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1.
Sci Rep ; 11(1): 19847, 2021 10 06.
Article in English | MEDLINE | ID: mdl-34615966

ABSTRACT

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states. The striatum is involved in the transition from flexible to inflexible responding, and interspersed throughout the striatum are patches, or striosomes, which make up ~15% of the volume of the striatum relative to the surrounding matrix compartment. Previous studies have suggested that patches are necessary for normal habit formation, but it remains unknown exactly how patches contribute to habit formation and expression. Here, using optogenetics, we stimulated striatal patches in Sepw1-NP67 mice during variable interval training (VI60), which is used to establish habitual responding. We found that activation of patches at reward retrieval resulted in elevated responding during VI60 training by modifying the pattern of head entry and pressing. Further, this optogenetic manipulation reduced subsequent responding following reinforcer devaluation, suggesting modified habit formation. However, patch stimulation did not generally increase extinction rates during a subsequent extinction probe, but did result in a small 'extinction burst', further suggesting goal-directed behavior. On the other hand, this manipulation had no effect in omission trials, where mice had to withhold responses to obtain rewards. Finally, we utilized fast-scan cyclic voltammetry to investigate how patch activation modifies evoked striatal dopamine release and found that optogenetic activation of patch projections to the substantia nigra pars compacta (SNc) is sufficient to suppress dopamine release in the dorsal striatum. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and provides a potential mechanism for how patches modify habitual behavior by exerting control over dopamine signaling.


Subject(s)
Corpus Striatum/physiology , Dopamine/metabolism , Habits , Optogenetics , Physical Stimulation , Animals , Corpus Striatum/metabolism , Learning , Locomotion , Mice , Mice, Transgenic , Optogenetics/methods , Substantia Nigra/physiology
2.
Mucosal Immunol ; 11(3): 958-967, 2018 05.
Article in English | MEDLINE | ID: mdl-29411775

ABSTRACT

Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.


Subject(s)
Cytokines/metabolism , Respiratory Mucosa/physiology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/physiology , Antigens, Viral/immunology , Cell Line , Down-Regulation , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Immunity , Interferon Regulatory Factor-1/metabolism , Respiratory Mucosa/pathology , Respiratory Mucosa/virology , Signal Transduction
3.
4.
Pulm Pharmacol Ther ; 22(6): 533-42, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19635581

ABSTRACT

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.


Subject(s)
Bronchodilator Agents/pharmacology , Cholinergic Antagonists/pharmacology , Scopolamine Derivatives/pharmacology , Acetylcholine/physiology , Animals , Bronchodilator Agents/therapeutic use , Cholinergic Antagonists/therapeutic use , Cough/drug therapy , Cough/physiopathology , Humans , Inflammation/pathology , Lung/innervation , Lung/physiology , Mucus/metabolism , Parasympathetic Nervous System/drug effects , Respiratory System/drug effects , Respiratory System/pathology , Scopolamine Derivatives/therapeutic use , Tiotropium Bromide
5.
Eur Respir J ; 32(4): 1068-81, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18827153

ABSTRACT

Inhaled air is contaminated with pathogens and particulates that may deposit in the airways and damage the host. In response to these invaders, the airway epithelium has developed innate immune responses that provide a defence against the invaders and protect the airway structure and function. Thus, the epithelium of conducting airways becomes the "battleground" between the invaders and the host. Recent evidence suggests that airway epithelial surface signalling through the epidermal growth factor receptor (EGFR) is a convergent pathway producing innate immune responses to a variety of infectious and noninfectious noxious stimuli. In the present review, the EGFR signalling pathways leading to airway mucin production, neutrophil recruitment (via interleukin-8 production) and airway epithelial repair were examined. The importance of these findings in human airway diseases was also investigated. The current authors suggest that the exaggerated innate immune responses found in chronic inflammatory airway diseases (e.g. chronic obstructive pulmonary disease, cystic fibrosis and severe asthma) contribute to the pathogenesis or the aggravation of these diseases. Potential therapies include inhibition of the various elements of the described epidermal growth factor receptor cascade. In considering each therapeutic intervention, the potential benefits must be considered in relation to potential deleterious effects.


Subject(s)
Asthma/metabolism , Cystic Fibrosis/metabolism , ErbB Receptors/metabolism , Immunity, Innate , Mucins/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , Animals , Asthma/diagnosis , Cystic Fibrosis/diagnosis , Humans , Interleukin-8/metabolism , Ligands , Models, Biological , Neutrophils/metabolism , Pulmonary Disease, Chronic Obstructive/diagnosis , Reactive Oxygen Species , Signal Transduction
6.
Respir Med ; 102(2): 173-88, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18023995

ABSTRACT

Formoterol is a selective long-acting beta2-adrenergic receptor agonist (LABA) that provides significant and sustained bronchodilatory effect for up to 12h following a single dose. The onset of effect is significantly faster with formoterol compared with an alternative LABA, salmeterol, although both have a similar duration of action. The overall efficacy of formoterol in improving lung function and controlling symptoms of chronic obstructive pulmonary disease (COPD) is comparable to that of salmeterol and potentially superior to that of ipratropium or theophylline. Formoterol provides additional benefit when administered in combination with other bronchodilators or inhaled corticosteroids. In clinical studies, formoterol was well tolerated and had an adverse-event profile similar to that of other beta2-adrenergic receptor agonists. Formoterol is a rapidly acting, well-tolerated, effective beta2-adrenergic receptor agonist that can be regularly used as a long-acting bronchodilator for patients with moderate to severe COPD, as per recommendations of the current treatment guidelines.


Subject(s)
Adrenergic beta-Agonists/therapeutic use , Bronchodilator Agents/therapeutic use , Ethanolamines/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Aged , Bronchodilator Agents/adverse effects , Dose-Response Relationship, Drug , Ethanolamines/adverse effects , Formoterol Fumarate , Humans , Middle Aged , Practice Guidelines as Topic , Randomized Controlled Trials as Topic
7.
Thorax ; 59(11): 992-6, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15516478

ABSTRACT

The epithelial cells lining the airways serve protective functions. The "barrier function" of the epithelium protects the individual from damage by inhaled irritants. The epithelium produces mucins which become hydrated and form a viscoelastic gel which spreads over the epithelial surface. In healthy individuals inhaled foreign materials become entrapped in the mucus and are cleared by mucociliary transport and by coughing. In many chronic inflammatory airway diseases, however, excessive mucus is produced and is inadequately cleared, leading to mucous obstruction and infection. At present there is no specific treatment for hypersecretion. However, the discovery that an epidermal growth factor receptor (EGFR) cascade is involved in mucin production by a wide variety of stimuli suggests that blockade may provide specific treatment for hypersecretory diseases. EGFR pathways have also been implicated in the repair of damaged airway epithelium. The roles of EGFR in airway epithelial cell hypersecretion and epithelial damage and repair are reviewed and future potential treatments are suggested.


Subject(s)
Bronchi/metabolism , Epithelial Cells/metabolism , ErbB Receptors/physiology , Mucins/metabolism , Respiratory Mucosa/metabolism , Humans , Stem Cells/metabolism
8.
Eur Respir J ; 24(4): 594-600, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15459138

ABSTRACT

Increased mucin expression is a feature of nasal polyposis. Corticosteroids reduce polyp size and symptoms, but their effect on mucin production remains unknown. In this study, the effects of intranasal corticosteroids on MUC5AC mucin expression, nasal resistance, eosinophil and neutrophil infiltration, epidermal growth factor receptor (EGFR), interleukin (IL)-8, and tumour necrosis factor (TNF)-alpha expression was assessed in nasal polyps. In nine subjects, one nasal polyp was removed surgically before treatment and another was removed after 8 weeks of intranasal fluticasone (400 microg.day(-1)). Tissues were processed for in situ hybridisation and immunohistochemical staining. Described effects of fluticasone on nasal polyps (reduction in nasal resistance and in eosinophil infiltration) were evaluated. Morphometric analysis was performed to assess the effect of fluticasone on epithelial-, MUC5AC-, EGFR- and IL-8-stained areas, TNF-alpha-stained cells, and neutrophil numbers. Treatment with fluticasone decreased nasal resistance and intra-epithelial eosinophils. The MUC5AC-stained area in the epithelium was unchanged by treatment; MUC5AC mRNA expression was unaffected by treatment. EGFR-stained area, intra-epithelial neutrophil numbers, IL-8 and TNF-alpha expression were also unchanged by therapy. Intranasal fluticasone was effective in decreasing nasal airflow resistance and intra-epithelial eosinophils but had no effect on mucin or epidermal growth factor receptor expression or on neutrophil recruitment.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Androstadienes/administration & dosage , Eosinophils/drug effects , Mucins/drug effects , Nasal Polyps/drug therapy , Administration, Intranasal , ErbB Receptors/biosynthesis , ErbB Receptors/drug effects , Fluticasone , Humans , Interleukin-8/biosynthesis , Mucin 5AC , Mucins/biosynthesis , Neutrophil Infiltration/drug effects , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/drug effects
9.
Eur Respir J ; 20(5): 1263-70, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12449183

ABSTRACT

Hypersecretory disease associated with Pseudomonas aeruginosa (PA) infections is characterised by increased goblet cells and increased mucin production. Recently, an epidermal growth factor receptor (EGFR) signalling cascade was shown to be a common pathway through which many stimuli induce mucin MUC5AC expression in airways by differentiation to a goblet cell phenotype. This study looked at whether PA products induce EGFR expression and activation and thus result in mucin MUC5AC production. Human airway epithelial (NCI-H292) cells were stimulated with PA culture supernatant (Sup). MUC5AC protein production, MUC5AC and EGFR messenger ribonucleic acid (mRNA) expression, and phosphorylated EGFR and phosphorylated p44/42 mitogen-activated protein kinase (MAPK) were all examined using enzyme-linked immunosorbent assay, by in situ hybridisation and by immunoblotting. PA Sup induced MUC5AC mRNA and subsequent protein expression, EGFR and p44/42 MAPK phosphorylation and EGFR mRNA expression. Induction of MUC5AC mRNA and protein expression and EGFR and p44/42 MAPK phosphorylation were inhibited completely by pretreatment with a selective EGFR tyrosine kinase inhibitor. Pretreatment with a selective inhibitor of MAPK kinase prevented MUC5AC production and p44/42 MAPK phosphorylation but not EGFR phosphorylation. The authors conclude that PA products induce mucin MUC5AC production in human airway epithelial cells via the expression and activation of epidermal growth factor receptor.


Subject(s)
ErbB Receptors/physiology , Mucins/biosynthesis , Pseudomonas aeruginosa/physiology , Respiratory Mucosa/metabolism , Cell Line , Cells, Cultured , Culture Media , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , Mucin 5AC , Phosphorylation , Respiratory Mucosa/microbiology
10.
J Immunol ; 167(10): 5948-54, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11698473

ABSTRACT

Eosinophil recruitment and mucus hypersecretion are characteristic of asthmatic airway inflammation, but eosinophils have not been shown to induce mucin production. Because an epidermal growth factor receptor (EGFR) cascade induces MUC5AC mucin in airways, and because EGFR is up-regulated in asthmatic airways, we examined the effect of eosinophils on MUC5AC mucin production in NCI-H292 cells (a human airway epithelial cell line that produces mucins). Eosinophils were isolated from the peripheral blood of allergic patients, and their effects on MUC5AC mucin gene and protein synthesis were assessed using in situ hybridization and ELISAs. When IL-3 plus GM-CSF or IL-3 plus IL-5 were added to eosinophils cultured with NCI-H292 cells, MUC5AC mucin production increased; eosinophils or cytokines alone had no effect. Eosinophil supernatant obtained by culturing eosinophils with IL-3 plus GM-CSF or IL-3 plus IL-5 also increased MUC5AC synthesis in NCI-H292 cells, an effect that was prevented by selective EGFR inhibitors (AG1478, BIBX1522). Supernatant of activated eosinophils induced EGFR phosphorylation in NCI-H292 cells. Supernatant of activated eosinophils contained increased concentrations of TGF-alpha protein (an EGFR ligand) and induced up-regulation of TGF-alpha expression and release in NCI-H292 cells. A blocking Ab to TGF-alpha reduced activated eosinophil-induced MUC5AC synthesis in NCI-H292 cells. These results show that activated eosinophils induce mucin synthesis in human airway epithelial cells via EGFR activation, and they implicate TGF-alpha produced by eosinophils and epithelial cells in the EGFR activation that results in mucin production in human airway epithelium.


Subject(s)
Asthma/immunology , Eosinophils/immunology , ErbB Receptors/metabolism , Mucins/biosynthesis , Pulmonary Eosinophilia/immunology , Respiratory Mucosa/immunology , Adult , Cells, Cultured , Culture Media, Conditioned/pharmacology , Enzyme Inhibitors/pharmacology , Eosinophils/drug effects , ErbB Receptors/antagonists & inhibitors , Humans , Hypersensitivity/immunology , Middle Aged , Mucin 5AC , Mucins/genetics , Phosphorylation , Quinazolines , RNA, Messenger/biosynthesis , Transforming Growth Factor alpha/physiology , Tumor Cells, Cultured , Tyrphostins/pharmacology , Up-Regulation
11.
Respir Res ; 2(2): 85-9, 2001.
Article in English | MEDLINE | ID: mdl-11686870

ABSTRACT

Healthy individuals have few goblet cells in their airways, but in patients with hypersecretory diseases goblet-cell upregulation results in mucus hypersecretion, airway plugging, and death. Multiple stimuli produce hypersecretion via epidermal growth factor receptor (EGFR) expression and activation, causing goblet-cell metaplasia from Clara cells by a process of cell differentiation. These cells are also believed to be the cells of origin of non-small-cell lung cancer, but this occurs via cell multiplication. The mechanisms that determine which pathway is chosen are critical but largely unknown. Although no effective therapy exists for hypersecretion at present, the EGFR cascade suggests methods for effective therapeutic intervention.


Subject(s)
ErbB Receptors/physiology , Mucins/biosynthesis , Animals , Asthma/pathology , Asthma/physiopathology , Cell Differentiation , Cell Division , Epithelial Cells/pathology , Goblet Cells/metabolism , Goblet Cells/pathology , Humans , Lung Neoplasms/pathology , Metaplasia , Mucus/metabolism , Nasal Polyps/pathology , Nasal Polyps/physiopathology , Smoke , Nicotiana
12.
Curr Opin Pharmacol ; 1(3): 254-8, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11712748

ABSTRACT

Airway hypersecretion is a serious and presently untreatable symptom of chronic inflammatory airway diseases. Recently, it has been discovered that epithelial growth factor receptor expression and activation causes mucin production in airways. An epithelial growth factor receptor pathway is implicated in mucus cell differentiation induced by various stimuli; therefore, inhibition of the epithelial growth factor receptor transduction cascade may provide effective new treatments for hypersecretory airway diseases.


Subject(s)
Epidermal Growth Factor/physiology , Mucus/physiology , Allergens/toxicity , Animals , ErbB Receptors/physiology , Humans , Mucins/biosynthesis , Respiratory Tract Diseases/metabolism , Respiratory Tract Diseases/physiopathology , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/physiopathology
13.
J Allergy Clin Immunol ; 107(6): 1046-50, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11398083

ABSTRACT

BACKGROUND: Mucus hypersecretion is a common response to inflammation in the lower airways and is a hallmark of chronic rhinitis. OBJECTIVE: The purpose of this study was to elucidate the mechanisms of regranulation (mucus production) of goblet cells in nasal epithelium. METHODS: Because neutrophils induce an epidermal growth factor (EGFR) cascade, we induced degranulation of goblet cells in rat nasal respiratory epithelium by means of intranasal inhalation of N-formyl-methionyl-leucyl-phenylalanine (fMLP), and we examined regranulation of the goblet cells and the role of EGFR inhibitors and neutrophils in the regranulation process. RESULTS: In the control state Alcian blue/periodic acid-Schiff and mucin MUC5AC staining was present. Degranulation was induced in the nasal septal epithelium 4 hours after intranasal inhalation of fMLP (10(-7) mol/L); 48 hours later, goblet-cell regranulation was complete. In the control state EGFR protein staining was absent in the epithelium, but after fMLP-induced degranulation, EGFR protein was expressed. After pretreatment with BIBX1522, a selective EGFR tyrosine kinase inhibitor, fMLP-induced degranulation was unaffected, but goblet-cell regranulation was prevented completely. CONCLUSION: These data suggest a role for the EGFR cascade in neutrophil-dependent production of goblet-cell mucins. Proving this theory will require the use of selective EGFR inhibitors in clinical studies of nasal hypersecretory states.


Subject(s)
ErbB Receptors/metabolism , Goblet Cells/physiology , Nasal Mucosa/cytology , Signal Transduction , Administration, Intranasal , Animals , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Male , Mucin 5AC , Mucins/metabolism , Mucus/metabolism , N-Formylmethionine Leucyl-Phenylalanine/administration & dosage , Nasal Mucosa/immunology , Neutrophil Activation/immunology , Neutrophils/immunology , Phosphorylation , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Rats
14.
Am J Respir Crit Care Med ; 163(2): 511-6, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11179132

ABSTRACT

To determine the relationship of epidermal growth factor receptor (EGFR) expression to mucin synthesis in human airways, we examined EGFR and MUC5AC expression at both gene and protein levels using in situ hybridization and immunohistochemical analysis in human bronchi. Bronchial mucosal biopsy specimens were obtained from 12 asthmatic subjects and 11 healthy subjects. In asthmatic airways, EGFR mRNA was expressed in the airway epithelium. EGFR immunoreactivity staining patterns varied among the asthmatic airways: staining was positive mainly in goblet cells, in basal cells, or in both. In contrast, healthy airways showed little expression of EGFR mRNA; EGFR immunoreactivity was observed mainly in goblet cells. In parallel to EGFR expression, MUC5AC mRNA expression was greater in asthmatic airways; mucous glycoconjugates that stained positively with Alcian blue/PAS were also increased in asthmatic airways. Ciliated cells were negative for EGFR and MUC5AC both in asthmatic and in healthy subjects at both mRNA and protein levels. There was a significant positive correlation between EGFR immunoreactivity and the area of MUC5AC-positive staining in both asthmatics and healthy subjects. These findings suggest a sequence of events by which EGFR activation is involved in mucin expression in asthmatic airway epithelium.


Subject(s)
Asthma/pathology , Bronchi/pathology , Goblet Cells/pathology , RNA, Messenger/genetics , Adult , Biopsy , Bronchoscopy , ErbB Receptors , Female , Gene Expression/physiology , Humans , Image Processing, Computer-Assisted , Immunoenzyme Techniques , Male , Mucin 5AC , Mucins/genetics
15.
Am J Physiol Lung Cell Mol Physiol ; 280(1): L134-40, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11133503

ABSTRACT

Mucus hypersecretion contributes to the morbidity and mortality in acute asthma. Both T helper 2 (Th2) cytokines and epidermal growth factor receptor (EGFR) signaling have been implicated in allergen-induced goblet cell (GC) metaplasia. Present results show that a cascade of EGFR involving neutrophils is implicated in interleukin (IL)-13-induced mucin expression in GC. Treatment with a selective EGFR tyrosine kinase inhibitor prevented IL-13-induced GC metaplasia dose dependently and completely. Instillation of IL-13 also induced tumor necrosis factor-alpha protein expression, mainly in infiltrating neutrophils. Control airway epithelium contained few leukocytes, but intratracheal instillation of IL-13 resulted in time-dependent leukocyte recruitment by IL-13-induced IL-8-like chemoattractant expression in airway epithelium. Pretreatment with an inhibitor of leukocytes in the bone marrow (cyclophosphamide) or with a blocking antibody to IL-8 prevented both IL-13-induced leukocyte recruitment and GC metaplasia. These findings indicate that EGFR signaling is involved in IL-13-induced mucin production. They suggest a potential therapeutic role for inhibitors of the EGFR cascade in the hypersecretion that occurs in acute asthma.


Subject(s)
ErbB Receptors/metabolism , Interleukin-13/pharmacology , Mucins/biosynthesis , Neutrophil Activation/immunology , Respiratory Mucosa/metabolism , Animals , Antibodies, Blocking/pharmacology , Chemotaxis, Leukocyte/drug effects , Chemotaxis, Leukocyte/immunology , Cyclophosphamide/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , ErbB Receptors/immunology , Goblet Cells/cytology , Goblet Cells/immunology , Goblet Cells/metabolism , Immunosuppressive Agents/pharmacology , Interleukin-8/immunology , Male , Metaplasia , Neutrophil Activation/drug effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Rats , Rats, Inbred F344 , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Specific Pathogen-Free Organisms , Th2 Cells/immunology , Tumor Necrosis Factor-alpha/biosynthesis
16.
Am J Physiol Lung Cell Mol Physiol ; 280(1): L165-72, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11133506

ABSTRACT

Mucus hypersecretion from hyperplastic airway goblet cells is a hallmark of chronic obstructive pulmonary disease (COPD). Although cigarette smoking is thought to be involved in mucus hypersecretion in COPD, the mechanism by which cigarette smoke induces mucus overproduction is unknown. Here we show that activation of epidermal growth factor receptors (EGFR) is responsible for mucin production after inhalation of cigarette smoke in airways in vitro and in vivo. In the airway epithelial cell line NCI-H292, exposure to cigarette smoke upregulated the EGFR mRNA expression and induced activation of EGFR-specific tyrosine phosphorylation, resulting in upregulation of MUC5AC mRNA and protein production, effects that were inhibited completely by selective EGFR tyrosine kinase inhibitors (BIBX1522, AG-1478) and that were decreased by antioxidants. In vivo, cigarette smoke inhalation increased MUC5AC mRNA and goblet cell production in rat airways, effects that were prevented by pretreatment with BIBX1522. These effects may explain the goblet cell hyperplasia that occurs in COPD and may provide a novel strategy for therapy in airway hypersecretory diseases.


Subject(s)
ErbB Receptors/metabolism , Goblet Cells/metabolism , Mucins/biosynthesis , Respiratory Mucosa/metabolism , Smoking/metabolism , Animals , Cell Differentiation/drug effects , Enzyme Inhibitors/pharmacology , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , ErbB Receptors/genetics , Gene Expression/drug effects , Goblet Cells/drug effects , Humans , In Vitro Techniques , Lung Diseases, Obstructive/etiology , Lung Diseases, Obstructive/metabolism , Mucin 5AC , Mucins/genetics , Phosphorylation , Protein-Tyrosine Kinases/antagonists & inhibitors , RNA, Messenger/analysis , Rats , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Smoking/adverse effects , Specific Pathogen-Free Organisms , Tyrosine/metabolism
17.
Acta Otolaryngol ; 120(6): 757-60, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11099154

ABSTRACT

Allergic rhinitis is an inflammatory disease associated with local leukotriene release during periods of symptoms. Zileuton, a leukotriene synthesis inhibitor, is known to inhibit the release of leukotriene B4. Because we previously showed that leukotriene B4 is a potent mediator of neutrophil-dependent nasal secretion, we investigated whether Zileuton inhibited allergen-induced nasal secretion. Using a newly developed method for isolating and superfusing a nasal segment, we examined the effect of Zileuton on nasal secretion and neutrophil recruitment in ragweed-sensitized dogs. Instillation of ragweed into the nasal segment caused time-dependent increases in the volume of airway fluid and the recruitment of neutrophils. Zileuton prevented ragweed-induced neutrophil recruitment and nasal secretion. These results indicate that leukotrienes are important mediators of allergy-induced nasal secretion in dogs. Future clinical studies in allergic patients will determine whether there is a therapeutic role for leukotriene synthesis inhibitors in modulating neutrophil recruitment and hypersecretion in the nose.


Subject(s)
Hydroxyurea/pharmacology , Hypersensitivity/etiology , Leukotriene Antagonists/pharmacology , Leukotriene B4/antagonists & inhibitors , Leukotriene B4/biosynthesis , Nasal Mucosa/metabolism , Nasal Obstruction/physiopathology , Plants , Pollen/adverse effects , Rhinitis, Allergic, Seasonal/physiopathology , Animals , Dogs , Hydroxyurea/analogs & derivatives , Hydroxyurea/therapeutic use , Leukotriene Antagonists/therapeutic use , Nasal Provocation Tests , Neutrophils/drug effects , Neutrophils/metabolism , Rhinitis, Allergic, Seasonal/drug therapy , Time Factors
18.
Clin Exp Allergy ; 30(12): 1799-803, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11122220

ABSTRACT

Leukotriene B4 (LTB4), an inflammatory mediator, is a potent chemoattractant for neutrophils that plays an important role in nasal secretion via release of elastase. Nitric oxide (NO) is an important modulator of leucocyte-endothelial cell interactions, endogenously produced in large quantities in the paranasal sinuses. To examine the role of NO in LTB4-stimulated nasal secretion. A newly-developed method for isolating and superfusing a nasal segment in dogs was used. Instillation of LTB4 into the nasal segment caused a time-dependent increase in the volume of airway fluid and in the recruitment of neutrophils. N(G)-nitro-L-arginine-methylester (L-NAME), an inhibitor of NO synthase, prevented LTB4-induced neutrophil recruitment and nasal secretion. These studies show that NO modulates LTB4-induced neutrophil recruitment and subsequent fluid secretion in the nose, and they suggest a therapeutic role for NO inhibitors in modulating neutrophil-dependent nasal secretion.


Subject(s)
Free Radical Scavengers/pharmacology , Nasal Mucosa/drug effects , Neutrophils/immunology , Nitric Oxide/pharmacology , Animals , Arginine/analogs & derivatives , Arginine/pharmacology , Dogs , Leukocyte Count , Leukotriene B4/pharmacology , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Neutrophil Activation/drug effects
19.
J Allergy Clin Immunol ; 106(4): 705-12, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11031341

ABSTRACT

BACKGROUND: Because the epidermal growth factor receptor (EGFR) system regulates mucin production in airway epithelium, we hypothesized a role for this system in mucus hypersecretion that occurs in nasal polyposis. OBJECTIVE: We examined the relationship between goblet cell hyperplasia, EGFR expression, and inflammatory mediators produced by eosinophils and neutrophils in nasal polyp tissues. METHODS: Nasal polyp tissue samples from 8 patients and nasal turbinate biopsy specimens from 6 normal control subjects were examined for alcian blue/PAS staining, mucin MUC5AC (MUC5AC), and EGFR immunoreactivity and EGFR gene expression (in situ hybridization). We also examined the role of eosinophils and neutrophils in goblet cell hyperplasia. RESULTS: In control nasal mucosa alcian blue/periodic acid-Schiff- and MUC5AC-stained areas were 18.40% +/- 1.31% and 21.89% +/- 1.43%, respectively. In polyps the alcian blue/periodic acid-Schiff- and MUC5AC-stained areas were 51.30% +/- 5.85% and 52.07% +/- 6.58%, which was significantly larger than that found in control subjects (each comparison, P <.01). Four of 6 control specimens expressed EGFR messenger RNA and protein weakly in the epithelium. In polyps 4 of 8 specimens expressed EGFR gene and EGFR protein strongly; the EGFR-stained area was greater in hyperplastic than in pseudostratified epithelium. TNF-alpha immunoreactivity, expressed in eosinophils, was increased in EGFR-positive polyps compared with EGFR-negative polyps, suggesting a role for TNF-alpha in EGFR expression. Neutrophils were increased in the epithelium of EGFR-positive compared with EGFR-negative polyps, suggesting a role for these cells in mucin expression and in goblet cell degranulation. CONCLUSION: These data suggest a role for EGFR cascade in the regulation of goblet cell mucins in nasal polyps. Proof of concept will require clinical studies using selective EGFR inhibitors.


Subject(s)
ErbB Receptors/biosynthesis , Goblet Cells/pathology , Nasal Polyps/metabolism , Nasal Polyps/pathology , Cell Movement , Epithelial Cells/metabolism , ErbB Receptors/genetics , Gene Expression , Humans , Hyperplasia/metabolism , Mucins/genetics , Neutrophils/cytology , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/immunology
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