Christopher Grainge

Effect of Bronchoconstriction on Airway Remodeling in Asthma

BACKGROUND Asthma is characterized pathologically by structural changes in the airway, termed airway remodeling. These changes are associated with worse long-term clinical outcomes and have been attributed to eosinophilic inflammation. In vitro studies indicate, however, that the compressive mechanical forces that arise during bronchoconstriction may induce remodeling independently of inflammation. We evaluated the influence of repeated experimentally induced bronchoconstriction on airway structural changes in patients with asthma. METHODS We randomly assigned 48 subjects with asthma to one of four inhalation challenge protocols involving a series of three challenges with one type of inhaled agent presented at 48-hour intervals. The two active challenges were with either a dust-mite allergen (which causes bronchoconstriction and eosinophilic inflammation) or methacholine (which causes bronchoconstriction without eosinophilic inflammation); the two control challenges (neither of which causes bronchoconstriction) were either saline alone or albuterol followed by methacholine (to control for nonbronchoconstrictor effects of methacholine). Bronchial-biopsy specimens were obtained before and 4 days after completion of the challenges. RESULTS Allergen and methacholine immediately induced similar levels of bronchoconstriction. Eosinophilic inflammation of the airways increased only in the allergen group, whereas both the allergen and the methacholine groups had significant airway remodeling not seen in the two control groups. Subepithelial collagen-band thickness increased by a median of 2.17 μm in the allergen group (interquartile range [IQR], 0.70 to 3.67) and 1.94 μm in the methacholine group (IQR, 0.37 to 3.24) (P<0.001 for the comparison of the two challenge groups with the two control groups); periodic acid-Schiff staining of epithelium (mucus glands) also increased, by a median of 2.17 percentage points in the allergen group (IQR, 1.03 to 4.77) and 2.13 percentage points in the methacholine group (IQR, 1.14 to 7.96) (P=0.003 for the comparison with controls). There were no significant differences between the allergen and methacholine groups. CONCLUSIONS Bronchoconstriction without additional inflammation induces airway remodeling in patients with asthma. These findings have potential implications for management.

Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma.

Background Molecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches. Objective We aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers. Methods Induced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis. Results In 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67–83) vs 43% (29–67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count. Conclusions Airway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that responds less well to current asthma therapies.

Exogenous IFN-β has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus

BACKGROUND Rhinoviruses are the major cause of asthma exacerbations. Previous studies suggest that primary bronchial epithelial cells (PBECs) from asthmatic subjects are more susceptible to rhinovirus infection because of deficient IFN-β production. Although augmenting the innate immune response might provide a novel approach for treatment of virus-induced asthma exacerbations, the potential of IFN-β to modulate antiviral and proinflammatory responses in asthmatic epithelium is poorly characterized. OBJECTIVES We sought to compare responses of PBECs from nonasthmatic and asthmatic subjects to exogenous IFN-β and test the inflammatory effects of IFN-β in response to rhinovirus infection. METHODS PBECs were treated with IFN-β and infected with a low inoculum of human rhinovirus serotype 1B to simulate a natural viral infection. Expression of interferon-responsive genes and inflammatory responses were analyzed by using reverse transcription-quantitative real-time PCR, cytometric bead arrays, or both; viral titers were assessed by using the 50% tissue culture infection dose. RESULTS Expression of IFN-β-stimulated antiviral genes was comparable in PBECs from nonasthmatic or asthmatic donors. Exogenous IFN-β significantly protected PBECs from asthmatic donors against rhinovirus infection by suppressing viral replication. Interferon-inducible protein 10 (IP-10), RANTES, and IL-6 release in response to rhinovirus infection was triggered only in PBECs from asthmatic donors. Although exogenous IFN-β alone stimulated some release of IP-10 (but not IL-6 or RANTES), it significantly reduced rhinovirus-induced IP-10, RANTES, and IL-6 expression when tested in combination with rhinovirus. CONCLUSIONS PBECs from asthmatic donors have a normal antiviral response to exogenous IFN-β. The ability of IFN-β to suppress viral replication suggests that it might limit virus-induced exacerbations by shortening the duration of the inflammatory response.

Epithelial Injury and Repair in Airways Diseases

Asthma is a common chronic disease characterized by variable respiratory distress with underlying airway inflammation and airflow obstruction. The incidence of asthma has risen inexorably over the past 50 years, suggesting that environmental factors are important in its etiology. All inhaled environmental stimuli interact with the lung at the respiratory epithelium, and it is a testament to the effectiveness of the airway innate defenses that the majority of inhaled substances are cleared without the need to elicit an inflammatory response. However, once this barrier is breached, effective communication with immune and inflammatory cells is required to protect the internal milieu of the lung. In asthma, the respiratory epithelium is known to be structurally and functionally abnormal. Structurally, the epithelium shows evidence of damage and has more mucus-producing cells than normal airways. Functionally, the airway epithelial barrier can be more permeable and more sensitive to oxidants and show a deficient innate immune response to respiratory virus infection compared with that in normal individuals. The potential of a susceptible epithelium and the underlying mesenchyme to create a microenvironment that enables deviation of immune and inflammatory responses to external stimuli may be crucial in the development and progression of asthma. In this review, we consider three important groups of environmental stimuli on the epithelium in asthma: oxidants, such as environmental pollution and acetaminophen; viruses, including rhinovirus; and agents that cause barrier disruption, such as house dust mite allergens. The pathology associated with each stimulus is considered, and potential future treatments arising from research on their effects are presented.

Management of phosgene-induced acute lung injury

Context. Phosgene is a substance of immense importance in the chemical industry. Because of its widespread industrial use, there is potential for small-scale exposures within the workplace, large-scale accidental release, or even deliberate release into a built-up area. Objective. This review aims to examine all published studies concerning potential treatments for phosgene-induced acute lung injury and incorporate them into up-to-date clinical guidance. In addition, it aims to contrast the approaches when dealing with small numbers of patients known to be exposed (possibly with dose information) with the presentation of a large and heterogeneous population of casualties following a significant industrial accident or deliberate release; no published guidelines have specifically addressed this second problem. Methods. PubMed and Embase were searched for all available years till April 2010 and 584 papers were identified and considered. Experimental studies. Because of the nature of the injury, there have been no human trials of patients exposed to phosgene. Multiple small and large animal studies have been performed to examine potential treatments of phosgene-induced acute lung injury, but many of these used isolated organ models, pretreatment regimens, or clinically improbable doses. Recent studies in large animals using both realistic time frames and dosing regimens have improved our knowledge, but clinical guidance remains based on incomplete data. Management of a small-scale, confirmed exposure. In the circumstance of a small-scale, confirmed industrial release where a few individuals are exposed and present rapidly, an intravenous bolus of high-dose corticosteroid (e.g., methylprednisolone 1 g) should be considered, although there are no experimental data to support this recommendation. The evidence is that there is no benefit from nebulized steroid even when administered 1 h after exposure, or methylprednisolone if administered intravenously ≥6 h after exposure. Consideration should also be given to administration of nebulized acetylcysteine 1–2 g, though there is no substantive evidence of benefit outside a small animal, isolated lung model and there is a possibility of adverse effects. If the oxygen saturation falls below 94%, patients should receive the lowest concentration of supplemental oxygen to maintain their SaO2 in the normal range. Once patients require oxygen, nebulized β-agonists [e.g., salbutamol (albuterol) 5 mg by nebulizer every 4 h] may reduce lung inflammation if administered within 1 h of exposure. Elective intubation should be considered early using an ARDSnet protective ventilation strategy. Management of a large-scale, non-confirmed exposure. In the circumstances of a large-scale industrial or urban release, not all patients presenting will have been exposed and health services are likely to be highly stretched. In this situation, patients should not be treated immediately as there is no evidence that delaying therapy causes harm, rather they should be rested and observed with regular physical examination and measurement of peripheral oxygen saturations. Once a patients oxygen saturation falls below 94%, treatment with the lowest concentration of oxygen required to maintain their oxygen saturations in the normal range should be started. Once oxygen has been started, nebulized β-agonists [e.g., salbutamol (albuterol) 5 mg by nebulizer every 4 h] may reduce lung inflammation if administered within 1 h of exposure, though delayed administration which is likely following a large-scale release has not been tested formally. There is no benefit from nebulized steroid even when administered 1 h after exposure, or high-dose corticosteroid if administered intravenously ≥6 h after exposure. Although there are no experimental data to support this recommendation, an intravenous bolus of high-dose corticosteroid (e.g., methylprednisolone 1 g) may be considered if presentation is <6 h and resources allow. Depending on the numbers of casualties presenting, invasive ventilation should be initiated either electively once symptoms present (especially where there is a short latent period, indicating likelihood of more significant injury), or delayed until required. Ventilation should be with high positive end expiratory pressure, ARDSnet recommended ventilation. Conclusions. The mechanisms underlying the phosgene-induced acute lung injury are not well understood. Future experimental work should ensure that potential treatments are tested in a large animal model using realistic dosing regimens and clinically relevant timings, such as those that might be found in a mass casualty situation.

Bronchoconstriction and Airway Biology : Potential Impact and Therapeutic Opportunities

Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma.

The allergen specificity of the late asthmatic reaction

To cite this article: Hatzivlassiou M, Grainge C, Kehagia V, Lau L, Howarth PH. The allergen specificity of the late asthmatic reaction. Allergy 2010; 65: 355–358.

Delayed low-dose supplemental oxygen improves survival following phosgene-induced acute lung injury

Phosgene is a chemical widely used in the plastics industry and has been used in warfare. It produces life-threatening pulmonary edema within hours of exposure; no antidote exists. This study examines pathophysiological changes seen following treatment with elevated inspired oxygen concentrations (Fio2), in a model of phosgene-induced acute lung injury. Anesthetized pigs were exposed to phosgene (Ct 2500 mg min m−3) and ventilated (intermittent positive pressure ventilation, tidal volume 10 ml kg−1, positive end-expiratory pressure 3 cm H2O, frequency 20 breaths min−1). The Fio2 was varied: group 1, Fio2 0.30 (228 mm Hg) throughout; group 2, Fio2 0.80 (608 mm Hg) immediately post exposure, to end; group 3, Fio2 0.30 from 30 min post exposure, increased to 0.80 at 6 h post exposure; group 4, Fio2 0.30 from 30 min post exposure, increased to 0.40 (304 mm Hg) at 6 h post exposure. Group 5, Fio2 0.30 from 30 min post exposure, increased to 0.40 at 12 h post exposure. The current results demonstrate that oxygen is beneficial, with improved survival, arterial oxygen saturation, shunt fraction, and reduced lung wet weight to body weight ratio in all treatment groups, and improved arterial oxygen partial pressure in groups 2 and 3, compared to phosgene controls (group 1) animals. The authors recommend that treatment of phosgene-induced acute lung injury with inspired oxygen is delayed until signs or symptoms of hypoxia are present or arterial blood oxygenation falls. The lowest concentration of oxygen that maintains normal arterial oxygen saturation and absence of clinical signs of hypoxia is recommended.

Early Treatment with Nebulised Salbutamol Worsens Physiological Measures and Does Not Improve Survival Following Phosgene Induced Acute Lung Injury

Objectives To examine the effectiveness of nebulised salbutamol in the treatment of phosgene induced acute lung injury. Method Using previously validated methods, 12 anaesthetised large white pigs were exposed to phosgene (Ct 1978 ± 8 mg min m-3), established on mechanical ventilation and randomised to treatment with either nebulised salbutamol (2.5mg per dose) or saline control. Treatments were given 1, 5, 9, 13, 17 and 21 hours following phosgene exposure. The animals were followed to 24 hours following phosgene exposure. Results Salbutamol treatment had no effect on mortality and had a deleterious effect on arterial oxygenation, shunt fraction and heart rate. There was a reduction in the number of neutrophils from 24.0% ± 4.4 to 12.17% ± 2.1 (p<0.05) in bronchoalveolar lavage, with some small decreases in inflammatory mediators in bronchoalveolar lavage but not in plasma. Conclusion Nebulised salbutamol treatment following phosgene induced acute lung injury does not improve survival, and worsens various physiological parameters including arterial oxygen partial pressure and shunt fraction. Salbutamol treatment reduces neutrophil influx into the lung. Its sole use following phosgene exposure is not recommended.

Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry

The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25–63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised. The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality. Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months–4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33–6.47, p<0.001) were strong predictors of mortality. Patients receiving anti-fibrotic medications had better survival (hazard ratio 0.56, 95% CI 0.34–0.92, p=0.022) than those not on anti-fibrotic medications, independent of underlying disease severity. The AIPFR provides important insights into the understanding of the natural history and clinical management of IPF. Data from the Australian IPF registry shows anti-fibrotic therapy and baseline physiology predict survival in IPF http://ow.ly/Ete2305OkU9