infants. Nevertheless, this evidence did not include patients with DM, for this reason perinatal results are not known in this group of patients.

Fetal Lung-Derived Exosomes in Term Labor Amniotic Fluid Induce Amniotic Membrane Senescence.

The mechanism of parturition is still unclear. Evidence has shown that delivery is associated with cellular senescence of the amniotic membrane. We isolated fetal lung-associated exosomes from the amniotic fluid from term labor (TL-exos) and verified that the exosomes can cause primary human amniotic epithelial cell (hAEC) senescence and apoptosis and can release higher levels of senescence-associated secretory phenotype (SASP)-related molecules and proinflammatory damage-associated molecular patterns (DAMPs) than exosomes isolated from the amniotic fluid from term not in labor (TNIL-exos). The human lung carcinoma cell lines (A549) can be used as an alternative to alveolar type 2 epithelial cells producing pulmonary surfactant. Therefore, we isolated A549 cell-derived exosomes (A549-exos) and found that they can trigger hAEC to undergo the same aging process. Finally, the animal experiments suggested that A549-exos induced vaginal bleeding and preterm labor in pregnant mice. Therefore, we conclude that exosomes derived from fetal lungs in term labor amniotic fluid induce amniotic membrane senescence, which may provide new insight into the mechanism of delivery.

Maduración pulmonar fetal en diabetes mellitus pregestacional y complicaciones crónicas / Fetal lung maturation in pregestational diabetes mellitus and chronic complications

Resumen Las pacientes embarazadas con diabetes mellitus (DM) pregestacional y complicaciones micro y macroangiopáticas tienen mayor riesgo de empeoramiento de las mismas y de presentar otros trastornos asociados al embarazo. La progresión de la retinopatía diabética ocurre durante el embarazo y el posparto. La nefropatía se asocia con un mayor riesgo de preeclampsia, parto prematuro, restricción del crecimiento fetal y mortalidad perinatal. Cuando hay enfermedad de arterias coronarias o gastroparesia se observa un aumento de la morbilidad materna y fetal. El parto prematuro es una condición prevalente en pacientes con DM. La maduración pulmonar fetal con corticosteroides fue extensamente estudiada, con numerosas pruebas controladas, hasta convertirse en una de las más importantes terapias prenatales basadas en evidencias para reducir la mortalidad perinatal y el síndrome de dificultad respiratoria, la hemorragia intraventricular y la enterocolitis necrosante en los niños prematuros. Sin embargo, en dicha evidencia no se han incluido a embarazadas con DM, por lo cual no se conocen resultados perinatales en este grupo de pacientes.

Abstract Pregnant patients with pregestational diabetes mellitus (DM) and micro and macroangiopathic complications have a higher risk of their worsening and of presenting other pregnancyassociated disorders. The progression of diabetic retinopathy occurs during pregnancy and postpartum. Nephropathy is associated with an increased risk of preeclampsia, preterm delivery, fetal growth restriction, and perinatal mortality. When there is coronary artery disease or gastroparesis, an increase in maternal and fetal morbidity is observed Preterm delivery is a prevalent condition in diabetic patients. Corticosteroid fetal lung maturation has been extensively studied, with numerous controlled trials, to become one of the most important evidence-based prenatal therapies to reduce perinatal mortality and decrease respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, in premature infants. Nevertheless, this evidence did not include patients with DM, for this reason perinatal results are not known in this group of patients.

A case report of misdiagnosed fetal lung mass and review of the literature.

The patient was a male neonate, and a prenatal ultrasound had detected a right lung mass. He was born at term and after delivery had tachypnea and feeding difficulties. A chest x-ray and a computed tomography (CT) scan revealed a large mass in the right chest with compression on the right lung after birth. We initially considered congenital pulmonary airway malformation (CPAM). After conservative treatment, his respiratory symptoms worsened gradually, and he required continuous supplemental oxygen. The symptoms could not be relieved by puncturing due to a postnatal ultrasound having shown a mass with anechoic microcystic spaces. He therefore underwent an emergency thoracotomy and lobectomy at 14 days of age. The pathology was consistent with fetal lung interstitial tumor (FLIT). The patient remained healthy at the three-month follow-up. We reviewed the literature on FLIT and found that, to date, 23 cases have been reported worldwide.

Distinct properties of pure- and mixed-type high-grade fetal lung adenocarcinomas by genetic profiling and transcription factor expression.

The clinicopathological differences among high-grade fetal lung adenocarcinomas completely comprising tumor cells that resemble fetal lung epithelium (pure type) and those with fetal lung-like components admixed with conventional adenocarcinoma cells (mixed type) remain undetermined. Here, we examined the clinicopathological, immunohistochemical, and molecular features of 11 lung adenocarcinomas with fetal lung-like morphology among 3895 consecutive cases of primary lung cancer based on the expression pattern of transcription factors. According to the current WHO classification, two cases (0.05%) were categorized as low-grade fetal adenocarcinoma, two cases (0.05%) were pure-type high-grade fetal adenocarcinoma, five cases (0.1%) were mixed-type high-grade fetal adenocarcinoma, and the remaining two cases (0.05%) were lung adenocarcinoma with high-grade fetal features (fetal lung-like morphology occupied less than 50%). CTNNB1 mutations were exclusively identified in low-grade fetal adenocarcinomas. In contrast, mixed-type high-grade fetal adenocarcinoma or lung adenocarcinoma with high-grade fetal features frequently harbored mitogenic drivers including EGFR mutations. Furthermore, almost all tumor cells expressed CDX2 and HNF4α in both cases of pure-type high-grade fetal lung adenocarcinoma, but lacked TTF-1 positivity. In contrast, TTF-1 was frequently expressed in mixed-type high-grade fetal lung adenocarcinoma and in lung adenocarcinoma with high-grade fetal features. Our data suggest similar prevalence of low-grade fetal lung adenocarcinoma and pure-type high-grade fetal lung adenocarcinoma, and indicate that pure- and mixed-type high-grade fetal lung adenocarcinomas are distinct, with the former akin to low-grade fetal adenocarcinoma with respect to purely embryonic morphology and absence of common lung adenocarcinoma mitogenic drivers, and the latter being genetically and transcriptionally related to conventional lung adenocarcinoma.

Impacts of lipopolysaccharide on fetal lung developmental maturity and surfactant protein B and surfactant protein C protein expression in gestational diabetes mellitus rats.

The rise of bioinformatics based on computer medicine provides a new method to reveal the complex biological data. This experiment is to explore the impacts of lipopolysaccharide on fetal lung developmental maturity and expressions of lung surfactant protein B (SP-B) and lung surfactant protein C (SP-C) in rats with gestational diabetes mellitus (GDM), thereby discussing the mechanism of developmental disorders in rats. Forty-eight conceived female rats were experimental subjects. Twenty-eight rats were randomly selected to construct the GDM models. All conceived rats underwent section on the 21st day of pregnancy. The ultrastructure of alveolar type II epithelial cells and the morphology of lung tissue were observed under a microscope. The protein localization and expression of SP-B and SP-C were determined by immunohistochemistry; the protein levels of SP-B and SP-C were determined by Western blot. Blood glucose and body weight of the GDM group were higher than those of the control group; the number of alveoli and alveolar area in the GDM group was lower than those in the control group; the alveolar interval in the GDM group was significantly higher than that in the control group (P < 0.05). The average absorbance of SP-B and SP-C in fetal lung tissue was significantly lower in the GDM group than that in the control group (P < 0.01). Changes in fetal lung tissue structure of rats were related to SP-B and SP-C, which was one of the main factors that affected the maturation of fetal lung tissue.

Hemi-Clamshell Approach for Fetal Lung Interstitial Tumor Resection in a Neonate: A Case Report.

Fetal lung interstitial tumor (FLIT) is a rare primary lung mass in neonates. Classical incisions, such as posterolateral thoracotomy or median sternotomy, do not provide optimal exposure of the operative field for the resection of pediatric thoracic giant tumors. Herein, we report a rare case of a FLIT in a full-term male neonate, with complete resection achieved using a hemi-clamshell approach, which provided the required visualization of the operative field. The neonate was transferred to our hospital because of mild respiratory distress, which developed 18-hour after normal vaginal delivery. A mass in his right chest, without a midline shift, was observed on chest radiographs. Computed tomography showed a well-circumscribed solid anterior cervicothoracic mass, with a uniform density and no apparent cysts, diagnosed as a primary thoracic giant tumor. Once the patient was clinically stabilized, we proceeded with right upper lobectomy, using a hemi-clamshell approach, full sternotomy, and anterolateral thoracotomy, on postnatal day 22. Histopathologic examination revealed an 8.5 × 6.5 × 4.0 cm solid mass within the right upper lobe, which was diagnosed as a FLIT. His postoperative recovery was uneventful. The patient was followed up for 1 year, with no complaints or symptoms and no postoperative shoulder dysfunction. Gross total resection of primary thoracic giant tumors can be accomplished in neonates with optimal exposure of the chest cavity using a hemi-clamshell approach.

Role of NRF2 in immune modulator expression in developing lung.

After birth, the alveolar epithelium is exposed to environmental pathogens and high O2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPß and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPß, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.

Vimentin regulation of autophagy activation in lung fibroblasts in response to lipopolysaccharide exposure in vitro.

BACKGROUND: The activation and assembly of the NLRP3 inflammasome is dependent on the interaction between NLRP3 and the intermediate filament protein vimentin in an acute respiratory distress syndrome (ARDS) model. We investigated the role of vimentin in this process using human fetal lung (HFL-1) fibroblasts with vimentin transfer genes or gene knockdown and lipopolysaccharide (LPS) intervention. METHODS: HFL-1 cells [con-vector + LPS, vimentin-pCMV3 (VIM-pCMV3), con-siRNA, and vimentin siRNA (VIM-siRNA)] were treated with LPS. An oxidative stress damage assessment, apoptosis analysis, and quantification of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-10 by enzyme linked immunosorbent assay (ELISA) were performed. Immunoblotting was used to reveal the autophagy pathway. RESULTS: We demonstrated that in response to LPS vimentin expression was lower in the HFL-1 cells with the vimentin gene knocked down. Specifically, an increase in oxidative stress, a decrease in mitochondrial membrane potential, or an increase in calcium ion permeability resulted in an increase in the fibroblast apoptosis rate. In addition, the inflammatory response after vimentin gene knockout was upregulated, as indicated by higher levels of TNF-a, IL-1ß, IL-6, and IL-10. Importantly, the mechanism of suppression of vimentin in the lung fibroblasts was caused by a decrease in autophagy, an increase in mitochondrial membrane protein, and a decrease in mitochondrial function, which may contribute to the augmented cellular injury generated during the response to LPS. CONCLUSIONS: This study provides insights into whether vimentin may interfere with the inflammatory cascade by activating the autophagy pathway of mitochondrial lung fibroblasts in the early stage of acute lung injury (ALI).