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Biomedical subjects

David B Jacoby

Publications and source records attributed to David B Jacoby.

At least 19 recordsLinked to original sources
PubMed2007

Atropine pretreatment enhances airway hyperreactivity in antigen-challenged guinea pigs through an eosinophil-dependent mechanism.

Airway hyperreactivity in antigen-challenged animals is mediated by eosinophil major basic protein (MBP) that blocks inhibitory M(2) muscarinic receptors on parasympathetic nerves, increasing acetylcholine release onto M(3) muscarinic receptors on airway smooth muscle. Acutely, anticholinergics block hyperreactivity in antigen-challenged animals and reverse asthma exacerbations in the human, but are less effective in chronic asthma. We tested whether atropine, given before antigen challenge, affected hyperreactivity, M(2) receptor function, eosinophil accumulation, and activation. Sensitized guinea pigs received atropine (1 mg/kg ip) 1 h before challenge and 6 h later. Twenty-four hours after challenge, animals were anesthetized, vagotomized, paralyzed, and ventilated. Airway reactivity to electrical stimulation of the vagi and to intravenous acetylcholine was not altered by atropine pretreatment in nonsensitized animals, indicating that atropine was no longer blocking postjunctional muscarinic receptors. Antigen challenge induced airway hyperreactivity to vagal stimulation that was significantly potentiated by atropine pretreatment. Bronchoconstriction induced by acetylcholine was not changed by antigen challenge or by atropine pretreatment. M(2) receptor function was lost in challenged animals but protected by atropine pretreatment. Eosinophils in bronchoalveolar lavage and within airway tissues were significantly increased by challenge but significantly reduced by atropine pretreatment. However, extracellular MBP in challenged airways was significantly increased by atropine pretreatment, which may account for reduced eosinophils. Depleting eosinophils with antibody to IL-5 before challenge prevented hyperreactivity and significantly reduced MBP in airways of atropine-pretreated animals. Thus atropine pretreatment potentiated airway hyperreactivity by increasing eosinophil activation and degranulation. These data suggest that anticholinergics enhance eosinophil interactions with airway nerves.

Animals↗
PubMed2005

Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction.

Eosinophils cluster around airway nerves in patients with fatal asthma and in antigen-challenged animals. Activated eosinophils release major basic protein, which blocks inhibitory M2 muscarinic receptors (M2Rs) on nerves, increasing acetylcholine release and potentiating vagally mediated bronchoconstriction. We tested whether GW701897B, an antagonist of CCR3 (the receptor for eotaxin as well as a group of eosinophil active chemokines), affected vagal reactivity and M2R function in ovalbumin-challenged guinea pigs. Sensitized animals were treated with the CCR3 antagonist before inhaling ovalbumin. Antigen-challenged animals were hyperresponsive to vagal stimulation, but those that received the CCR3 antagonist were not. M2R function was lost in antigen-challenged animals, but not in those that received the CCR3 antagonist. Although the CCR3 antagonist did not decrease the number of eosinophils in lung tissues as assessed histologically, CCR3 antagonist prevented antigen-induced clustering of eosinophils along the nerves. Immunostaining revealed eotaxin in airway nerves and in cultured airway parasympathetic neurons from both guinea pigs and humans. Both IL-4 and IL-13 increased expression of eotaxin in cultured airway parasympathetic neurons as well as in human neuroblastoma cells. Thus, signaling via CCR3 mediates eosinophil recruitment to airway nerves and may be a prerequisite to blockade of inhibitory M2Rs by eosinophil major basic protein.

Animals↗
PubMed2005

The changing role of eosinophils in long-term hyperreactivity following a single ozone exposure.

Ozone hyperreactivity over 24 h is mediated by blockade of inhibitory M(2) muscarinic autoreceptors by eosinophil major basic protein. Because eosinophil populations in the lungs fluctuate following ozone, the contribution of eosinophils to M(2) dysfunction and airway hyperreactivity was measured over several days. After one exposure to ozone, M(2) function, vagal reactivity, smooth muscle responsiveness, and inflammation were measured in anesthetized guinea pigs. Ozone-induced hyperreactivity to vagal stimulation persisted over 3 days. Although hyperreactivity one day after ozone is mediated by eosinophils, AbVLA-4 did not inhibit either eosinophil accumulation in the lungs or around the nerves or prevent hyperreactivity at this time point. Two days after ozone, eosinophils in BAL, around airway nerves and in lungs, were decreased, and neuronal M(2) receptor function was normal, although animals were still hyperreactive to vagal stimulation. Depleting eosinophils with AbIL-5 prevented hyperreactivity, thus eosinophils contribute to vagal hyperreactivity by mechanisms separate from M(2) receptor blockade. Three days after ozone, vagal hyperreactivity persisted, eosinophils were again elevated in BAL in lungs and around nerves, and M(2) receptors were again dysfunctional. At this point, airway smooth muscle was also hyperresponsive to methacholine. Eosinophil depletion with AbIL-5, AbVLA-4, or cyclophosphamide protected M(2) function 3 days after ozone and prevented smooth muscle hyperreactivity. However, vagal hyperreactivity was significantly potentiated by eosinophil depletion. The site of hyperreactivity, muscle or nerve, changes over 3 days after a single exposure to ozone. Additionally, the role of eosinophils is complex; they mediate hyperreactivity acutely while chronically may be involved in repair.

Animals↗
PubMed2004

Pathophysiology of airway viral infections.

Viral infections are major causes of cough. Virus-induced changes in airway sensory nerve function include increased tachykinin expression and, more specifically, expression of tachykinins by Adelta fibers. This change may be mediated by neurotrophins produced in response to viral infection. At the same time, activity of neutral endopeptidase, an enzyme that is important in degrading and inactivating tachykinins, is decreased by airway viral infections. Viral infections can activate eosinophils, releasing proteins that can cause tachykinin release. Moreover, expression of the NK1 receptor is increased by viral infections of the lungs. The expression of M2 muscarinic receptors, which normally decrease the sensitivity of sensory nerves, is decreased by viral infections. So it is possible that viral infections (1) increase expression of tachykinins (by causing neurotrophin expression), (2) increase release of tachykinins (by causing release of eosinophil proteins), (3) decrease degradation of tachykinins (by decreasing neutral endopeptidase activity), (4) increase expression of the NK1 receptor (again mediated by neurotrophins), and (5) increase the sensitivity of airway afferents (by decreasing M2 muscarinic receptor expression). All these changes may potentiate the tachykininergic input into the cough reflex, and may provide new therapeutic targets for controlling virus-induced cough.

Cough↗
PubMed2004

Virus-induced asthma attacks.

Viral infections are responsible for the majority of asthma attacks in both children and adults. Vagally mediated reflex bronchoconstriction is potentiated due to loss of function of inhibitory M2 muscarinic receptors on the airway parasympathetic nerves. Multiple mechanisms are involved. Production of interferons may down regulate the expression of the M2 receptor gene. This effect is reversed by steroids. In allergic animals (and perhaps in atopic humans) eosinophils are recruited to the airway nerves, where they are activated, releasing major basic protein, which binds to the M2 receptors, blocking their function. Despite these negative physiological consequences of eosinophil activation, eosinophils are capable of exerting a potent antiviral effect. Thus, the inflammatory response to viral infections may have positive, as well as negative, consequences.

Adult↗
PubMed2004

Role of macrophages in virus-induced airway hyperresponsiveness and neuronal M2 muscarinic receptor dysfunction.

Viral infections exacerbate asthma. One of the pathways by which viruses trigger bronchoconstriction and hyperresponsiveness is by causing dysfunction of inhibitory M(2) muscarinic receptors on the airway parasympathetic nerves. These receptors normally limit acetylcholine (ACh) release from the parasympathetic nerves. Loss of M(2) receptor function increases ACh release, thereby increasing vagally mediated bronchoconstriction. Because viral infection causes an influx of macrophages into the lungs, we tested the role of macrophages in virus-induced airway hyperresponsiveness and M(2) receptor dysfunction. Guinea pigs infected with parainfluenza virus were hyperresponsive to electrical stimulation of the vagus nerves but not to intravenous ACh, indicating that hyperresponsiveness was due to increased release of ACh from the nerves. In addition, the muscarinic agonist pilocarpine no longer inhibited vagally induced bronchoconstriction, indicating M(2) receptor dysfunction. Treating animals with liposome-encapsulated dichloromethylene-diphosphonate depleted macrophages as assessed histologically. In these animals, viral infection did not cause airway hyperresponsiveness or M(2) receptor dysfunction. These data suggest that macrophages mediate virus-induced M(2) receptor dysfunction and airway hyperresponsiveness.

Animals↗
PubMed2003

Insulin regulates neuronal M2 muscarinic receptor function in the ileum of diabetic rats.

Acetylcholine release from cholinergic nerves in the gastrointestinal tract is limited by neuronal M(2) muscarinic receptors. In diabetic animals, M(2) muscarinic receptor function in the ileum is increased, leading to decreased acetylcholine release and smooth muscle contraction in response to nerve stimulation. The mechanisms responsible for increased M(2) muscarinic receptor function are unknown but may contribute to the gastrointestinal dysmotility that occurs frequently in diabetics. In this study, we investigated whether insulin modulates M(2) muscarinic receptor function in the gastrointestinal tract of diabetic rats. M(2) muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of ileum in vitro. Insulin administration (0.2, 0.6, and 2 U s.c. daily for 7 days) reversed the diabetes-induced increase in M(2) muscarinic receptor function and restored normal contractions to EFS. Insulin had no effect on the function of postjunctional M(3) muscarinic receptors, determined by measuring contractile responses to acetylcholine. These data suggest that insulin tonically inhibits neuronal M(2) muscarinic receptors. Thus, loss of insulin removes this inhibition and increases M(2) muscarinic receptor function leading to decreased acetylcholine release and contraction to EFS. In nondiabetic rats, there was a trend that higher insulin doses (0.6 and 2 U) increased M(2) muscarinic receptor function, suggesting a bell-shaped concentration-response relationship for insulin. In conclusion, lack of insulin or excess insulin increases M(2) muscarinic receptor function in rat ileum. This mechanism may contribute to decreased acetylcholine release in the gastrointestinal tract of diabetics, resulting in dysmotility.

Acetylcholine↗
PubMed2003

Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms.

In the lungs, neuronal M2 muscarinic receptors inhibit acetylcholine release from the parasympathetic nerves. Parainfluenza virus infection causes loss of M2 receptor function, which increases acetylcholine release and vagally mediated bronchoconstriction. Because glucocorticoids are known to inhibit airway hyperresponsiveness, we tested whether dexamethasone (6.5 or 65 microg/kg i.p.) prevents virus-induced hyperresponsiveness and M2 receptor dysfunction in guinea pigs. In controls, pilocarpine, a muscarinic agonist, inhibited vagally induced bronchoconstriction, demonstrating functional M2 receptors. However, in virus-infected animals, pilocarpine failed to inhibit vagally induced bronchoconstriction, demonstrating M2 receptor dysfunction. Frequency-dependent bronchoconstriction was greater in virus-infected animals than in controls, indicating airway hyperresponsiveness. Low-dose dexamethasone (6.5 microg/kg i.p.) treatment prevented virus-induced airway hyperresponsiveness, ameliorated M2 receptor dysfunction, and decreased viral content in the lungs without inhibiting virus induced inflammation. High-dose dexamethasone (65 microg/kg i.p.) prevented virus-induced hyperresponsiveness, completely reversed M2 receptor dysfunction, decreased viral titers, and decreased virus-induced inflammation. This high-dose dexamethasone also increased M2 receptor function in uninfected animals. In conclusion, dexamethasone prevented virus-induced hyperresponsiveness and M2 receptor dysfunction via multiple mechanisms.

Acetylcholine↗
PubMed2002

CD8+ T lymphocytes in viral hyperreactivity and M2 muscarinic receptor dysfunction.

In the airways, inhibitory M2 muscarinic receptors (M2Rs) on parasympathetic nerves limit acetylcholine release. Viral infection causes M2R dysfunction, which increases acetylcholine release and leads to airway hyperreactivity. In these studies we tested the role of CD8+ T cells in parainfluenza virus-induced hyperreactivity and M2R dysfunction in normal guinea pigs and in guinea pigs previously sensitized to ovalbumin. Depleting CD8+ T cells prevented virus-induced M2R dysfunction and hyperreactivity in sensitized animals, but not in nonsensitized animals. Sensitization increased the number of eosinophils in close relation to the airway nerves where, when activated, they release major basic protein, which binds to and blocks the M2Rs. Regardless of sensitization, viral infection decreased the number of visible tissue eosinophils, likely reflecting eosinophil degranulation via cytolysis. Depleting CD8+ T cells prevented this virus-induced eosinophil degranulation. In addition, an antiviral effect of sensitization, which we previously showed to be eosinophil mediated, was again seen. This was prevented by depletion of CD8+ Tcells. Thus, CD8+ T cells play a role in airway hyperreactivity and M2R dysfunction of sensitized virus-infected guinea pigs by mediating eosinophil degranulation near airway nerves. In contrast, CD8+ T cells are not necessary for virus-induced hyperreactivity and M2R dysfunction in nonsensitized guinea pigs.

Analysis of Variance↗
PubMed2002

Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea pigs.

Immunohistochemistry was combined with retrograde labeling to characterize the effect of respiratory infection with Sendai virus on the number of Substance P/Neurokinin A-containing vagal afferent neurons whose cell bodies resided in the nodose ganglia and whose receptive fields were located in guinea pig trachea. Of the neurons labeled from the trachea of vehicle-inoculated guinea pigs, few stained positively for Substance P/Neurokinin A (approximately 3% of total labeled neurons). These neurons had small diameter cell bodies (mode = 16-20 microm), a feature of nociceptive-like C-fibers. Viral infection (Day 4 after inoculation) was associated with a significantly greater number of labeled neurons containing Substance P/Neurokinin A (approximately 20% of total labeled neurons). The majority of these had a relatively large cell body diameter (mode = 36- 40 microm), a feature of nonnociceptive afferent neurons. This induction appeared to be reversible as there were significantly fewer Substance P/Neurokinin A positive neurons in nodose ganglia from virus-inoculated guinea pigs at Day 28 after inoculation, a time point when virus-induced airway inflammation had all but resolved. These findings support the hypothesis that viral infection leads to a qualitative change in the vagal afferent innervation of guinea pig airways such that both small diameter nociceptive-like neurons and large diameter nonnociceptive neurons express tachykinins.

Action Potentials↗
PubMed2002

Virus-induced asthma attacks.

Viral respiratory tract infections are a common cause of asthma attacks. Study of this phenomenon has revealed multiple mechanisms and contributed to understanding of the increase in airway inflammation and bronchoconstriction observed in this context. Changes in the neural control of the airways contribute to bronchoconstriction, which is reflected in an increased efficacy of anticholinergic medications during acute asthma attacks. The ability to prevent or treat viral respiratory tract infections is currently limited. However, as more effective antiviral treatments and vaccines become available, such therapies are likely to be effective in patients with asthma. Clinical management of this problem is illustrated in this article by the case of a 40-year-old woman with history of mild asthma who was admitted to an intensive care unit with severe bronchospasm and an upper respiratory tract infection.

Adult↗
PubMed2002

Increased function of inhibitory neuronal M2 muscarinic receptors in trachea and ileum of diabetic rats.

1. Release of acetylcholine from parasympathetic nerves is inhibited by neuronal M(2) muscarinic receptors. The effects of streptozotocin-induced diabetes on prejunctional M(2) and postjunctional M(3) muscarinic receptor function in rat trachea and ileum were investigated in vitro. 2. Neuronal M(2) muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of trachea and ileum. Concentration-response curves to pilocarpine and methoctramine were shifted to the left in both to a greater degree in diabetics than controls. 3. In trachea, post-junctional M(3) muscarinic receptor function was increased since maximum contractile responses to the muscarinic agonists acetylcholine and carbachol were greater in diabetics than controls. This increase offset the increased function of the inhibitory neuronal M(2) muscarinic receptors since EFS-induced, frequency-dependent contraction was equal in control and diabetic rats. 4. In contrast, post-junctional M(3) muscarinic receptor function was unchanged by diabetes since concentration-response curves to acetylcholine and carbachol were not different between groups. Thus, EFS-induced contractions of the ileum were decreased in diabetics versus controls. 5. In conclusion, inhibitory M(2) muscarinic receptors on parasympathetic nerves in the trachea and ileum are hyperfunctional in diabetic rats. The function of post-junctional M(3) muscarinic receptors in the trachea, but not the ileum, is also increased in diabetes. 6. The dysfunction of inhibitory, neuronal M(2) muscarinic receptors in the airways may protect against hyperreactivity and in the ileum may contribute to gastrointestinal dysmotility associated with diabetes.

Animals↗
PubMed2002

Eosinophil adhesion to cholinergic nerves via ICAM-1 and VCAM-1 and associated eosinophil degranulation.

In vivo, eosinophils localize to airway cholinergic nerves in antigen-challenged animals, and inhibition of this localization prevents antigen-induced hyperreactivity. In this study, the mechanism of eosinophil localization to nerves was investigated by examining adhesion molecule expression by cholinergic nerves. Immunohistochemical and functional studies demonstrated that primary cultures of parasympathetic nerves express vascular cell adhesion molecule-1 (VCAM-1) and after cytokine pretreatment with tumor necrosis factor-alpha and interferon-gamma intercellular adhesion molecule-1 (ICAM-1). Eosinophils adhere to these parasympathetic neurones after cytokine pretreatment via a CD11/18-dependent pathway. Immunohistochemistry and Western blotting showed that a human cholinergic nerve cell line (IMR-32) expressed VCAM-1 and ICAM-1. Inhibitory experiments using monoclonal blocking antibodies to ICAM-1, VCAM-1, or CD11/18 and with the very late antigen-4 peptide inhibitor ZD-7349 showed that eosinophils adhered to IMR-32 cells via these adhesion molecules. The protein kinase C signaling pathway is involved in this process as a specific inhibitor-attenuated adhesion. Eosinophil adhesion to IMR-32 cells was associated with the release of eosinophil peroxidase and leukotriene C(4). Thus eosinophils adhere to cholinergic nerves via specific adhesion molecules, and this leads to eosinophil activation and degranulation; this may be part of the mechanism of eosinophil-induced vagal hyperreactivity.

Acetylcholine↗
PubMed2002

Double-stranded RNA causes airway hyperreactivity and neuronal M2 muscarinic receptor dysfunction.

Viral infection causes dysfunction of inhibitory M2 muscarinic receptors (M2Rs) on parasympathetic nerves, leading to airway hyperreactivity. The mechanisms of M2R dysfunction are incompletely understood. Double-stranded RNA (dsRNA), a product of viral replication, promotes the expression of interferons. Interferon-gamma decreases M2R gene expression in cultured airway parasympathetic neurons. In this study, guinea pigs were treated with dsRNA (1 mg/kg ip) on 2 consecutive days. Twenty-four hours later, anesthetized guinea pigs had dysfunctional M2Rs and were hyperresponsive to electrical stimulation of the vagus nerves, in the absence of inflammation. DsRNA did not affect either cholinesterase or the function of postjunctional M3 muscarinic receptors on smooth muscle. M2Rs on the nerves supplying the heart were also dysfunctional, but M2Rs on the heart muscle itself functioned normally. Thus dsRNA causes increased bronchoconstriction and bradycardia via increased release of ACh from the vagus nerves because of loss of M2R function on parasympathetic nerves in the lungs and heart. Production of dsRNA may be a mechanism by which viruses cause dysfunction of neuronal M2Rs and airway hyperreactivity.

Animals↗