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Christopher G Wilson

Publications and source records attributed to Christopher G Wilson.

12 recordsLinked to original sources
PubMed2006

Dynamic compression regulates the expression and synthesis of chondrocyte-specific matrix molecules in bone marrow stromal cells.

The overall objective of the present study was to investigate the mechanotransduction of bovine bone marrow stromal cells (BMSCs) through the interactions between transforming growth factor beta1 (TGF-beta1), dexamethasone, and dynamic compressive loading. Overall, the addition of TGF-beta1 increased cell viability, extracellular matrix (ECM) gene expression, matrix synthesis, and sulfated glycosaminoglycan content over basal construct medium. The addition of dexamethasone further enhanced extracellular matrix gene expression and protein synthesis. There was little stimulation of ECM gene expression or matrix synthesis in any medium group by mechanical loading introduced on day 8. In contrast, there was significant stimulation of ECM gene expression and matrix synthesis in chondrogenic media by dynamic loading introduced on day 16. The level of stimulation was also dependent on the medium supplements, with the samples treated with basal medium being the least responsive and the samples treated with TGF-beta1 and dexamethasone being the most responsive at day 16. Both collagen I and collagen II gene expressions were more responsive to dynamic loading than aggrecan gene expression. Dynamic compression upregulated Smad2/3 phosphorylation in samples treated with basal and TGF-beta1 media. These findings suggest that interactions between mechanical stimuli and TGF-beta signaling may be an important mechanotransduction pathway for BMSCs, and they indicate that mechanosensitivity may vary during the process of chondrogenesis.

Animals↗
PubMed2006

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties.

Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase- or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors that were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP- and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the losses of dynamic compression and shear moduli were delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

Aggrecans↗
PubMed2005

Adenosine A2A receptors mediate GABAergic inhibition of respiration in immature rats.

Adenosine is a known inhibitor of respiratory output during early life. In this study we investigated the developmental changes in adenosine A2A-receptor activation on respiratory timing, as well as the relationship between adenosine and GABA. The specific adenosine A2A-receptor agonist CGS-21680 (CGS) or vehicle control was injected into the fourth ventricle of 14-day (n = 9), 21-day (n = 9), and adult (n = 5) urethane-anesthetized rats while diaphragm electromyogram was monitored as an index of respiratory neural output. CGS injection resulted in a decrease in frequency and/or apnea in all 14-day-old rats and in 66% of 21-day-old rats. There was no effect of CGS injection on respiratory timing in adult rats. Prior injection of the GABA(A)-receptor blocker bicuculline at 14 and 21 days eliminated the CGS-induced decrease in frequency and apnea. We conclude from these studies that the inhibitory effect of A2A-receptor activation on respiratory drive is age dependent and is mediated via GABAergic inputs to the inspiratory timing neural circuitry. These findings demonstrate an important mechanism by which xanthine therapy alleviates apnea of prematurity.

Adenosine↗
PubMed2005

An astrocyte toxin influences the pattern of breathing and the ventilatory response to hypercapnia in neonatal rats.

Recent in vitro data suggest that astrocytes may modulate respiration. To examine this question in vivo, we treated 5-day-old rat pups with methionine sulfoximine (MS), a compound that alters carbohydrate and glutamate metabolism in astrocytes, but not neurons. MS-treated pups displayed a reduced breathing frequency (f) in baseline conditions relative to saline-treated pups. Hypercapnia (5% CO(2)) increased f in both groups, but f still remained significantly lower in the MS-treated group. No differences between treatment groups in the responses to hypoxia (8% O(2)) were observed. Also, MS-treated rats showed an enhanced accumulation of glycogen in neurons of the facial nucleus, the nucleus ambiguus, and the hypoglossal nucleus, structures that regulate respiratory activity and airway patency. An altered transfer of nutrient molecules from astrocytes to neurons may underlie these effects of MS, although direct effects of MS upon neurons or upon peripheral structures that regulate respiration cannot be completely ruled out as an explanation.

Animals↗
PubMed2005

Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses.

This review summarizes recent work on two basic processes of central nervous system (CNS) control of cholinergic outflow to the airways: 1) transmission of bronchoconstrictive signals from the airways to the airway-related vagal preganglionic neurons (AVPNs) and 2) regulation of AVPN responses to excitatory inputs by central GABAergic inhibitory pathways. In addition, the autocrine-paracrine modulation of AVPNs is briefly discussed. CNS influences on the tracheobronchopulmonary system are transmitted via AVPNs, whose discharge depends on the balance between excitatory and inhibitory impulses that they receive. Alterations in this equilibrium may lead to dramatic functional changes. Recent findings indicate that excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second-order neurons within the nucleus of the solitary tract (NTS), via a glutamate-AMPA signaling pathway. These neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command to airway effector organs: smooth muscle, submucosal secretory glands, and the vasculature, through intramural ganglionic neurons. The strength and duration of reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs and autocrine-paracrine controlling mechanisms. Downregulation of GABAergic inhibitory influences may result in a shift from inhibitory to excitatory drive that may lead to increased excitability of AVPNs, heightened airway responsiveness, and sustained narrowing of the airways. Hence a better understanding of these normal and altered central neural circuits and mechanisms could potentially improve the design of therapeutic interventions and the treatment of airway obstructive diseases.

Animals↗
PubMed2004

Adenosine A2A receptors interact with GABAergic pathways to modulate respiration in neonatal piglets.

GABA and adenosine contribute to respiratory inhibition in early postnatal life. In this study the adenosine A2A receptor agonist CGS21680 was used to evaluate adenosine receptor specificity and the interrelation of adenosine and GABA in the inhibition of inspiratory drive. In neonatal piglets (n = 10), CGS21680 was injected into the fourth ventricle resulting in apnea and/or decreased burst area and frequency of phrenic discharge. Phrenic burst area decreased to 58.9 +/- 8.6% (S.E.M.) after CGS21680 injection (control = 91.8 +/- 1.0%). Expiratory time increased 261.0 +/- 59.9% after CGS21680 from control (87.7 +/- 2.7%). When bicuculline was injected locally within the rostral ventrolateral medulla (n = 5), or into the fourth ventricle (n = 5), the CGS21680 induced inhibition of phrenic was abolished. To define expression of A2A receptor at the message level (mRNA), we employed in situ hybridization with a digoxigenin-coupled oligonucleotide. Adenosine A2A receptor mRNA was expressed in regions of the medulla oblongata known to contain GABAergic neurons. We conclude that GABAergic inputs affecting respiratory timing and inspiratory drive are modulated by activation of A2A receptors. These findings offer new insight into the mechanism whereby xanthine therapy diminishes apnea of prematurity.

Adenosine↗
PubMed2004

Strain differences in murine ventilatory behavior persist after urethane anesthesia.

Differences in breathing pattern between awake C57BL/6J (B6) and A/J mice are such that A/J mice breathe slower, deeper, and with greater variability than B6. We theorized that urethane anesthesia, by affecting cortical and subcortical function, would test the hypothesis that strain differences require a fully functional neuroaxis. We anesthetized B6 and A/J mice with urethane, placed them in a whole-body plethysmograph, and measured the durations of inspiration and expiration, respiratory frequency (Fr), and peak amplitude during exposure to room air (21% O2), hyperoxia (5 min, 100% O2), hypoxia (5 min, 8% O2), and posthypoxic reoxygenation (5 min, 100% O2). Breathing variability was assessed by calculating the coefficient of variation (CV) and by applying spatial statistics to Poincaré plots constructed from the timing and amplitude data. Even though Fr in anesthetized B6 and A/J mice was greater than that for unanesthetized animals, anesthetized A/J mice still breathed slower, deeper, and with greater variability than B6 mice at rest and during hyperoxia. During the fourth minute of hypoxia, Fr and its CV were not significantly different between strains. Even though Fr was similar between strains immediately after hypoxia, its CV was significantly greater for B6 than A/J mice. Posthypoxic Fr was significantly less than baseline Fr in B6 but not A/J mice, and the CV for posthypoxic Fr was greater for B6 but less for AJ mice compared with baseline CV. This difference in patterning was confirmed by spatial statistical analysis. We conclude that strain-specific differences in respiratory pattern and its variability are robust genetic traits. The neural substrate for these differences, at least partially, exists within subcortical structures generating the breathing pattern.

Anesthetics, Intravenous↗
PubMed2003

A GABAergic inhibitory microcircuit controlling cholinergic outflow to the airways.

GABA is the main inhibitory neurotransmitter that participates in the regulation of cholinergic outflow to the airways. We have tested the hypothesis that a monosynaptic GABAergic circuit modulates the output of airway-related vagal preganglionic neurons (AVPNs) in the rostral nucleus ambiguus by using a dual-labeling electron microscopic method combining immunocytochemistry for glutamic acid decarboxylase (GAD) with retrograde tracing from the trachea. We also determined the effects of blockade of GABAA receptors on airway smooth muscle tone. The results showed that retrogradely labeled AVPNs received a significant GAD-immunoreactive (GAD-IR) terminal input. Out of a pooled total of 3,161 synaptic contacts with retrogradely labeled somatic and dendritic profiles, 20.2% were GAD-IR. GAD-IR terminals formed significantly more axosomatic synapses than axodendritic synapses (P < 0.02). A dense population of GABAergic synaptic contacts on AVPNs provides a morphological basis for potent physiological effects of GABA on the excitability of AVPNs. GAD-IR terminals formed exclusively symmetric synaptic specializations. GAD-IR terminals were significantly larger (P < 0.05) in both length and width than unlabeled terminals synapsing on AVPNs. Therefore, the structural characteristics of certain nerve terminals may be closely correlated with their function. Pharmacological blockade of GABAA receptors within the rostral nucleus ambiguus increased activity of putative AVPNs and airway smooth muscle tone. We conclude that a tonically active monosynaptic GABAergic circuit utilizing symmetric synapses regulates the discharge of AVPNs.

Animals↗
PubMed2003

Sleep networks and the anatomic and physiologic connections with respiratory control.

A central neuronal network regulates airway functions from the nares to the bronchioles and is an integral component of a regulatory system for brain control of breathing and airway patency during wakefulness and sleep. This network, components of which include sleep generating sites and monoaminergic neurons in particular, is characterized by reciprocal interconnections, parallel organization, and state-dependent activity patterns, which can be influenced by both genes and environment. Sleep generating neurons are interconnected with the monoaminergic containing cells to the extent that sleep-related changes in upper and lower airway patency could be due to inhibitory influences of sleep-activated neurons on serotonergic and noradrenergic producing cells. Neurochemical studies and physiologic experiments show that serotonergic and noradrenergic producing cells can make parallel pathways, directly innervating the hypoglossal motor cells regulating upper airway dilating muscles, and vagal preganglionic neurons providing cholinergic outflow to the airways. Activation of serotonergic and noradrenergic cell groups preferentially increases activity of the genioglossus muscle, but diminishes cholinergic outflow to the airways. Hence, inhibition of monoaminergic neurons during sleep may lead to a decrease in upper airway dilating forces and an elevation of cholinergic outflow to the airways. Qualitatively different responses of hypoglossal and airway-related vagal preganglionic neurons (AVPNs) occur in response to endogenously released serotonin or norepinephrine and could be related to its simultaneous action on different serotonin or norepinephrine receptor subtypes. Dysfunction of monaminergic cell groups during sleep may predispose to upper airway occlusion as well as bronchoconstriction. Pharmacological corrections of alterations of these transmitter specific converging systems might be an avenue for treatment of sleep related airway disorders such as sleep apnea and worsening of asthma.

Animals↗
PubMed2002

Modeling the dynamic composition of engineered cartilage.

Mathematical models to describe extracellular matrix (ECM) deposition and scaffold degradation in cell-polymer constructs for the design of engineered cartilage were developed and validated. The ECM deposition model characterized a product-inhibition mechanism in the concentration of cartilage molecules, collagen and glycosaminoglycans (GAG). The scaffold degradation model used first-order kinetics to describe hydrolysis (not limited by diffusion) of biodegradable polyesters, polyglycolic acid and polylactic acid. Each model was fit to published accumulation and degradation data. As experimental validation, cell-polymer constructs (n=24) and unseeded scaffolds (n=24) were cultured in vitro. Biochemical assays for ECM content and measurements of scaffold mass were performed at 1, 2, 4, 6, 8, or 10 weeks (n=8 per time point). The models demonstrated a strong fit with published data and experimental results (R(2)=0.75 to 0.99) and predicted the temporal total construct mass with reasonable accuracy (30% RMS error). This approach can elucidate mechanisms governing accumulation/degradation and may be coupled with structure-function relationships to describe time-dependent changes in construct elastic properties.

Animals↗
PubMed2002

Periodicity, mixed-mode oscillations, and quasiperiodicity in a rhythm-generating neural network.

We studied patterns of oscillatory neural activity in the network that generates respiratory rhythm in mammals. When isolated in vitro, this network spontaneously generates an inspiratory-related motor rhythm, with stable amplitude from cycle to cycle. We show that progressively elevating neuronal excitability in vitro causes periodic modulation of this inspiratory rhythm, evoking (in order): mixed-mode oscillations, quasiperiodicity, and ultimately disorganized aperiodic activity. Thus, the respiratory network oscillator follows a well defined sequence of behavioral states characterized by dynamical systems theory, which includes discrete stages of periodic and quasiperiodic amplitude modulation and progresses (according to theory) to aperiodic chaos-like behavior. We also observed periodic, mixed-mode periodic, and quasiperiodic breathing patterns in neonatal rodents and human infants in vivo, suggesting that breathing patterns generated by the intact nervous system reflect deterministic neural activity patterns in the underlying rhythm-generating network.

Animals↗