Biomedical subjects

Richard W Costello

Publications and source records attributed to Richard W Costello.

18 recordsLinked to original sources

PubMed2006

Subjects with non-allergic non-infectious perennial rhinitis do not show nasal hyper-responsiveness to bradykinin.

Symptoms in non-allergic non-infectious perennial rhinitis (NANIPER) are characteristically trigged by non-specific irritants. Hyper-responsiveness to cold dry air has been demonstrated in NANIPER. Bradykinin is a peptide involved in allergic inflammation. Neurally mediated hyper-responsiveness to bradykinin has been demonstrated in allergic rhinitis. The purpose of the present study was to investigate whether hyper-responsiveness to bradykinin is present in NANIPER. Normal subjects (n = 13) and subjects with NANIPER (n = 10) were subjected to a nasal bradykinin challenge protocol. Secretory responses were measured using filter paper disks, and congestive responses measured using acoustic rhinometry. Compared to normal subjects, with NANIPER had a greater secretory response to control challenge with Hartman's solution. On the other hand, the normal ipsilateral secretory and congestive response to bradykinin was absent in NANIPER. Subjects with NANIPER did not demonstrate any evidence of reflex responses to bradykinin, and no evidence of nasal hyper-responsiveness to bradykinin. Hyper-responsiveness to bradykinin is absent in NANIPER. These results suggest that autonomic hyporesponsiveness rather than neural hyper-responsiveness may be an important factor in the etiology of NANIPER.

Adult↗

PubMed2006

Eosinophil-mediated cholinergic nerve remodeling.

Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. We hypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M2 muscarinic receptor, with this induction being mediated via an adhesion-dependent release of eosinophil proteins, including major basic protein and nerve growth factor. Studies on the promoter sequence of the M2 receptor indicated that this induction was initiated at a transcription start site 145 kb upstream of the gene-coding region. This promoter site contains binding sites for a variety of transcription factors including SP1, AP1, and AP2. Eosinophils also induced the expression of several cholinergic genes involved in the synthesis, storage, and metabolism of acetylcholine, including the enzymes choline acetyltransferase, vesicular acetylcholine transferase, and acetylcholinesterase. The observed eosinophil-induced changes in enzyme content were associated with a reduction in intracellular neural acetylcholine but an increase in choline content, suggesting increased acetylcholine turnover and a reduction in acetylcholinesterase activity, in turn suggesting reduced catabolism of acetylcholine. Together these data suggest that eosinophil localization to cholinergic nerves induces neural remodeling, promoting a cholinergic phenotype.

Acetylcholine↗

PubMed2006

Hyperresponsiveness of congestive nasal reflexes in allergic rhinitis.

BACKGROUND: Nasal secretory hyperresponsiveness is well documented in allergic rhinitis, and is mediated in part by neural mechanisms. In contrast, reflex-mediated congestion is poorly documented in both normal and allergic subjects. OBJECTIVE: To characterize congestive responses to unilateral nasal bradykinin challenge in normal and allergic subjects, and to investigate whether congestive hyperresponsiveness is present in allergic rhinitis. METHODS: Normal subjects (n = 13), and subjects with out-of-season seasonal allergic rhinitis (SAR) (n = 16) underwent a unilateral nasal challenge protocol using filter paper disks, using Hartman's solution and bradykinin as challenge substances. Congestive responses were measured using acoustic rhinometry. RESULTS: Normal subjects demonstrated a transient ipsilateral congestive response, and a circumscribed contralateral congestive response away from the major flow limiting section. Subjects with SAR demonstrated a more persistent ipsilateral congestive response, and a more pronounced, generalized contralateral congestive response affecting all areas of the contralateral nasal cavity. Significant differences were present between normal and SAR subjects. CONCLUSION: Congestive reflexes are present in normal and allergic subjects. Congestive hyperresponsiveness is present in allergic rhinitis.

Adult↗

PubMed2005

Neutrophil sphingosine 1-phosphate and lysophosphatidic acid receptors in pneumonia.

The phospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) act via transmembrane receptors S1P 1-5 and LPA 1-3, respectively. Both have been implicated in inflammatory responses. S1P and LPA receptor profiles on neutrophils of patients with pneumonia compared with healthy subjects were determined by PCR and Western blotting. Chemotaxis studies were performed to assess functional differences. S1P or LPA receptors were immunoprecipitated from neutrophils to assess receptor heterodimerization with CXCR1, an IL-8 receptor, by Western blotting. Receptors S1P 1, 4, and 5 and LPA 2 were expressed on neutrophils from both subject groups, but S1P 3 and LPA 1 receptor expression was mainly confined to neutrophils of patients with pneumonia. Chemotaxis of neutrophils from patients with pneumonia compared with control subjects was significantly increased in response to S1P and LPA. Pretreatment with S1P or LPA reduced IL-8-induced neutrophil chemotaxis and transcriptional expression of the CXCR1 receptor. Receptors S1P 3 and 4 and LPA 1 formed constitutive heterodimers with CXCR1. LPA treatment reduced the amount of LPA 1/CXCR1 heterodimer. Therefore, profiles of S1P and LPA receptors differ between neutrophils of patients with pneumonia and control subjects, with consequences for neutrophil function.

Adult↗

PubMed2005

Lung mechanics and dyspnea during exacerbations of chronic obstructive pulmonary disease.

RATIONALE: Exacerbation of chronic obstructive pulmonary disease commonly causes hospitalization. The change in lung mechanics during exacerbation and its relationship to symptoms in spontaneously breathing individuals has not been described. OBJECTIVE: We hypothesized that changes in both airflow and lung volumes would occur during an exacerbation, but that only volume change would relate to symptomatic improvement. METHODS: Lung mechanics and resting dyspnea were recorded in 22 hospitalized patients during recovery from exacerbation. MEASUREMENTS: Spirometry, inspiratory capacity, respiratory system resistance and reactance, tidal breathing patterns, and expiratory flow limitation were recorded after nebulized bronchodilator therapy on the first 3 d after admission, at discharge, and 6 wk postadmission (Day 42). Prebronchodilator measurements were taken on Day 2, at discharge, and on Day 42. MAIN RESULTS: Postbronchodilator inspiratory capacity increased 0.23 +/- 0.07 L by discharge and 0.42 +/- 0.1 L by Day 42, FEV1 rose 0.09 +/- 0.04 and 0.2 +/- 0.05 L at discharge and Day 42, respectively, and FVC increased 0.21 +/- 0.08 and 0.47 +/- 0.09 L at discharge and Day 42 (all p < 0.05). Consistent reduction in dyspnea was seen as the exacerbation resolved. Respiratory system resistance, FEV1/FVC, and expiratory flow limitation were unchanged throughout, indicating that changes in lung volume rather than airflow resistance predominated. CONCLUSIONS: Improvement in operating lung volumes is the principal change seen as a chronic obstructive pulmonary disease exacerbation resolves and increase in inspiratory capacity is a useful guide to a reduction in dyspnea.

Aged↗

PubMed2005

Diverse effects of eosinophil cationic granule proteins on IMR-32 nerve cell signaling and survival.

Activated eosinophils release potentially toxic cationic granular proteins, including the major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN). However, in inflammatory conditions including asthma and inflammatory bowel disease, localization of eosinophils to nerves is associated with nerve plasticity, specifically remodeling. In previous in vitro studies, we have shown that eosinophil adhesion to IMR-32 nerve cells, via nerve cell intercellular adhesion molecule-1, results in an adhesion-dependent release of granule proteins. We hypothesized that released eosinophil granule proteins may affect nerve cell signaling and survival, leading to nerve cell remodeling. Culture in serum-deprived media induced apoptosis in IMR-32 cells that was dose-dependently abolished by inclusion of MBP1 but not by EDN. Both MBP1 and EDN induced phosphorylation of Akt, but with divergent time courses and intensities, and survival was independent of Akt. MBP1 induced activation of neural nuclear factor (NF)-kappaB, from 10 min to 12 h, declining by 24 h, whereas EDN induced a short-lived activation of NF-kappaB. MBP1-induced protection was dependent on phosphorylation of ERK 1/2 and was related to a phospho-ERK-dependent upregulation of the NF-kappaB-activated anti-apoptotic gene, Bfl-1. This signaling pathway was not activated by EDN. Thus, MBP1 released from eosinophils at inflammatory sites may regulate peripheral nerve plasticity by inhibiting apoptosis.

Apoptosis↗

PubMed2005

Extending a home from hospital care programme for COPD exacerbations to include pulmonary rehabilitation.

The principals of rehabilitation medicine are to prevent muscle atrophy and improve mobility. Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with muscle atrophy and yet many patients do not undergo pulmonary rehabilitation until they have been in stable health for some time. We investigated the outcome of a supervised home exercise programme initiated immediately after hospitalisation for an exacerbation of COPD. Thirty-one patients were randomised into an exercise group (n=16, FEV(1) 0.94+/-0.34 L) and a control group (n=15, FEV(1) 1.08+/-0.33 L). The exercise group received a twice-weekly supervised exercise programme, in their homes, for 6 weeks. Spirometry, exercise capacity, isometric muscle strength, dyspnea level, quality of life at baseline and 6 weeks as well as subsequent exacerbations were quantified. At 6 weeks, the exercise group, improved the shuttle walk test (198 m+/-95-304+/-136 m) and increased 3 min step test capacity (119+/-40-163+/-26s) (both P<0.001). Knee extensor muscle strength and quality of life scores also increased. Neither exercise capacity nor muscle strength altered in the control group. Follow-up at 3 months showed that three of the control group and none of the exercise group had experienced subsequent exacerbations (P=0.06). Early rehabilitation via a home from hospital programme improved exercise tolerance, muscle strength, dyspnea scores, quality of life in COPD patients and reduced the number of subsequent exacerbations.

Aged↗

PubMed2004

Eosinophil adhesion to cholinergic IMR-32 cells protects against induced neuronal apoptosis.

Eosinophils release a number of mediators that are potentially toxic to nerve cells. However, in a number of inflammatory conditions, such as asthma and inflammatory bowel disease, it has been shown that eosinophils localize to nerves, and this is associated with enhanced nerve activity. In in vitro studies, we have shown that eosinophil adhesion via neuronal ICAM-1 leads to activation of neuronal NF-kappaB via an ERK1/2-dependent pathway. In this study, we tested the hypothesis that eosinophil adhesion to nerves promotes neural survival by protection from inflammation-associated apoptosis. Exposure of differentiated IMR-32 cholinergic nerve cells to IL-1beta, TNF-alpha, and IFN-gamma, or culture in serum-deprived medium, induced neuronal apoptosis, as detected by annexin V staining, caspase-3 activation, and DNA laddering. Addition of human eosinophils to IMR-32 nerve cells completely prevented all these features of apoptosis. The mechanism of protection by eosinophils was by an adhesion-dependent activation of ERK1/2, which led to the induced expression of the antiapoptotic gene bfl-1. Adhesion to nerve cells did not influence the expression of the related genes bax and bad. Thus, prevention of apoptosis by eosinophils may be a mechanism by which these cells regulate neural plasticity in the peripheral nervous system.

Apoptosis↗

PubMed2004

Use of Sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis.

Respiratory muscle weakness is the usual cause of death in amyotrophic lateral sclerosis. The prognostic value of the forced vital capacity (FVC), mouth-inspiratory force, and sniff nasal-inspiratory force were established in a group of 98 patients with amyotrophic lateral sclerosis who were followed trimonthly for 3 years. Sniff nasal-inspiratory force correlated with the transdiaphragmatic pressure (r = 0.9, p < 0.01). Sniff nasal-inspiratory force was most likely to be recorded at the last visit (96% of cases), compared with either the FVC or mouth-inspiratory force (86% and 81%, respectively, p < 0.01). A sniff nasal-inspiratory force less than 40 cm H(2)O was significantly related with nocturnal hypoxemia. When sniff nasal-inspiratory force was less than 40 cm H(2)O, the hazard ratio for death was 9.1 (p = 0.001), and the median survival was 6 +/- 0.3 months. The sensitivity of FVC < 50% for predicting 6-month mortality was 58% with a specificity of 96%, whereas sniff nasal-inspiratory force less than 40 H(2)O had a sensitivity of 97% and a specificity of 79% for death within 6 months. Thus the sniff nasal-inspiratory force test is a good measure of respiratory muscle strength in amyotrophic lateral sclerosis, it can be performed by patients with advanced disease, and it gives prognostic information.

Adult↗

PubMed2004

Mechanism of eosinophil induced signaling in cholinergic IMR-32 cells.

Eosinophils interact with nerve cells, leading to changes in neurotransmitter release, altered nerve growth, and protection from cytokine-induced apoptosis. In part, these interactions occur as a result of activation of neural nuclear factor (NF)-kappaB, which is activated by adhesion of eosinophils to neural intercellular adhesion molecule-1 (ICAM-1). The mechanism and consequence of signaling after eosinophil adhesion to nerve cells were investigated. Eosinophil membranes, which contain eosinophil adhesion molecules but not other eosinophil products, were coincubated with IMR-32 cholinergic nerve cells. The studies showed that there were two mechanisms of activation of NF-kappaB, one of which was dependent on reactive oxygen species, since it was inhibited with diphenyleneiodonium. This occurred at least 30 min after coculture of eosinophils and nerves. An earlier phase of NF-kappaB activation occurred within 2 min of eosinophil adhesion and was mediated by tyrosine kinase-dependent phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1). Coimmunoprecipitation experiments showed that both extracellular signal-regulated kinase 1/2 and IRAK-1 were recruited to ICAM-1 rapidly after coculture with eosinophil membranes. This was accompanied by an induction of ICAM-1, which was mediated by an IRAK-1-dependent pathway. These data indicate that adhesion of eosinophils to IMR-32 nerves via ICAM-1 leads to important signaling events, mediated via IRAK-1, and these in turn lead to expression of adhesion molecules.

Cell Adhesion↗

PubMed2003

Eosinophil-induced release of acetylcholine from differentiated cholinergic nerve cells.

One immunological component of asthma is believed to be the interaction of eosinophils with parasympathetic cholinergic nerves and a consequent inhibition of acetylcholine muscarinic M2 receptor activity, leading to enhanced acetylcholine release and bronchoconstriction. Here we have used an in vitro model of cholinergic nerve function, the human IMR32 cell line, to study this interaction. IMR32 cells, differentiated in culture for 7 days, expressed M2 receptors. Cells were radiolabeled with [3H]choline and electrically stimulated. The stimulation-induced release of acetylcholine was prevented by the removal of Ca2+. The muscarinic M1/M2 receptor agonist arecaidine reduced the release of acetylcholine after stimulation (to 82 +/- 2% of control at 10(-7) M), and the M2 receptor antagonist AF-DX 116 increased it (to 175 +/- 23% of control at 10(-5) M), indicating the presence of a functional M2 receptor that modulated acetylcholine release. When human eosinophils were added to IMR32 cells, they enhanced acetylcholine release by 36 +/- 10%. This effect was prevented by inhibitors of adhesion of the eosinophils to the IMR32 cells. Pretreatment of IMR32 cells with 10 mM carbachol, to desensitize acetylcholine receptors, prevented the potentiation of acetylcholine release by eosinophils or AF-DX 116. Acetylcholine release was similarly potentiated (by up to 45 +/- 7%) by degranulation products from eosinophils that had been treated with N-formyl-methionyl-leucyl-phenylalanine or that had been in contact with IMR32 cells. Contact between eosinophils and IMR32 cells led to an initial increase in expression of M2 receptors, whereas prolonged exposure reduced M2 receptor expression.

Acetylcholine↗

PubMed2003

Effect of eosinophil adhesion on intracellular signaling in cholinergic nerve cells.

Eosinophil localization to cholinergic nerves occurs in a variety of inflammatory conditions, including asthma. This localization is mediated by interactions between eosinophil integrins and neuronal vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Eosinophil-nerve cell interactions lead to generation of neuronal reactive oxygen species and release of eosinophil proteins. The effects of eosinophil adhesion on neuronal intracellular signaling pathways were investigated. Eosinophil adhesion to IMR32 cholinergic nerves led to a rapid and sustained activation of the nuclear transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 in the nerve cells. Eosinophil binding to neuronal ICAM-1 led to a rapid activation of ERK1/2 in nerve cells. Inhibition of ERK1/2 prevented NF-kappaB activation. Eosinophil adhesion to VCAM-1 resulted in AP-1 activation, mediated partially by rapid activation of the p38 mitogen-activated protein kinase. These data show that adhesion of eosinophils induces mitogen-activated protein kinase-dependent activation of the transcription factors NF-kappaB and AP-1 in nerve cells, indicating that eosinophil adhesion may control nerve growth and phenotype.

Acetylcholine↗

PubMed2003

Effects of eosinophils on nerve cell morphology and development: the role of reactive oxygen species and p38 MAP kinase.

The adhesion of eosinophils to nerve cells and the subsequent release of eosinophil products may contribute to the pathogenesis of conditions such as asthma and inflammatory bowel disease. In this study we have separately examined the consequences of eosinophil adhesion and degranulation for nerve cell morphology and development. Eosinophils induced neurite retraction of cultured guinea pig parasympathetic nerves and differentiated IMR32 cholinergic neuroblastoma cells. Inhibition of eosinophil adhesion to IMR32 cells attenuated this retraction. Eosinophil adhesion to IMR32 cells led to tyrosine phosphorylation of a number of nerve cell proteins, activation of p38 MAP kinase, and generation of neuronal reactive oxygen species (ROS). Inhibition of tyrosine kinases with genistein prevented both the generation of ROS in the nerve cells and neurite retraction. The p38 MAP kinase inhibitor SB-239063 prevented neurite retraction but had no effect on the induction of ROS. Thus eosinophils induced neurite retraction via two distinct pathways: by generation of tyrosine kinase-dependent ROS and by p38 MAP kinase. Eosinophils also prevented neurite outgrowth during differentiation of IMR32 cells. In contrast to their effect on neurite retraction, this effect was mimicked by medium containing products released from eosinophils and by eosinophil major basic protein. These results indicate that eosinophils modify the morphology of nerve cells by distinct mechanisms that involve adhesion and released proteins.

Animals↗

PubMed2003

Eosinophil and airway nerve interactions.

In vivo, eosinophils localise to airway nerves in patients with asthma as well as in animal models of hyperreactivity. In both, in vivo and in vitro studies, we have shown that this localisation changes both cholinergic nerve and eosinophil function. In particular, it leads to an increase in acetylcholine release due to loss of function of a neuronal autoreceptor, the M(2) muscarinic receptor. This loss of M(2) receptor function occurs because eosinophils become activated and degranulate as a result of interactions that occur via specific adhesion molecules expressed on nerves that are recognised by counter ligands on eosinophils.

Acetylcholine↗

PubMed2002

Interactions between inflammatory cells and nerves.

In the lungs, motor parasympathetic nerves and sensory nerves both innervate a variety of inflammatory cells. Interactions between these cells provide a means of extending the influence of each other's function. Neurotransmitters influence inflammatory cell function by either augmenting or limiting the inflammatory response. On the other hand, chemical factors released from inflammatory cells lead to local, reflex and long-lasting central changes in neural function.

Animals↗

PubMed2002

A pilot study examining the relationship between stress and serum cortisol concentrations in women with asthma.

The mechanism (s) by which stress exacerbates asthma is unknown. One explanation could be a reduction in endogenous serum cortisol concentrations as a result of stress. Our objective was to determine if a reduction in morning serum cortisol concentrations is associated with higher levels of stress in women with asthma. In this pilot study, seven women with a history of allergic-asthma were prospectively assigned to either low, moderate, or high stress groups based on a combination of their level of current stress and their resources to cope with the stress. After stress group assignment, women donated a morning blood sample, which was analyzed for serum cortisol concentration by an independent laboratory whose personnel were blinded to the subjects' stress status. Three women were assigned to the low stress group, two to the moderate stress group and two to the high stress group. Serum cortisol concentrations ranged from 8 to 23 microg/dl, averaging 14 +/- 6 microg/dl. A Spearman rank correlation indicated that serum cortisol concentrations were significantly inversely related to the stress groupings (r(s) = -0.915; P = 0.025). These results suggest that a reduction in morning serum cortisol concentration may be associated with higher levels of stress and lower resources to cope with the stress in women with allergic-asthma.

Adult↗

PubMed2002

Adhesion-dependent interactions between eosinophils and cholinergic nerves.

Eosinophils adhere to airway cholinergic nerves and influence nerve cell function by releasing granule proteins onto inhibitory neuronal M(2) muscarinic receptors. This study investigated the mechanism of eosinophil degranulation by cholinergic nerves. Eosinophils were cocultured with IMR32 cholinergic nerve cells, and eosinophil peroxidase (EPO) or leukotriene C(4) (LTC(4)) release was measured. Coculture of eosinophils with nerves significantly increased EPO and LTC(4) release compared with eosinophils alone. IMR32 cells, like parasympathetic nerves, express the adhesion molecules vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1). Inhibition of these adhesion molecules alone or in combination significantly inhibited eosinophil degranulation. IMR32 cells also significantly augmented the eosinophil degranulation produced by formyl-Met-Leu-Phe. Eosinophil adhesion to IMR32 cells resulted in an ICAM-1-mediated production of reactive oxygen species via a neuronal NADPH oxidase, inhibition of which significantly inhibited eosinophil degranulation. Additionally, eosinophil adhesion increased the release of ACh from IMR32 cells. These neuroinflammatory cell interactions may be relevant in a variety of inflammatory and neurological conditions.

Acetylcholine↗

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↗