Publications by authors named "Michael R Van Scott"

Article Synopsis
  • GAL-021 is a new drug that enhances breathing and counters the respiratory depression caused by opioids like morphine, without affecting pain relief in rats.
  • The study involved various methods to evaluate GAL-021's effects on ventilation, opioid analgesia, and blood pressure in both rodents and nonhuman primates.
  • Results showed GAL-021 primarily works through the carotid body by inhibiting specific potassium channels, indicating its potential for treating breathing disorders related to opioid use and conditions like sleep apnea.
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Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways.

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Current husbandry and care guidelines for laboratory animals recommend social housing for nonhuman primates and all other social species. However, not all individuals of a social species are compatible, which can lead to psychosocial stress on certain members. Because stress affects immune responses, we undertook the present study to determine whether psychosocial stress associated with changes in the group housing of nonhuman primates affected allergic responses in a nonhuman primate model of allergic asthma.

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Background: Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible.

Objective: Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment.

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Asthma is often associated with cardiovascular complications, and recent observations in animal models indicate that induction of pulmonary allergic inflammation increases susceptibility of the myocardium to ischemia and reperfusion injury. In this study, we used a murine model of allergen sensitization in which aspiration of allergen induces pulmonary and systemic inflammation, to test the hypothesis that pulmonary exposure to allergen alters vascular relaxation responses. BALB/C mice were sensitized by intraperitoneal injection of ragweed and challenged by intratracheal instillation of allergen.

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Circadian rhythm is expressed in most organisms, and many functions and parameters in the immune system are associated with time-of-day. However, it is largely unknown if local circadian clocks in immune cells directly control physiological outcomes. We hypothesized that a circadian clock in murine bone marrow derived mast cells (BMMCs) modulates IgE-dependent activation in vitro.

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Nocturnal bronchoconstriction is a common symptom of asthma in humans, but is poorly documented in animal models. Thoracoabdominal asynchrony (TAA) is a noninvasive clinical indication of airway obstruction. In this study, respiratory inductive plethysmography (RIP) was used to document nocturnal TAA in house dust mite (HDM)-sensitive Cynomolgus macaques.

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We observed previously that lipopolysaccharide (LPS) 18 h after i.p. injection of guinea pigs increased transepithelial potential difference (V(t)), hyperpolarization responses to methacholine, and hyperosmolarity-induced, epithelium-derived relaxing factor (EpDRF)-mediated relaxation responses, in excised and perfused tracheal segments.

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The isolated, perfused trachea preparation has been used to compare reactivity of the intact airway in response to differential exposure of the mucosal (intraluminal) and serosal (extraluminal) surfaces to contractile and relaxant agonists and other agents, and to gain insight into the modulatory role of the epithelium and the pathways involved. The apparatus has also been configured for simultaneous measurement of transepithelial potential difference and changes in tracheal diameter, thereby providing parallel observations of epithelial and smooth muscle function and reactivity to drugs. The transepithelial potential difference is a product of transepithelial resistance and short circuit current, and the present study describes a novel isolated, perfused tracheal apparatus which allows simultaneous measurement of transepithelial potential difference, transepithelial resistance and mechanical responses of the smooth muscle.

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Crosslinking Fc(epsilon)RI and FcgammaRIIB receptors inhibits mast cell and basophil activation, decreasing mediator release. In this study, a fusion protein incorporating human Fcgamma and Fc(epsilon) domains, hGE2, was shown to inhibit degranulation of human mast cells and basophils, and to exhibit efficacy in a nonhuman primate model of allergic asthma. hGE2 increased the provocative concentration of dust mite aeroallergen that induced an early phase asthmatic response.

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Exercise-induced airway obstruction is thought to involve evaporative water loss and hyperosmolarity of the airway surface liquid. Hyperosmolar challenge of the epithelium of isolated, perfused guinea pig trachea rapidly alters transepithelial potential difference (V(t)), and it elicits smooth muscle relaxation mediated by epithelium-derived relaxing factor (EpDRF). In many cell types, protein kinases mediate responses to hyperosmolarity and regulatory volume increase.

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Increased ambient air particulate matter (PM) concentrations are associated with risk for myocardial infarction, stroke, and arrhythmia, and ultrafine PM (UFPM) might be particularly toxic to the cardiovascular system. Recent epidemiological studies are beginning to offer mechanistic insights, yet the rodent model remains a valuable tool to explore potential mechanisms. This article reviews a series of studies from our laboratory demonstrating the promise of mouse models to link health effects to biological mechanisms.

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Epidemiological studies have linked levels of particulate matter (PM) in ambient air to cardiovascular mortality and hospitalizations for myocardial infarction (MI) and stroke. Thrombus formation plays a primary role in potentiating acute cardiovascular events, and this study was undertaken to determine whether pulmonary exposure to PM alters hemostasis. PM was collected from the Chapel Hill, NC airshed and was administered to mice by intratracheal instillation at a dose previously shown to exacerbate myocardial ischemia-reperfusion injury.

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Recent observations demonstrated that translation of mRNAs may occur in axonal processes at sites that are long distances away from the neuronal perikaria. While axonal protein synthesis has been documented in several studies, the mechanism of its regulation remains unclear. The aim of this study was to investigate whether RNA interference (RNAi) may be one of the pathways that control local protein synthesis in axons.

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Cardiovascular disease is common in asthmatic patients but often is attributed to respiratory drug therapy. With mounting evidence for an inflammatory role in the development of cardiovascular disease, we hypothesized that the inflammation associated with asthma adversely affects the cardiovascular system independent of therapeutic interventions. The hypothesis was tested in a murine model of myocardial ischemia-reperfusion injury.

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Introduction: Challenge of guinea-pig tracheal epithelium with hyperosmolar solution alters ion transport and evokes the release of epithelium-derived relaxing factor (EpDRF). Cultured tracheal epithelial cells (CE) offer the potential to examine biochemical pathways related to EpDRF release, but whether the bioelectric properties and responses of fresh, adherent epithelial cells (FE) are modeled by CE has not been established.

Methods: Tracheal epithelial cells grown in air-interface culture and fresh tracheal segments were mounted in Ussing chambers to determine short circuit current (I(sc)) and transepithelial resistance (R(t)) and to compare responses to transport inhibitors, methacholine and hyperosmolarity.

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Epidemiological studies have linked ambient particulate matter (PM) levels to an increased incidence of adverse cardiovascular events. Yet little is definitively known about the mechanisms accounting for the cardiovascular events associated with PM exposure. The goal of this study was to determine the effects of ultrafine (<0.

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The relationship between allergen-induced ventilatory drive and bronchoconstriction was investigated in dust mite-sensitive cynomolgus macaques periodically exposed to low doses of aerosolized antigen for up to 5.5 yr. Initially, the animals responded to aerosolized dust mite allergen at a concentration of 350 arbitrary units (AU)/ml with simultaneous increases in lung resistance (RL) and respiratory rate (RR).

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Advances in our understanding of asthma pathogenesis and delineation of the human genome project are yielding novel candidate targets for therapeutic intervention. In parallel with target identification, the past decade has produced novel approaches to normalizing expression genes that are upregulated in disease processes. Single-stranded antisense oligonucleotides and double-stranded short-interfering RNA molecules, which specifically mark target transcripts for degradation, are being investigated for their ability to modulate disease processes.

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Despite epidemiological evidence of cardiovascular complications in asthmatics, the direct contribution of asthmatic pathophysiology to cardiovascular effects is unknown. Considering parallels in underlying pathophysiology, we tested the hypothesis that presence of systemic allergy and asthma worsens the outcome of myocardial ischemia-reperfusion injury. Systemic allergy and asthma were created in rabbits by repeated intraperitoneal injections of allergen with adjuvant, followed by an airway challenge in two groups.

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Animal models exhibiting high homology with humans at the genetic and pathophysiological levels will facilitate identification and validation of gene targets underlying asthma. In the present study, a nonhuman primate model of allergic asthma was developed by sensitizing cynomolgus monkeys to dust mite antigen. Sensitization elevated allergen-specific serum IgE and IgG levels, and peripheral blood mononuclear cells isolated from sensitized animals released IL-4, IL-5, and IL-10, but not IFN-gamma.

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We investigated the in vivo and in vitro effects of lipopolysaccharide (LPS) treatment (4 mg/kg i.p.) on guinea pig airway smooth muscle reactivity and epithelial bioelectric responses to methacholine (MCh) and hyperosmolarity.

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Hyperosmolar challenge of airway epithelium stimulates the release of epithelium-derived relaxing factor (EpDRF), but the identity of EpDRF is not known. We examined the effects of pharmacological agents on relaxant responses of methacholine (3 x 10(-7) M)-contracted guinea pig perfused trachea to mucosal hyperosmolar challenge using D-mannitol. Responses were inhibited by gossypol (5 x 10(-6) M), an agent with diverse actions, by the carbon monoxide (CO) scavenger hemoglobin (10(-6) M), and by the heme oxygenase (HO) inhibitor zinc (II) protoporphyrin IX (10(-4) M).

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Osmotic challenge of airways alters the bioelectric properties of the airway epithelium and induces the release of factors that modulate smooth muscle tone. Recent studies in our laboratory suggested that methacholine-contracted airways relax in response to incremental increases in osmolarity, rather than from cell shrinkage or absolute solute concentration. In the present study, guinea pig tracheae were mounted in Ussing chambers to elucidate the bioelectric effects of challenge of the epithelium with hyperosmolar and isosmolar solutions.

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In the guinea pig isolated perfused trachea contracted with serosal methacholine (MCh), increasing the osmolarity of the mucosal bathing solution elicits relaxation of smooth muscle mediated by epithelium-derived relaxing factor (EpDRF). The present study was undertaken to determine whether a specific modality of the hyperosmolar stimulus induced the relaxation response. Mucosal hyperosmolar challenge with D-mannitol, N-methyl-D-glucamine (NMDG)-chloride, NMDG-gluconate (NMDG-Glu), or urea elicited relaxation with equal potency.

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