Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases.
Neuroinflammation plays a central role in the neuropathogenesis of a wide-spectrum of neurologic and psychiatric disease, but current neuroimaging methods to detect and characterize neuroinflammation are limited. We explored the sensitivity of quantitative multi-compartment diffusion MRI, and specifically neurite orientation dispersion and density imaging (NODDI), to detect changes in microglial density in the brain. Monte Carlo simulations of water diffusion using a NODDI acquisition scheme were performed to measure changes in a virtual MRI signal following modeled cellular changes within the extra-neurite space. 12-week-old C57BL/6J male mice ( n = 48; 24 control, 24 treated with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622) were sacrificed at 0, 1, 3, and 7 days following withdrawal of CSF1R inhibition and were imaged ex-vivo to obtain measures of the orientation dispersion index (ODI). Following imaging, all brains were immunostained with Iba-1, NeuN, and GFAP for quantitative fluorescence microscopy. Cell populations were calculated with the ImageJ particle analyzer tool; correlation between microglial density and mean ODI values were calculated with Kendall's tau. Monte Carlo simulations demonstrate the sensitivity and positive correlation of ODI to increased occupancy in the extra-neurite space. Commensurate with our simulation data, ex-vivo NODDI imaging demonstrates an increase in ODI as microglia repopulate the brain following the withdrawal of CSF1R inhibition. Quantitative immunofluorescence of microglial density reveals that microglial density is positively correlated with ODI and greater hindered diffusion in the extra-neurite space (τ = 0.386, p < 0.05). Our results demonstrate that clinically feasible multi-compartment diffusion weighted imaging techniques such as NODDI are sensitive to microglial density and the cellular changes associated with microglial activation and highlights its potential to improve clinical diagnostic accuracy, patient risk stratification, and therapeutic monitoring of neuroinflammation in neurologic and psychiatric disease.
Ecto-5¢-nucleotidase (CD73), a cell surface protein that hydrolyzes extracellular AMP into adenosine and phosphate, is overexpressed in many solid tumors. In this study, we tested the hypothesis that increased CD73 may promote tumor progression by examining the effect of CD73 suppression via RNA interference and CD73 overexpression on tumor growth in vivo and in vitro. Using digitized whole-body images, plate clone forming assay and TUNEL assay in frozen tissue sections, we found that the cell growth rate was significantly lower in vivo and in vitro after CD73 suppression and late apoptosis was much higher in xenograft tumors developed from the CD73-siRNA transfected MB-MDA-231 clone (P1). By flow cytometry, the P1 cell cycle was arrested in the G0/G1 phase. Moreover, Bcl-2 was downregulated, while Bax and caspase-3 were upregulated with CD73 suppression. CD73 inhibitor a,b-methylene adenosine-5¢-disphosphate (APCP) functioned similarly with RNAimediated CD73 suppression. In addition, in transfected MCF-7 cells, we found that CD73 overexpression increased cell viability and promoted cell cycle progression, depending on its enzyme activity. More intriguingly, CD73 overexpression in MCF-7 breast cancer cells produces a tumorigenic phenotype. We conclude that CD73 plays an important role in breast cancer growth by affecting cell cycle progression and apoptosis. (Cancer Sci 2010; 101: 2561-2569 B reast cancer develops in 14% of women and is a leading cause of cancer death in women around the world.(1)Understanding the molecular mechanisms of breast carcinoma progression is important for effective treatments. Ecto-5¢-nucleotidase (CD73) is a 70 kDa glycosylated protein that is bound to the outer surface of the plasma membrane by a glycosyl phosphatidyl inositol anchor and co-localized with detergent-resistant and glycolipid-rich membrane sub-domains called lipid rafts.(2) CD73 hydrolyzes extracellular AMP into adenosine and phosphate. Adenosine, a proliferative factor, acting through Gprotein coupled receptors, produces a spectrum of physiological functions.(3) In addition, it causes tumor growth, angiogenesis and immune suppression.(4) CD73 upregulation is associated with a highly invasive cancer phenotype, drug resistance and tumor-promoting functions.(5) In addition to acting as a hydrolytic enzyme to generate adenosine, CD73 may serve as an adhesive molecule and interact with extracellular matrix glycoprotein, such as fibronectin and laminin, to produce cancer-invasive properties.(6) Bavaresco et al. (7) reported that CD73 mediated glioma cell proliferation depends upon adenosine. Furthermore, CD73 is overexpressed in the progression of many human solid tumors, such as breast cancer, (8,9) papillary thyroid carcinomas, (10) melanoma (11) and prostate cancer. (12) All these factors implicate the crucial role of CD73 in tumorigenesis. To date, our knowledge on the mechanisms of CD73 on tumor growth is still limited. Previously, we showed that CD73 may promote metastasis by facilitating the migration, adhesion and i...
Angiogenesis is essential for tumor growth, progression and metastasis. Studies indicate that expression and activity of ecto-5'-nucleotidase (CD73) are elevated in metastatic carcinomas. Our previous studies found that angiogenesis of tumor xenografts was decreased when the activity of CD73 in cancer cells was inhibited, implying that this enzyme is involved in tumor angiogenesis. To elucidate the mechanism, we investigated CD73 influence on tumor angiogenesis in both in vitro assays and in tumor bearing mice. We found that capillary-like structures were formed more in CD73(+/+) pulmonary microvascular endothelial cells (PMECs) than CD73(-/-) PMECs, and this was more pronounced when the cells were cultured in cancer-conditioned medium. Meanwhile, CD73 decreased endothelial cells adhesion to collagen IV and promoted migration. Additionally, the extent of tumor angiogenesis and the size of tumors were greater in CD73(+/+) mice than in CD73(-/-) mice. Thus, we concluded that CD73 can promote endothelial cells forming new vessels in cancer condition, facilitating tumor growth and hematogenous metastasis.
A mechanosensory unit is a functional unit that contains multiple receptors (or encoders) with different characteristics, including rapidly adapting receptors, slowly adapting receptors, and deflation-activated-receptors. Each is capable of sensing different aspects of lung mechanics. The sensory unit is both a transducer and a processor. Significant information integration occurs at the intra-encoder and inter-encoder levels. Within an encoder, the information is encoded as analog signals and integrated by amplitude modulation. Information from each single stretch-activated channel is processed through several levels of temporal and spatial summation, producing a generator potential that encodes averaged overall information within the encoder. This analog signal is transformed into a digital signal in the form of action potentials that are encoded as frequency (frequency modulation). These all-or-none propagated action potentials from different encoders interact through a competitive selection mechanism. Such inter-encoder interaction may occur at several levels, because of the fractal nature of the sensory unit. Inter-encoder interaction retains representative information but eliminates redundant information, resulting in the final output to the central nervous system, where multiple decoders specific for different variables decipher the encoded information for further processing.
To identify the role and to explore the mechanism of extracellular 5'-nucleotidase (CD73) in human breast cancer growth, CD73 expression was measured firstly in breast cancer tissues and cell lines, and then interfered with or over-expressed by recombinant lentivirus in cell lines. Impacts of CD73 on breast cancer cell proliferation and cell cycle were investigated with colony formation assay, CCK-8 and flow cytometry. The relationship between CD73 and AKT/GSK-3β/β-catenin pathway was assessed with adenosine, adenosine 2A receptor antagonist (SCH-58261), adenosine 2A receptor agonist (NECA), CD73 enzyme inhibitor (APCP) and Akt inhibitor (MK-2206). Moreover, the effect of CD73 on breast cancer growth in vivo was examined with human breast cancer transplanting model of nude mice. The results showed that the expression of CD73 was high in breast cancer tissues and increased with advanced tumor grades and lympho-node status. CD73 expression was higher in more malignant cells, and CD73 overexpression promoted breast cancer cell proliferation in both in vivo and in vitro. It activated AKT/GSK-3β/β-catenin/cyclinD1 signaling pathway through CD73 enzyme activity and other mechanism.
Excessive, binge alcohol drinking is a potent and pernicious obstacle to treating alcohol use disorder (AUD), and heavy-drinking humans are responsible for much of the substantial costs and harms of AUD. Thus, identifying key mechanisms that drive intake in higher-drinking individuals may provide important, translationally useful therapeutic interventions. Orexin-1-receptors (Ox1Rs) promote states of high motivation, and studies with systemic Ox1R inhibition suggest a particular role in individuals with higher intake levels. However, little has been known about circuits where Ox1Rs promote pathological intake, especially excessive alcohol consumption. We previously discovered that binge alcohol drinking requires Ox1Rs in medial nucleus accumbens shell (Shell), using two-bottle-choice Drinking-in-the-Dark (2bc-DID) in adult, male C57BL/6 mice. Here, we show that Shell Ox1Rs promoted intake during intermittent-access alcohol drinking as well as 2bc-DID, and that Shell inhibition with muscimol/baclofen also suppressed 2bc-DID intake. Importantly, with this large data set, we were able to demonstrate that Shell Ox1Rs and overall activity were particularly important for driving alcohol consumption in higher-drinking individuals, with little overall impact in moderate drinkers. Shell inhibition results were compared with control data combined from drug treatments that did not reduce intake, including NMDAR or PKC inhibition in Shell, Ox1R inhibition in accumbens core, and systemic inhibition of dopamine-1 receptors; these were used to understand whether more specific Shell Ox1R contributions in higher drinkers might simply result from intrinsic variability in mouse drinking. Ineffectiveness of Shell inhibition in moderate-drinkers was not due to a floor effect, since systemic baclofen reduced alcohol drinking regardless of basal intake levels, without altering concurrent water intake or saccharin consumption. Finally, alcohol intake in the first exposure predicted consumption levels weeks later, suggesting that intake level may be a stable trait in each individual. Together, our studies indicate that Shell Ox1Rs are critical mediators of binge alcohol intake in higher-drinking individuals, with little net contribution to alcohol drinking in more moderate bingers, and that targeting Ox1Rs may substantially reduce AUD-related harms.
Respiratory response to selective activation of vagal afferents in the peripheral airways was investigated in anesthetized, open-chest, and artificially ventilated rabbits. Phrenic activity was used as an index of central respiratory drive before and after injection of hypertonic saline (8.1%, 0.1 ml) into the periphery of the lung to stimulate the afferents. The amplitude of “integrated” phrenic activity and phrenic burst rate increased by 19 ± 3.4 and 53.7 ± 12.7% ( n = 23; P < 0.001), respectively. The response peaked at 5.5 ± 1.6 s and returned to the baseline at 7 min (median) after the injection. The magnitude of the response was positively related to the concentration of injected NaCl. The response could not be elicited by injection of normal saline and was abolished by vagotomy. Because artificial ventilation caused phrenic activity to be entrained with the ventilator, respiratory drive was further assessed after the ventilator was stopped. Again, neural hyperpnea and tachypnea were observed. Because activation of a small fraction of the pulmonary peripheral afferents resulted in vigorous stimulation of respiratory drive, we speculate that initiation of this reflex may contribute to hyperpnea and tachypnea under both physiological and pathophysiological conditions.
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