scholarly journals Fetal and Neonatal Exposure to Nicotine Disrupts Postnatal Lung Development in Rats: Role of VEGF and Its Receptors

2011 ◽  
Vol 30 (2) ◽  
pp. 244-252 ◽  
Author(s):  
Maria A. Petre ◽  
Jim Petrik ◽  
Russ Ellis ◽  
Mark D. Inman ◽  
Alison C. Holloway ◽  
...  
Keyword(s):  
Lung Development ◽  
Female Rats ◽  
Neonatal Exposure ◽  
Nicotine Exposure ◽  
Smoking During Pregnancy ◽  
Vegf Signaling ◽  
Lung Structure ◽  
And Function ◽  
Postnatal Lung Development ◽  
Endothelial Growth Factor

Many women are unable to quit smoking during pregnancy and therefore are prescribed drugs, including nicotine (nicotine replacement therapy [NRT]), to aid with smoking cessation. However, the consequences to the offspring of pregnant NRT users have not been well studied. The goals of this study were to determine the consequences of fetal and neonatal exposure to nicotine on lung development and function. Female rats were exposed to nicotine for 2 weeks prior to mating until weaning. Lungs were collected from saline and nicotine-treated rats from birth to adulthood to assess postnatal lung structure and function. Although nicotine exposure altered alveolarization at weaning, an effect that resolved by adulthood, it did not affect lung function at any of the ages investigated. However, nicotine exposure significantly decreased lung vascularization. The current study suggests that perinatal exposure to nicotine alters lung development, an effect which may be mediated via decreased vascular endothelial growth factor (VEGF) signaling.

Abstract 215: Allogeneic MSCs Improve Endothelial Function in Patients with Dilated Cardiomyopathy via an SDF-1α-mediated Mechanism and the Suppression of Pathologic Cytokines

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Courtney Premer ◽  
Ivonne H Schulman ◽  
Wayne Balkan ◽  
Valeria Porras ◽  
Michael A Bellio ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Dilated Cardiomyopathy ◽  
Necrosis Factor Alpha ◽  
Allogeneic Mscs ◽  
Vegf Signaling ◽  
Factor Alpha ◽  
And Function ◽  
Endothelial Growth Factor

Endothelial dysfunction is central to the pathophysiology of heart failure, including dilated cardiomyopathy (DCM). Current drug therapies are unable to halt the progression of DCM, compelling the emergence of novel stem cell therapy approaches. Mesenchymal stem cells (MSCs) are pro-angiogenic, immunomodulatory, antifibrotic, and stimulate endogenous endothelial progenitor (EPC) proliferation and function, thus having the potential to ameliorate endothelial dysfunction. We demonstrated that patients with DCM who received allogeneic MSCs had a significant improvement in endothelial function 3-months post treatment, whereas patients who received autologous MSCs had no improvement. Therefore, we hypothesized that allogeneic MSCs preferentially improve endothelial function via a mechanism involving the suppression of pathologic levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 alpha (SDF-1α), and tumor necrosis factor alpha (TNFα). Accordingly, patient serum VEGF and TNFα were measured at baseline and 3 months post MSC treatment. In vitro, MSC secretion of SDF-1α and TNFα was also measured. Our results show that patients with DCM had elevated levels of VEGF (n=21, 581.2±812.2 pg/mL) and TNFα (n=15, 22±9.4 pg/mL) at baseline, and that only allogeneic MSCs were able to restore these levels toward normal (VEGF: n=10, Δ-267.1±252.1, P=0.01; TNFα: n=8, Δ-7.1±3.1 pg/mL, P=0.0005). While there was no difference in TNFα secretion by autologous or allogeneic MSCs (0.01±0.14 vs. 0.4±0.6 pg/mL), autologous MSCs secreted significantly higher levels of SDF-1α compared to allogeneic MSCs (n=12, 79.3±16.7 vs. 14.2±9.4 pg/mL, P=0.0001). In vitro secreted SDF-1α and serum VEGF and TNFα levels correlated with EPC bioactivity (ΔSDF-1α to ΔEPC-CFUs, R=-0.9, P<0.0001; ΔVEGF to ΔEPC-CFUs, R=-0.7, P=0.001; ΔTNFα to ΔEPC-CFUs, R=-0.6, P=0.01). These findings reveal a novel mechanism by which allogeneic MSCs secrete physiologic levels of SDF-1α resulting in physiologic levels of VEGF signaling, reduced TNFα, increased EPC bioactivity, and improved endothelial function. These findings have important clinical and biological implications for the use of MSCs in patients with DCM.

scholarly journals Tenascin-C inactivation impacts lung structure and function beyond lung development

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sandrine Gremlich ◽  
Matthias Roth-Kleiner ◽  
Lucile Equey ◽  
Kleanthis Fytianos ◽  
Johannes C. Schittny ◽  
...  
Keyword(s):  
Lung Development ◽  
Structure And Function ◽  
Tenascin C ◽  
Lung Structure ◽  
And Function

scholarly journals The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

2019 ◽  
Vol 116 (28) ◽  
pp. 14174-14180 ◽  
Author(s):  
Ameer L. Elaimy ◽  
John J. Amante ◽  
Lihua Julie Zhu ◽  
Mengdie Wang ◽  
Charlotte S. Walmsley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Strand Break ◽  
Vegf Receptor ◽  
Vegf Signaling ◽  
Dna Double Strand Break ◽  
Essential Enzyme ◽  
And Function ◽  
Platinum Chemotherapy ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF–NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF–NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF–NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ–TEAD transcriptional target. We also discovered that VEGF–NRP2–YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF–NRP2 or YAP/TAZ. These findings reveal roles for VEGF–NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF–NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

scholarly journals Leptin Matures Aspects of Lung Structure and Function in the Ovine Fetus

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 395-404 ◽  
Author(s):  
Miles J. De Blasio ◽  
Maria Boije ◽  
Sarah L. Kempster ◽  
Gordon C. S. Smith ◽  
D. Stephen Charnock-Jones ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Structure And Function ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Lung Structure ◽  
Lung Compartment ◽  
Ovine Fetus ◽  
And Function ◽  
Endothelial Growth Factor

Abstract In human and ovine fetuses, glucocorticoids stimulate leptin secretion, although the extent to which leptin mediates the maturational effects of glucocorticoids on pulmonary development is unclear. This study investigated the effects of leptin administration on indices of lung structure and function before birth. Chronically catheterized singleton sheep fetuses were infused iv for 5 days with either saline or recombinant ovine leptin (0.5 mg/kg · d leptin (LEP), 0.5 LEP or 1.0 mg/kg · d, 1.0 LEP) from 125 days of gestation (term ∼145 d). Over the infusion, leptin administration increased plasma leptin, but not cortisol, concentrations. On the fifth day of infusion, 0.5 LEP reduced alveolar wall thickness and increased the volume at closing pressure of the pressure-volume deflation curve, interalveolar septal elastin content, secondary septal crest density, and the mRNA abundance of the leptin receptor (Ob-R) and surfactant protein (SP) B. Neither treatment influenced static lung compliance, maximal lung volume at 40 cmH2O, lung compartment volumes, alveolar surface area, pulmonary glycogen, protein content of the long form signaling Ob-Rb or phosphorylated signal transducers and activators of transcription-3, or mRNA levels of SP-A, C, or D, elastin, vascular endothelial growth factor-A, the vascular endothelial growth factor receptor 2, angiotensin-converting enzyme, peroxisome proliferator-activated receptor γ, or parathyroid hormone-related peptide. Leptin administration in the ovine fetus during late gestation promotes aspects of lung maturation, including up-regulation of SP-B.

Dexamethasone and epinephrine stimulate surfactant secretion in type II cells of embryonic chickens

2001 ◽  
Vol 281 (3) ◽  
pp. R770-R777 ◽  
Author(s):  
Lucy C. Sullivan ◽  
Sandra Orgeig
Keyword(s):  
Lung Development ◽  
Pulmonary Surfactant ◽  
Egg Laying ◽  
Lung Fibroblasts ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Lung Structure ◽  
Cellular Pathways ◽  
And Function

Pulmonary surfactant (PS), a mixture of phospholipids and proteins secreted by alveolar type II cells, functions to reduce the surface tension in the lungs of all air-breathing vertebrates. Here we examine the control of PS during lung development in a homeothermic egg-laying vertebrate. In mammals, glucocorticoids and autonomic neurotransmitters contribute to the maturation of the surfactant system. We examined whether dexamethasone, epinephrine, and carbamylcholine hydrochloride (agonist for acetylcholine) increased the amount of PS secreted from cultured type II cells of the developing chicken lung. In particular, we wanted to establish whether dexamethasone would increase PS secretion through a process involving lung fibroblasts. We isolated and cocultured type II cells and lung fibroblasts from chickens after 16, 18, and 20 days of incubation and from hatchlings ( day 21). Epinephrine stimulated phosphatidylcholine (PC) secretion at all stages, whereas dexamethasone stimulated secretion of PC at days 16 and 18. Carbamylcholine hydrochloride had no effect at any stage. This is the first study to establish the existence of similar cellular pathways regulating the development of surfactant in chickens and eutherian mammals, despite the vastly different birthing strategies and lung structure and function.

scholarly journals Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1949
Author(s):  
Yawen Dong ◽  
Jeffrey Sum Lung Wong ◽  
Ryohichi Sugimura ◽  
Ka-On Lam ◽  
Bryan Li ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Advanced Hcc ◽  
Oncogenic Pathways ◽  
Vegf Pathway ◽  
And Function ◽  
Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

scholarly journals Lung ultrasound presentation of COVID-19 patients: phenotypes and correlations

2021 ◽  
Author(s):  
Gianmarco Secco ◽  
◽  
Marzia Delorenzo ◽  
Francesco Salinaro ◽  
Caterina Zattera ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Lung Ultrasound ◽  
Structure And Function ◽  
General Ward ◽  
Prognostic Role ◽  
Interstitial Syndrome ◽  
Lung Structure ◽  
And Function ◽  
The Relationship

AbstractBedside lung ultrasound (LUS) can play a role in the setting of the SarsCoV2 pneumonia pandemic. To evaluate the clinical and LUS features of COVID-19 in the ED and their potential prognostic role, a cohort of laboratory-confirmed COVID-19 patients underwent LUS upon admission in the ED. LUS score was derived from 12 fields. A prevalent LUS pattern was assigned depending on the presence of interstitial syndrome only (Interstitial Pattern), or evidence of subpleural consolidations in at least two fields (Consolidation Pattern). The endpoint was 30-day mortality. The relationship between hemogasanalysis parameters and LUS score was also evaluated. Out of 312 patients, only 36 (11.5%) did not present lung involvment, as defined by LUS score < 1. The majority of patients were admitted either in a general ward (53.8%) or in intensive care unit (9.6%), whereas 106 patients (33.9%) were discharged from the ED. In-hospital mortality was 25.3%, and 30-day survival was 67.6%. A LUS score > 13 had a 77.2% sensitivity and a 71.5% specificity (AUC 0.814; p < 0.001) in predicting mortality. LUS alterations were more frequent (64%) in the posterior lower fields. LUS score was related with P/F (R2 0.68; p < 0.0001) and P/F at FiO2 = 21% (R2 0.59; p < 0.0001). The correlation between LUS score and P/F was not influenced by the prevalent ultrasound pattern. LUS represents an effective tool in both defining diagnosis and stratifying prognosis of COVID-19 pneumonia. The correlation between LUS and hemogasanalysis parameters underscores its role in evaluating lung structure and function.

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