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Biomedical subjects

G P Anderson

Publications and source records attributed to G P Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Therapeutic potential of treating chronic obstructive pulmonary disease (COPD) by neutralising granulocyte macrophage-colony stimulating factor (GM-CSF).

Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation. This inflammation, where macrophages and neutrophils are prominent, leads to oxidative stress, emphysema (loss of lung structure), small airways fibrosis and mucus hypersecretion. However, COPD responds poorly to current anti-inflammatory treatments including potent glucocorticosteroids, which produce little or no benefit. In this review we consider the therapeutic potential of targeting granulocyte macrophage-colony stimulating factor (GM-CSF) for the treatment of COPD. GM-CSF is a major regulator of both macrophage and neutrophil activation and survival in the lung-these cells are intimately linked to COPD. Animal data indicates that neutralisation of GM-CSF ameliorates experimental COPD and predicts therapeutic utility in treating stable COPD and treating exacerbations. As such, GM-CSF represents an attractive therapeutic target for the treatment of COPD.

Animals↗
PubMed2006

Follistatin is a candidate endogenous negative regulator of activin A in experimental allergic asthma.

BACKGROUND: Activin A is a member of the transforming growth factor-beta superfamily which is directly implicated in airway structural change and inflammation in asthma. In vitro, the biological effects of activin A are neutralized by the soluble binding protein follistatin. OBJECTIVE: To determine the potential of endogenous follistatin to suppress activin A in vivo by analysing their relative tissue and kinetic compartmentalization during the effector phase of subchronic Th2-driven mucosal inflammation in a murine model of allergic asthma. METHODS: Eosinophilic mucosal inflammation was elicited by triggering Th2 recall responses by antigen challenge in ovalbumin-sensitized BALB/c mice. The kinetics and distribution of activin A and follistatin protein were assessed in lung tissue and bronchoalveolar lavage fluid and measured in relation to airway eosinophilia, goblet cell metaplasia and Th2 cytokine production in mediastinal lymph nodes. RESULTS: Follistatin was released concurrently with activin A suggesting it acts as an endogenous regulator: peak BAL concentrations coincided with maximal airway eosinophilia, and frequency of IL-4, IL-5 and IL-13 producing cells in mediastinal lymph nodes but induction lagged behind the onset of inflammation. Follistatin and activin A immunoreactivity were lost in airway epithelial cells in parallel with goblet cell metaplasia. Exogenous follistatin inhibited the allergen-specific Th2 immune response in mediastinal lymph nodes and mucus production in the lung. CONCLUSION: Follistatin is preformed in the normal lung and released in concert with activin A suggesting it serves as an endogenous regulator. Disturbance of the fine balance between activin A and its endogenous inhibitor follistatin may be a determinant of the severity of allergic inflammation or tissue phenotypic shift in asthma.

Activins↗
PubMed2005

Differential protease, innate immunity, and NF-kappaB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice.

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.

Animals↗
PubMed2005

Modelling COPD in mice.

Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow limitation, neutrophilic inflammation, macrophage accumulation, and the production of cytokines, chemokines and proteases. Cigarette smoking is the major cause of COPD and there is currently no satisfactory therapy to help treat individuals with this disease. A better understanding of the cellular and molecular responses triggered by cigarette smoke may provide new molecular targets for the development of therapeutic agents. This brief review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure.

Animals↗
PubMed2005

Neutrophils, interleukin-17A and lung disease.

It is now established that an excessive and sustained mobilisation of neutrophils is a hallmark of several chronic inflammatory lung disorders, including severe obstructive lung disease. This article reviews evidence that the cytokine interleukin (IL)-17A is a major orchestrator of sustained neutrophilic mobilisation. Current evidence suggests that IL-17A is produced by T-lymphocytes, and that it exerts an orchestrating effect on the accumulation and associated activity of neutrophils in the bronchoalveolar space indirectly, through an induced release of specific cytokines and colony-stimulating factors in resident lung cells. Although the involvement of IL-17A in inflammatory lung disorders is supported by several recent studies, its causative role is still uncertain. However, the unique position of interleukin-17A at the interface between acquired and innate immunity puts this cytokine forward as an important signal for the reinforcement of host defence; it also implies that interleukin-17A may constitute a useful target for pharmacotherapeutic intervention.

Biomarkers↗
PubMed2004

Increased matrix metalloproteinase-9 concentration and activity after stimulation with interleukin-17 in mouse airways.

BACKGROUND: The proteolytic enzyme matrix metalloproteinase (MMP)-9 can degrade structural compounds such as the extracellular matrix and the basement membrane in the airways and lungs. MMP-9 has therefore been implicated in remodelling of the airways and lungs during severe asthma and chronic obstructive pulmonary disease (COPD). METHODS: The effect of the T lymphocyte derived proinflammatory cytokine interleukin (IL)-17 on MMP-9 protein release and activity in the airways was studied in vivo and in vitro. RESULTS: In vivo, intranasal stimulation of mice with IL-17 induced the release of the precursor molecule proMMP-9 in bronchoalveolar lavage (BAL) fluid, associated with a pronounced local accumulation of neutrophils that stained positive for MMP-9. Stimulation with IL-17 also increased the concentration of free soluble MMP-9 that was proteolytically active as determined by a gelatinase substrate assay. The concentration of MMP-9 in BAL fluid had a strong positive correlation with the number of neutrophils; the amount of MMP-9 per neutrophil was not increased by IL-17 stimulation. In vitro, stimulation of mouse neutrophils with IL-17 did not increase the concentration of proMMP-9 in the conditioned medium. CONCLUSION: Local stimulation with IL-17 increases the concentration of biologically active MMP-9 as well as its precursor molecule in mouse airways in vivo. This increase in proteolytic load is probably mainly due to an increased number of neutrophils and not to an increase in the release of MMP-9 from each neutrophil. These findings indicate a link between the T lymphocyte cytokine IL-17 and increased proteolytic load in the airways which may be relevant for chronic inflammatory airway diseases such as severe asthma and COPD.

Animals↗
PubMed2004

TRPV1 and cough.

Explore the source record for details and available documents.

Animals↗
PubMed2003

Murine models of asthma.

In vivo animal models can offer valuable information on several aspects of asthma pathogenesis and treatment. The mouse is increasingly used in these models, mainly because this species allows for the application in vivo of a broad range of immunological tools, including gene deletion technology. Mice, therefore, seem particularly useful to further elucidate factors influencing the response to inhaled allergens. Examples include: the role of immunoregulatory mechanisms that protect against T-helper cell type 2 cell development; the trafficking of T-cells; and the contribution of the innate immunity. However, as for other animal species, murine models also have limitations. Mice do not spontaneously develop asthma and no model mimics the entire asthma phenotype. Instead, mice should be used to model specific traits of the human disease. The present task force report draws attention to specific aspects of lung structure and function that need to be borne in mind when developing such models and interpreting the results. In particular, efforts should be made to develop models that mimic the lung function changes characteristic of asthma as closely as possible. A large section of this report is therefore devoted to an overview of airway function and its measurement in mice.

Animals↗
PubMed2001

Dual neurokinin NK(1)/NK(2) antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamides.

Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1), attempts to improve the NK(2) affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK(2) receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK(1)/NK(2) antagonist.

Animals↗
PubMed2000

N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide: an orally active neurokinin NK1/NK2 antagonist.

The stereoselective synthesis of N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl+ ++)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (4) and its NK1 and NK2 receptor binding properties are reported. In addition the potent inhibitory effects in vivo on sar9-SP- and beta-Ala-NKA-induced airway bronchoconstriction in guinea pigs are demonstrated.

Administration, Oral↗
PubMed2000

Rapid isolation of homogeneous murine bronchoalveolar lavage fluid eosinophils by differential lectin affinity interaction and negative selection.

Murine models have advanced our understanding of the immune regulation of eosinophilic inflammation but there are few methods for the reliable isolation of viable populations of eosinophils from the inflamed lung. Here we describe a method to isolate murine eosinophils in high yield and purity from lung lavage fluid after induction of eosinophilic inflammation by inhalation of ovalbumin antigen in presensitized BALB/c mice. Thirteen biotinylated plant lectins were screened for their ability to bind selectively alveolar macrophages/monocytes thus permitting the purification of eosinophils by negative selection with streptavidin-conjugated magnetic beads. Bandierea (Griffonia) simplifora isolectin I and, to a lesser extent, Jacalin, provided selective enrichment of viable eosinophils which could be further purified with biotinylated anti-lymphocyte antibodies (up to 98.5% pure). FACS analysis revealed a surface marker phenotype consistent with active effector function (Fas/CD95(+), B7-1/CD80(+), L-selectin/CD62L(Lo), ICAM-1/CD54(+), CD51(+)). Eosinophils retained functional responsiveness, responding to PMA by producing superoxide, as detected by the reduction of dihydrorhodamine-123 to rhodamine. The eosinophils were also able to undergo active apoptosis, as detected by propidium iodide DNA staining, when exposed to a cross-linking anti-Fas antibody, Jo-2. The method may be of general use in studies of murine eosinophil biology.

Administration, Inhalation↗
PubMed2000

Multi-analyte interrogation using the fiber optic biosensor.

The capabilities of the portable, automated fiber optic biosensor, RAPTOR, have recently been evaluated. Developed to perform rapid fluoroimmunoassays in the field, the RAPTOR was designed to test samples for up to four different target analytes simultaneously. Assay time could be varied from a 3-min rapid screen to a standard 10-min test. A trial of 203 blind samples tested for Staphylococcal enterotoxin B, ricin, Francisella tularensis, and Bacillus globigii has been conducted. Sensitivities obtained were 10, 50 ng/ml, 5 x 10(5), and 5 x 10(4) cfu/ml, respectively.

Bacillus↗
PubMed1999

Comparative effects of a glucocorticosteroid, theophylline and the peptido-leukotriene-antagonist CGP 45715A on antigen-induced early and late phase airway response and inflammatory cell influx in sensitised guinea pigs.

A novel model of allergic early and late-phase reaction in the airways of conscious guinea pigs was developed and the effect of established and novel antiasthmatic drugs on peak of immediate response, late phase response and associated inflammatory cell influx investigated. Guinea pigs were sensitised twice in adjuvant (50 mg/kg silica + 0.1 ml/kg Bordetella pertussis). Under cover of 10 mg/kg i.p. mepyramine guinea pigs exhibited still a pronounced immediate reaction. During a screening phase about 75% of guinea pigs demonstrated a late phase reaction of decrease of tidal volume between 4-10 h after ovalbumin inhalation. In a cross over study theophylline at 50 mg/kg p.o. (-1 h before ovalbumin) tended to attenuate not only the peak of the immediate reaction by about 69% (P>0.05, n = 12), but inhibited the airway late phase response significantly (P<0.05, 5-10 h, n = 12). Methylprednisolone (40 mg/kg p.o. 1 h before ovalbumin) did not inhibit the immediate response, but the late phase response. In contrast the cysteinyl-leukotriene antagonist CGP 45715A (Iralukast; 30 mg/kg p.o. 2 h before ovalbumin) neither interfered with the peak of the immediate, nor with the late phase response. When bronchoalveolar lavage by orotracheal route was performed 24 h after ovalbumin inhalation, total cell count, eosinophils, neutrophils, macrophages and lymphocytes were significantly increased in ovalbumin-controls compared to sham (n = 5; P<0.05). Methylprednisolone reduced significantly the antigen-induced increase of total cell count and eosinophil number. Neither theophylline nor the cysteinyl-leukotriene receptor antagonist attenuated the antigen-associated cell influx. The results do not provide evidence for a major role of cysteinyl-leukotrienes in the late phase response and inflammatory cell influx in this model.

Animals↗
PubMed1999

A protective role for protease-activated receptors in the airways.

The protection of cells in the upper intestine against digestion by pancreatic trypsin depends on the prostanoid prostaglandin E2 (PGE2) and is mediated by protease-activated receptors in the epithelium. As the airway epithelium is morphologically similar and also expresses one of these receptors, PAR2, and is a major source of PGE2, we reasoned that bronchial epithelial PAR2 might also participate in prostanoid-dependent cytoprotection in the airways. Here we show that activation of PAR2, which co-localizes immunohistochemically with trypsin(ogen) in airway epithelium, causes the relaxation of airway preparations from mouse, rat, guinea-pig and humans by the release of a cyclooxygenase product from the epithelium. This physiological protective response in isolated airways also occurred in anaesthetized rats, where activation of PAR2 caused a marked and prolonged inhibition of bronchoconstriction. After desensitization of PAR2, the response to trypsin recovered rapidly by mechanisms dependent on de novo synthesis and trafficking of proteins. Our results indicate that trypsin released from the epithelium can initiate powerful bronchoprotection in the airways by activation of epithelial PAR2.

Animals↗
PubMed1999

Detecting staphylococcal enterotoxin B using an automated fiber optic biosensor.

The Man-portable Analyte Identification System (MANTIS), the first fully automated, self-contained, portable fiber optic biosensor, was utilized for the detection of Staphylococcal Enterotoxin B (SEB), a bacterial toxin produced by Staphylococcus aureus that commonly causes food poisoning. Because of its remarkable toxicity and stability, SEB is considered a prime threat as a biological weapon of mass destruction. The assay for SEB was used to evaluate the MANTIS' ability to function in the presence of various environmental interferents. The sensor could reliably detect SEB spiked into liquid samples containing a variety of smoke particles. However, substantial interference occurred when SEB was mixed into matrices capable of adsorbing SEB, such as 1% solutions of clay, topsoil, or pollen. Of equal importance, none of the interferents produced false positives in the MANTIS. The MANTIS demonstrated the capability to perform simultaneous immunoassays rapidly in the field with little or no user intervention.

Biosensing Techniques↗
PubMed1999

Tumoral calcinosis in the premaxillary region.

Tumoral calcinosis, an uncommon pathologic condition that manifests itself in many forms, has rarely been described in the craniofacial region. This report describes a case of tumoral calcinosis affecting the premaxillary region.

Aged↗