[Show abstract][Hide abstract] ABSTRACT: Background and Objective
Abnormal vocal cord movement may coexist with asthma and cause additional upper/middle airway obstruction. The condition may be a form of muscular dystonia that could contribute to asthma resistant to optimised treatments. Botulinum toxin causes temporary paralysis of muscle and may be an effective local treatment that improves asthma control.Methods
In an observational study, we evaluated the benefits of unilateral vocal cord injection with botulinum toxin in 11 patients (total 24 injections). Subjects had asthma resistant to optimised treatment and abnormal vocal cord movement. Responses after botulinum toxin treatment were assessed using asthma control test (ACT) scores, vocal cord narrowing quantified by computerised tomography (CT) of the larynx and spirometry. Side-effects were recorded.ResultsACT scores improved overall (9.1 ± 2.4 before and 13.5 ± 4.5 after treatment; difference 4.4 ± 4.2; P < 0.001). There was also an improvement in airway size on CT larynx (time below lower limit of normal at baseline 39.4 ± 37.63% and improved to 17.6 ± 25.6% after injection; P = 0.032). Spirometry was not altered. One patient experienced an asthma exacerbation but overall side-effects were moderate, chiefly dysphonia and dysphagia.Conclusions
Although a placebo effect cannot be ruled out, local injection of botulinum toxin may be an effective treatment for intractable asthma associated with abnormal vocal cord movement. Further mechanistic studies and a double-blind randomised controlled trial of botulinum toxin treatment are merited.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary emphysema is linked to T cell-mediated autoimmune inflammation, although the pathogenic role of specific pro-inflammatory cytokines remains unclear. The Th17 type response, characterized by the production of the cytokine interleukin (IL)-17A, is modulated in part by the IL-6/signal transducer and activator of transcription (Stat)3 signalling axis and is associated with numerous autoimmune diseases. We therefore evaluated a causal role for IL-17A in the IL-6-driven gp130(F) (/) (F) mouse model for spontaneous pulmonary inflammation and emphysema.
The expression of Th17-related factors was quantified in the lungs of gp130(F) (/) (F) mice and emphysematous patients, and the degree of pulmonary inflammation and emphysema was measured in gp130(F) (/) (F) : Il17a(-/-) mice by immunohistochemistry, stereology and respiratory mechanics.
In gp130(F) (/) (F) mice, lung gene expression of Il17a and other Th17-related factors was augmented compared with gp130(+/+) (wild-type), gp130(F) (/) (F) : Il6(-/-) and gp130(F) (/) (F) : Stat3(-/+) mice displaying normalized Stat3 activity and no lung inflammation. Importantly, genetic ablation of Il17a in gp130(F) (/) (F) : Il17a(-/-) mice prevented lung inflammation; however, emphysema still developed. Additionally, messenger RNA expression of inflammatory genes Cxcl1, Cxcl2, Ccl2 and Tnfα; as well as Il6 and the Stat3-target gene, Socs3, were upregulated in the lungs of gp130(F) (/) (F) mice compared with gp130(F) (/) (F) : Il17a(-/-) and gp130(+/+) mice. Consistent with these findings, augmented IL17A expression was observed in emphysema patients presenting with inflammation compared with inflammation-free individuals.
Collectively, our data suggest that the integration of IL-17A into the IL-6/Stat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL-17A may alleviate pulmonary inflammatory-related diseases.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic bilateral vocal cord paralysis (VCP) is a rare and difficult condition often undiagnosed and frequently confused with asthma and other respiratory conditions. Accurate diagnosis is crucial since 80% of cases patients require surgical intervention, such as tracheostomy or laser surgery, to relieve symptoms. The “gold standard” for diagnosing VCP has been laryngoscopy. In this case study, we demonstrate for the first time that idiopathic bilateral VCP can be accurately diagnosed by means of a novel noninvasive methodology: dynamic volume 320-slice computed tomography larynx. Three-dimensional reconstruction of laryngeal motion during the breathing cycle permitted functional assessment of the larynx showing absence of vocal cord movements. The new methodology may be valuable for noninvasive diagnosis of vocal cord movement disorders before and for follow-up after surgery.
[Show abstract][Hide abstract] ABSTRACT: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically 'phenotype' AECOPD have been proposed, and 52 hospitalized chronic obstructive pulmonary disease exacerbations according to underlying aetiology have now been prospectively phenotyped. Multiple exacerbation phenotypes were identified. A subpopulation coinfected with virus and bacteria had a significantly longer length of hospital stay, and this pilot study indicates that exacerbation phenotyping may be advantageous.
[Show abstract][Hide abstract] ABSTRACT: Tracheomalacia, tracheobronchomalacia, and excessive dynamic airway collapse are all terms used to describe tracheal narrowing in expiration. The first two describe luminal reduction from cartilage softening and the latter refers to luminal reduction from exaggerated posterior membrane movement. Expiratory tracheal narrowing is a frequent occurrence that can cause symptoms of airway obstruction, such as dyspnoea, wheeze, and exercise intolerance. The accurate diagnosis and quantification of expiratory tracheal narrowing has important aetiological, therapeutic, and prognostic implications. The reference standard for diagnosis has traditionally been bronchoscopy; however, this method has significant limitations. Expiratory tracheal disorders are readily detected by four-dimensional dynamic volume multidetector computed tomography (4D-CT), an emerging, non-invasive method that will potentially enable detection and quantification of these conditions. This review discusses the morphological forms of expiratory tracheal narrowing and demonstrates the utility of 4D-CT in the diagnosis, quantification, and treatment of these important conditions.
[Show abstract][Hide abstract] ABSTRACT: Human Rhinovirus (HRV) infection results in shut down of essential cellular processes, in part through disruption of nucleocytoplasmic transport by cleavage of the nucleoporin proteins (Nups) that make up the host cell nuclear pore. Although the HRV genome encodes two proteases (2A and 3C) able to cleave host proteins such as Nup62, little is known regarding the specific contribution of each. Here we use transfected as well as HRV-infected cells to establish for the first time that 3C protease is most likely the mediator of cleavage of Nup153 during HRV infection, while Nup62 and Nup98 are likely to be targets of HRV2A protease. HRV16 3C protease was also able to elicit changes in the appearance and distribution of the nuclear speckle protein SC35 in transfected cells, implicating it as a key mediator of the mislocalisation of SC35 in HRV16-infected cells. In addition, 3C protease activity led to the redistribution of the nucleolin protein out of the nucleolus, but did not affect nuclear localisation of hnRNP proteins, implying that complete disruption of nucleocytoplasmic transport leading to relocalisation of hnRNP proteins from the nucleus to the cytoplasm in HRV-infected cells almost certainly requires 2A in addition to 3C protease. Thus, a specific role for HRV 3C protease in cleavage and mislocalisation of host cell nuclear proteins, in concert with 2A, is implicated for the first time in HRV pathogenesis.
PLoS ONE 01/2013; 8(8):e71316. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation that persists after the cessation of smoking. T cells have a major role in driving inflammation in patients with COPD and are activated by specific antigens to produce mediators, such as cytokines. The antigens that activate lung T cells have not been clearly defined. Nontypeable Haemophilus influenzae (NTHi) is the dominant bacterium isolated from the lungs of patients with COPD. Objective: We sought to measure the response of lung tissue T cells to stimulation with NTHi. METHODS: We obtained lung tissue from 69 subjects having lobectomies for lung cancer. Of the group, 39 subjects had COPD, and 30 without COPD were classified as control subjects. The lung tissue was dispersed into single-cell suspensions and stimulated with live NTHi. Cells were labeled with antibodies for 5 important inflammatory mediators in patients with COPD and analyzed by using flow cytometry. RESULTS: NTHi produced strong activation of both T(H) cells and cytotoxic T cells in the COPD cohort. The COPD cohort had significantly higher levels of cells producing TNF-α, IL-13, and IL-17 in both T-cell subsets. When control subjects were divided into those with and without a significant smoking history and compared with patients with COPD, there was a progressive increase in the numbers of T cells producing cytokines from nonsmoking control subjects to smoking control subjects to patients with COPD. CONCLUSION: NTHi activates lung T cells in patients with COPD. This proinflammatory profibrotic response might be a key cause of inflammation in patients with COPD and has implications for treatment.
The Journal of allergy and clinical immunology 11/2012; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Lower airway obstruction has evolved to denote pathologies associated with diseases of the lung, whereas, conditions proximal to the lung embody upper airway obstruction. This approach has disconnected diseases of the larynx and trachea from the lung, and removed the 'middle airway' from the interest and involvement of respiratory physicians and scientists. However, recent studies have indicated that dysfunction of this anatomical region may be a key component of overall airway obstruction, either independently or in combination with lung disease. New diagnostic modalities to effectively diagnose middle airway obstruction are being developed, and it has become feasible to identify and quantify middle airway obstruction. CONCLUSION: We, therefore, propose adding 'middle airway obstruction' to our nomenclature to embed it in diagnostic approaches, and to allow due emphasis on this neglected anatomical region.
[Show abstract][Hide abstract] ABSTRACT: Respiratory syncytial virus (RSV) is the major respiratory pathogen of infants and children worldwide, with no effective treatment or vaccine available. Steady progress has been made in understanding the respiratory syncytial virus lifecycle and the consequences of infection, but some areas of RSV still remain poorly understood. Although many of the interactions between virus proteins that are required for efficient RSV assembly have been elucidated, many questions still remain regarding viral assembly, as well as the mechanisms of RSV budding. This review will summarise the current understanding of RSV assembly, including the various interactions between virus proteins and the involvement of cellular factors with a view to identifying possible attenuation and/or drug targets within the assembly pathway.
Infectious disorders drug targets. 02/2012; 12(2):103-9.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-6 is a potent immunomodulatory cytokine that is associated with emphysema, a major component of chronic obstructive pulmonary disease (COPD). IL-6 signaling via the gp130 coreceptor is coupled to multiple signaling pathways, especially the latent transcription factor signal transducer and activator of transcription (Stat)3. However, the pathological role of endogenous gp130-dependent Stat3 activation in emphysema is ill defined. To elucidate the role of the IL-6/gp130/Stat3 signaling axis in the cellular and molecular pathogenesis of emphysema, we employed a genetic complementation strategy using emphysematous gp130(F/F) mice displaying hyperactivation of endogenous Stat3 that were interbred with mice to impede Stat3 activity. Resected human lung tissue from patients with COPD and COPD-free individuals was also evaluated by immunohistochemistry. Genetic reduction of Stat3 hyperactivity in gp130(F/F):Stat3(-/+) mice prevented lung inflammation and excessive protease activity; however, emphysema still developed. In support of these findings, Stat3 activation levels in human lung tissue correlated with the extent of pulmonary inflammation but not airflow obstruction in COPD. Furthermore, COPD lung tissue displayed increased levels of IL-6 and apoptotic alveolar cells, supporting our previous observation that increased endogenous IL-6 expression in the lungs of gp130(F/F) mice contributes to emphysema by promoting alveolar cell apoptosis. Collectively, our data suggest that IL-6 promotes emphysema via upregulation of Stat3-independent apoptosis, whereas IL-6 induction of lung inflammation occurs via Stat3. We propose that while discrete targeting of Stat3 may alleviate pulmonary inflammation, global targeting of IL-6 potentially represents a therapeutically advantageous approach to combat COPD phenotypes where emphysema predominates.
[Show abstract][Hide abstract] ABSTRACT: Upper airway dysfunction may complicate asthma but has been largely ignored as an etiological factor. Diagnosis using endoscopic evaluation of vocal cord function is difficult to quantify, with limited clinical application.
A novel imaging technique, dynamic 320-slice computerized tomography (CT), was used to examine laryngeal behavior in healthy individuals and individuals with asthma.
Vocal cord movement was imaged using 320-slice CT larynx. Healthy volunteers were studied to develop and validate an analysis algorithm for quantification of normal vocal cord function. Further studies were then conducted in 46 patients with difficult-to-treat asthma.
Vocal cord movement was quantified over the breathing cycle by CT using the ratio of vocal cord diameter to tracheal diameter. Normal limits were calculated, validated, and applied to evaluate difficult-to-treat asthma. Vocal cord movement was abnormal with excessive narrowing in 23 of 46 (50%) patients with asthma and severe in 9 (19%) patients (abnormal > 50% of inspiration or expiration time). Imaging also revealed that laryngeal dysfunction characterized the movement abnormality rather than isolated vocal cord dysfunction.
Noninvasive quantification of laryngeal movement was achieved using CT larynx. Significant numbers of patients with difficult-to-treat asthma had excessive narrowing of the vocal cords. This new approach has identified frequent upper airway dysfunction in asthma with potential implications for disease control and treatment.
American Journal of Respiratory and Critical Care Medicine 03/2011; 184(1):50-6. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The IL-6 cytokine family, which signals via the shared gp130 coreceptor, is linked with the pathogenesis of emphysema. However, the definitive mechanisms by which these cytokines cause emphysema remain ill-defined. We took an in vivo genetic complementation approach to identify the specific IL-6 cytokine family members and gp130-regulated cellular processes that cause emphysema. We used gp130(F/F) mice homozygous for a subtle knock-in mutation in gp130 that deregulates intracellular signaling by the IL-6 cytokine family. The gp130(F/F) mice spontaneously develop emphysema by age 6 months. Within the IL-6 cytokine family, only IL-6 was significantly up-regulated in the lungs of gp130(F/F) mice, and the genetic targeting of IL-6 in gp130(F/F) mice (gp130(F/F):IL-6(-/-)) prevented emphysema. By contrast, the genetic ablation of receptor signaling via IL-11, which like IL-6 signals via a gp130 homodimer and uses the same signaling machinery, failed to ameliorate emphysema in gp130(F/F) mice. Among the disease-associated processes examined, emphysema strongly correlated with elevated alveolar cell apoptosis. Acute (4-day) exposure to cigarette smoke (CS) further augmented the expression of IL-6 in lungs of gp130(F/F) mice, and subchronic (6-week) exposure to CS exacerbated emphysematous and apoptotic changes in the lungs of gp130(F/F) but not gp130(F/F): IL-6(-/-) mice. IL-6 is the main causative agent of IL-6 cytokine family-induced emphysema, and operates to induce apoptosis in the lung. We propose that the discrete targeting of IL-6 signaling may provide an effective therapeutic strategy against human lung disease.
American Journal of Respiratory Cell and Molecular Biology 02/2011; 45(4):720-30. · 4.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: COPD exacerbations have traditionally been defined on the basis of symptoms or health-care utilization without specific reference to the suspected aetiology. Consequently, the term 'exacerbation' has been used to include all patients experiencing an acute deterioration of symptoms associated with COPD. However, exacerbations are known to result from a variety of causes and do not necessarily constitute an equivalent event in the same patient, between different patients or between individual research studies. We therefore hypothesize that phenotyping exacerbations by aetiology may identify exacerbation subgroups, clarify benefits of therapeutic intervention in the subgroups and overall improve clinical care. An acronym is proposed to facilitate phenotyping COPD exacerbations.
[Show abstract][Hide abstract] ABSTRACT: A 56-year-old female nonsmoker presented with episodic hemoptysis, without any other associated respiratory symptoms. Her medical history was notable for polycythemia rubra vera with portal vein thrombosis, which was treated with warfarin, but was complicated by portal hypertension. Esophageal varices were controlled by endoscopic band ligation. Chest radiograph and 64-slice computed tomography scanning failed to identify a culprit lesion. Bronchoscopy identified a vascular structure in the proximal trachea. A contrast-enhanced 320-multidetector row computed tomography scan of the neck showed a tortuous vascular channel in the trachea, which changed in appearance over time, consistent with a tracheal varix. The patient was changed to aspirin therapy and was evaluated by a cardiothoracic surgeon. A conservative approach was adopted, and the patient has had no recurrence of symptoms.
Journal of thoracic imaging 02/2011; 27(1):W10-2. · 1.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Swallowing is closely coordinated with breathing but in COPD altered synchronization may predispose patients to a breach of the upper airway protective mechanisms. However, aspiration during swallow has never been shown in COPD. We examined penetration of liquid material into the airway of patients with COPD and correlated it with breathing-swallow patterns.
A case-control study was performed. Patients with COPD (n = 16) were matched with normal control subjects (n = 15). Sub-mandibular videofluoroscopy was carried out during swallow of graduated volumes of barium to detect penetration (contrast enters the airway and may contact vocal folds) and aspiration (contrast passes glottis). Respiration was monitored simultaneously to gauge synchronization. Hospitalization and mortality were assessed after 36 months.
Penetration/aspiration scores were higher in patients with COPD (3.3 ± 0.7 vs 1.6 ± 0.4 in healthy controls, P = 0.03; mean ± SE). Penetration with aspiration was observed in 4/16 patients with COPD versus 1/15 controls (P = 0.07). Penetration with or without aspiration was found in 6/16 patients (P = 0.04). Inspiration-swallow-expiration patterns were favoured in individuals with COPD (P = 0.02). Penetration/aspiration was associated with higher respiratory rates (P = 0.01), reduced hyoid elevation (P = 0.04), post-swallow larynx penetration (P = 0.05) and oxygen desaturation (P = 0.01). There was a trend for the penetration/aspiration group to have an adverse outcome.
Upper airway protective mechanisms may be flawed in COPD, possibly through reduced coordination of breathing with swallowing. This abnormality may contribute to COPD morbidity in a subgroup of patients.
[Show abstract][Hide abstract] ABSTRACT: Allergy and allergens have been implicated in asthma and it has historically been assumed that deteriorating asthma is related to allergen exposure. In the current pro/con debate some leading academics and researchers in the field consider this notion in the light of recent evidence. They conclude that allergy does not directly cause exacerbations but suggest that it may contribute to acute asthma in a different fashion. Possibilities that are proposed by the authors include specific allergy phenotypes acting as risk factors for virus-associated exacerbations or alternatively that allergy may be implicated in the blunted innate immune responses detected in asthma.