ABSTRACT
Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover ...that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target‐derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, NT4−/− mice were protected from allergen‐induced mucus overproduction and changes along the nerve–PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in NT4−/− mice after early life allergen exposure. Together, our findings provide the first evidence for NT4‐dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve–PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma.—Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus‐Randall, V. E., Ai, X. Early life allergen‐induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 31, 4117–4128 (2017). www.fasebj.org—Barrios, Juliana, Patel, Kruti R., Aven, Linh, Achey, Rebecca, Minns, Martin S., Lee, Yoonjoo, Trinkaus‐Randall, Vickery E., Ai, Xingbin Early life allergen‐induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 31, 4117–4128 (2017)
Pulmonary neuroendocrine cells (PNECs) have crucial roles in airway physiology and immunity by producing bioactive amines and neuropeptides (NPs). A variety of human diseases exhibit PNEC ...hyperplasia. Given accumulated evidence that PNECs represent a heterogenous population of cells, we investigate how PNECs differ, whether the heterogeneity is similarly present in mouse and human cells, and whether specific disease involves discrete PNECs. Herein, we identify three distinct types of PNECs in human and mouse airways based on single and double positivity for TUBB3 and the established NP markers. We show that the three PNEC types exhibit significant differences in NP expression, homeostatic turnover, and response to injury and disease. We provide evidence that these differences parallel their distinct cell of origin from basal stem cells (BSCs) or other airway epithelial progenitors.
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•Rare TUBB3+ solitary pulmonary neuroendocrine cells reside in the conducting airway•Airway basal stem cells generate TUBB3+ pulmonary neuroendocrine cells•TUBB3 is required for cellular protrusions of pulmonary neuroendocrine cells•TUBB3+ pulmonary neuroendocrine cells are amplified in infant diseases
Mou et al. find that the conducting airway harbors three distinct types of pulmonary neuroendocrine cells, distinguished by gene expression, cell of origin, and existence in solitary and clustered configurations. The expansion of PNEC types is selectively associated with NEHI and SIDS, suggesting their contribution to disease.
Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung ...cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.
Hypothalamic hamartomas are congenital lesions that typically present with gelastic seizures, refractory epilepsy, neurodevelopmental delay, and severe cognitive impairment. Surgical procedures have ...been reported to be effective in removing the hamartomas, however, they are associated with significant morbidity. Therefore, it is not considered a safe therapeutic modality. Image-guided robotic radiosurgery (CyberKnife® Radiosurgery System) has been shown to provide good outcomes without lasting complications.
This series of cases describes the clinical, radiological, radiotherapeutic, and postsurgical outcomes of five patients with epileptic encephalopathies secondary to hypothalamic hamartomas who were treated with CyberKnife®.
All patients exhibited refractory epilepsy with gelastic seizures and were unsuitable candidates for surgical resection The prescribed dose ranged between 16 and 25 Gy, delivered in a single fraction for four patients and five fractions for one patient while adhering strictly to visual pathway constraints. After radiosurgery, four patients maintained seizure control (one with an Engel class Ia, three with an Engel class 1d), and another presented sporadic, nondisabling gelastic seizures (with an Engel class IIa). After 24-26 months of follow-up, in three patients, their intelligence quotient scores increased. No complications were reported.
This report suggests that Cyberknife may be a good option for treating hypothalamic hamartoma, particularly in cases where other noninvasive alternatives are unavailable. Nevertheless, additional studies are essential in order to evaluate the effectiveness of the technique in these cases.
The regeneration of alveolar epithelial cells is a critical aspect of alveolar reorganization after lung injury. Although alveolar Type II (AT2) cells have been described as progenitor cells for ...alveolar epithelia, more remains to be understood about how their progenitor cell properties are regulated. A nuclear, chromatin-bound green fluorescence protein reporter (H2B-GFP) was driven from the murine surfactant protein-C (SPC) promoter to generate SPC H2B-GFP transgenic mice. The SPC H2B-GFP allele allowed the FACS-based enrichment and gene expression profiling of AT2 cells. Approximately 97% of AT2 cells were GFP-labeled on Postnatal Day 1, and the percentage of GFP-labeled AT2 cells decreased to approximately 63% at Postnatal Week 8. Isolated young adult SPC H2B-GFP(+) cells displayed proliferation, differentiation, and self-renewal capacity in the presence of lung fibroblasts in a Matrigel-based three-dimensional culture system. Heterogeneity within the GFP(+) population was revealed, because cells with distinct alveolar and bronchiolar gene expression arose in three-dimensional cultures. CD74, a surface marker highly enriched on GFP(+) cells, was identified as a positive selection marker, providing 3-fold enrichment for AT2 cells. In vivo, GFP expression was induced within other epithelial cell types during maturation of the distal lung. The utility of the SPC H2B-GFP murine model for the identification of AT2 cells was greatest in early postnatal lungs and more limited with age, when some discordance between SPC and GFP expression was observed. In adult mice, this allele may allow for the enrichment and future characterization of other SPC-expressing alveolar and bronchiolar cells, including putative stem/progenitor cell populations.
Neurotrophins in Asthma Barrios, Juliana; Ai, Xingbin
Current allergy and asthma reports,
02/2018, Letnik:
18, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
Asthma is a chronic airway disease that affects more than 300 million people worldwide. Current treatment focuses on symptomatic relief by temporally dampening inflammation and ...relaxing the airway. Novel combative strategies against asthma and hopefully a cure are yet to be developed. The goal of this review is to summarize recent literature on neurotrophins (NTs) in experimental models and clinical settings of asthma research.
Recent Findings
We highlight studies of early phases of asthma that collectively reveal a profound impact of elevated NT levels following initial detrimental insults on long-term airway dysfunction.
Summary
We hope this review will foster insights into the complex interaction between NTs, nerves, immune cells, and airway structural cells during a critical time window of development and disease susceptibility. Future studies are required to better understand the role of NTs in asthma pathophysiology and to evaluate whether NTs and their receptors may serve as new drug targets.
Objetivo: Caracterizar los pacientes diagnosticados con tumores del sistema nervioso central en el Instituto Neurológico de Colombia durante el periodo 2010-2015. Métodos: Estudio descriptivo ...retrospectivo. Para los tumores primarios se usó la clasificación de la Organización Mundial de la Salud y para los metastásicos se usó la Clasificación Internacional de Enfermedades en Oncología. Resultados: Se identificaron 288 pacientes, 194 de ellos con tumores primarios y 94 tumores metastásicos. No se lograron clasificar los tumores primarios en el 23,7 % de los casos y para los metastásicos no se obtuvo la clasificación morfológica (histológica) en el 35,1 % de los casos. Los hombres presentaron con mayor frecuencia tumores de comportamiento maligno tipo glioblastoma NEO (no especificado de otra manera) (14,9 %) y en las mujeres predominaron los tumores de comportamiento benigno tipo meningioma (23,2 %). En mayores de 65 años, tanto el glioblastoma NEO como el meningioma fueron más frecuentes en mujeres con 17,4 % y 28,3 %, respectivamente. Entre los pacientes con tumores metastásicos, de acuerdo con la clasificación topográfica, los tumores primarios más frecuentes se localizaron en pulmón (39,4 %) y mama (17 %). No se identificó el sitio primario de metástasis en el 11,7 % de los casos. La histología más comúnmente identificada fue el adenocarcinoma (14,9 %), seguido del carcinoma (8,5 %). Conclusiones: Para una vigilancia efectiva de la enfermedad es necesario realizar un monitoreo epidemiológico y clínico de tumores primarios y metastásicos, mediante el uso de registros institucionales de cáncer incluyendo datos topográficos, histológicos y moleculares, según disponibilidad.
Inflammation of the airway involves the recruitment of highly active immune cells to combat and clear microbes and toxic factors; however, this inflammatory response can result in unintended damage ...to lung tissue. Tissue damage resulting from inflammation is often mitigated by resolving factors that limit the scope and duration of the inflammatory response. Both inflammatory and resolving processes require the actions of a vast array of lipid mediators that can be rapidly synthesized through a variety of airway resident and infiltrating immune cells. Eicosanoids and endocannabinoids represent two major classes of lipid mediators that share synthetic enzymes and have diverse and overlapping functions. This review seeks to provide a summary of the major bioactive eicosanoids and endocannabinoids, challenges facing researchers that study them, and their roles in modulating inflammation and resolution. With a special emphasis on cystic fibrosis, a variety of therapeutics are discussed that have been explored for their potential anti‐inflammatory or proresolving impact toward alleviating excessive airway inflammation and improving lung function.
Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue ...inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.
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•Sympathetic innervation in the lung undergoes a dopaminergic-to-adrenergic transition•Dopamine signals through DRD4 in CD4+ T cells to induce a Th2 phenotype•Dopaminergic nerves in the early lung foster susceptibility to allergic inflammation
Children are more prone to developing allergic asthma than adults. Wang et al. find that sympathetic nerves undergo a dopaminergic-to-adrenergic transition during post-natal development of the lung. Dopamine signaling in CD4+ T cells promotes a Th2 phenotype, which makes young mice more susceptible to allergy. These findings provide an age-related mechanism underlying the susceptibility of the young to allergic inflammation.
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