Smoking tobacco results in an irreversible change to gene expression in the bronchial epithelium, according to new research by Wan L Lam and Stephen Lam from the British Columbia Cancer Research Centre, Canada. This permanent alteration to genes due to smoking seems likely to explain the increased incidence of lung cancer among former smokers compared with those who have never smoked. In total, 85% of lung cancers are caused by smoking and half of newly diagnosed cases are in former smokers.
In the study, the genetic activity of eight current, 12 former and four never smokers was compared using serial analysis of gene expression (SAGE). The data were validated using a second cohort of never, former and current smokers. Irreversible changes included a reduced expression of the GSK3B gene.GSK3B regulates the expression of COX2, an enzyme that has been linked to cancer. In addition to irreversible changes, some gene alterations were found to be reversible, in particular, those involved in xenobiotic metabolism, nucleotide metabolism and mucus secretion, such as the genes TFF3 and CABYR. Of the genes found to be increased in current smokers, 18 were not previously thought to be smoking related.
The study has also generated important starting points for future investigations. Raj Chari, first author of the study, wrote, “By comprehensively identifying gene expression changes that are reversible upon smoking cessation, we have introduced genes which may in future studies be investigated for polymorphisms, as those genes which are not sufficiently induced in response to smoking may identify candidate loci of susceptibility.” This study substantiates the notion that cessation of smoking does reduce the extent of DNA damage, but that starting in the first place leads to irreversible DNA damage.
Source: Chari R, Lonergan K, Raymond T, MacAulay C, Lam W, Lam S. Effect of active smoking on the human bronchial epithelium transciptome. BMC Genomics 8(1), 297 (2007).
Chronic obstructive pulmonary disease and indoor air quality
Poor indoor air quality, specifically air containing high levels of fine particles, has been shown to heighten the symptoms of those that suffer from chronic obstructive pulmonary disease (COPD). Liesl Osman and her colleagues in Aberdeen, Scotland, measured the air quality in the living rooms of 148 patients with severe COPD from North East Scotland using DustTrakTM moniters. Three measurements were taken to assess air quality: the levels of particulate matter with a diameter under 2.5 µm (PM2.5 µg/m3) over 8–14 h; the nitrogen dioxide exposure (ppm) over a week; and the endotoxin levels in dust. Particles of such size were quantified as they are small enough to be inhaled below the tracheobronchial region and have been linked to poor pulmonary health. The St George’s Respiratory Health Questionnaire, which takes account of symptoms, activity limitation and disease impact, was used to gauge the health of the patients.
The PM2.5 was found to be significantly (p < 0.01) higher in the living rooms of patients suffering from the most severe symptoms. The living rooms of smokers had PM2.5 significantly higher than that of nonsmokers (p < 0.001). The researchers found that, “The highest levels of PM2.5 were, on average, four-times the maximum recommended by the US Environmental Protection Agency for 24-h periods.” Smoking households were found also to have higher levels of endotoxin and nitrogen dioxide; however, exposure to these pollutants did not correlate with poor health.
The idea that poor-quality outdoor air has a detrimental effect to respiratory health has been considered in previous studies, but this study indicates that poor air quality is also a problem in the homes of COPD sufferers. The research is part of the Home Environment And Respiratory HealTH Study (HEARTH).
Source: Osman L, Douglas J, Garden C et al. Indoor air quality in homes of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 176, 465–472 (2007).
Acute respiratory distress syndrome treated with ANGPT1 therapy
Treating acute respiratory distress syndrome (ARDS) with bone marrow-derived mesenchymal cells and the human ANGPT1 gene has great protential, according to research carried out by Duncan Stewart and colleagues in Toronto (ON, Canada). ARDS, which can occur as a result of acute lung injury (ALI), is a grave condition with a death rate of over 30% in those that develop it. ARDS is identified by the breakdown of the alveolar–capillary membrane barrier, resulting in noncardiogenic pulmonary edema. Currently, the main avenue for treatment is mechanical ventilation and treatment of the underlying cause, rather than tackling ARDS itself.
In the study, lung injury was induced in mice by intratracheal instillation of lipopolysaccharide (LPS). The extent of pulmonary inflammation was ascertained by looking at the total cell and neutrophil counts in bronchoalveolar lavage fluid and the levels of proinflammatory cytokines. The extent of LPS-induced injury was reduced with the administration of mesenchymal cells alone. Furthermore, almost complete recovery from LPS-induced increases in lung permeability was observed with the administration of mesenchymal cells transfected with the human pANGPT1 gene.
ANGPT1 is crucial to establish and maintain blood vessels during embryogenesis by inducing vascular branching and recruitment of smooth muscle via the receptor TEK tyrosine kinase. ANGPT1 was therefore proposed by the authors as a therapy for ARDS, “Given its anti-inflammatory, antipermeability and endothelial-protective characteristics, we hypothesized that ANGPT1 gene transfer may be beneficial in the treatment of ALI.”
The authors conclude that, “Our data show, to our knowledge for the first time, the synergistic action of combined cell and gene therapy for ALI, and may provide a basis for the development of an innovative approach for the prevention and treatment of ARDS, which continues to be a major cause of morbidity and mortality in critically ill patients.”
Source: Mei S, McCarter S, Deng Y, Colleen H, Liles W, Stewart D. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 4(9) (2007).
Pulmonary arterial hypertension triggered by antioxidant
Mice treated with high doses of the antioxidant N-acetylcysteine (NAC) unexpectedly developed pulmonary arterial hypertension (PAH). This was observed during a study on nitric oxide (NO) transfer reactions between protein and peptide cysteines, which are thought to correspond to regulated signaling processes. In order to quantify NO transfer reactions and to study their effects on blood vessels, NAC was used as a bait reactant. High-dose NAC was administered to mice for 3 weeks and was found to be converted to the erythrocyte-derived molecule S-nitroso-N-acetylcysteine (SNOAC).
Further experiments involving mice lacking endothelial NO synthase indicated that it is the conversion of NAC to SNOAC that causes PAH. The researchers therefore propose that PAH occurs as a result SNOAC signaling to blood vessels that are not getting sufficient oxygen.
The study provides innovative thoughts to the process of oxygen sensing and of NO signaling, such as the proposition that NO signaling may use S-nitrosothiol to desaturate erythrocytic oxygen. In addition, it provides a novel murine model of PAH, which will be useful for future studies.
In light of these new understandings, the potential of NAC to treat cystic fibrosis and other conditions is being tested in clinical trials. The researchers are also hopeful that this work will lead to new ways to sense hypoxia or modify signaling to treat PAH.
NAC treatment does have beneficial anti-inflamatory and antioxidant effects. NAC is found in certain nutritional and bodybuilding formulas intended to improve athletic performance; therefore, the findings from this research raise concerns regarding the safety of such supplements. However, the threshold at which NAC use induces PAH and becomes detrimental to lung or heart function has not been ascertained. The researchers from the University of Virginia (VA, USA) comment that, “PAH has not previously been considered as a NAC toxicity. Surveillance for this toxicity may be appropriate for long-term human trials with NAC. “
Source: Palmer L, Doctor A, Chhabra P et al.S-nitrosothiols signal hypoxia-mimetic vascular pathology. J. Clin. Invest. 117, 2592–2601 (2007).
Diacetyl linked to popcorn worker’s lung
Researchers from The Netherlands have investigated the risk of bronchiolitis obliterans for workers who produce diacetyl. Frits van Rooy and colleagues looked at 175 employees who worked at a chemical production plant between 1960 and 2003, when the plant closed. Historical exposure data were compared with results from interviews and spirometry tests. Those found to have fixed airway obstruction were given further pulmonary function testing and high-resolution computed tomography studies. A total of four workers had results consistent with bronchiolitis obliterans syndrome and three of those were in the group with the highest exposure to diacetyl. They therefore concluded that, “Exposure to an agent during diacetyl production appears to be responsible for causing bronchiolitis obliterans syndrome in chemical process operators, consistent with the suspected role of diacetyl in downstream food production.”
Bronchiolitis obliterans is also known as popcorn workers’ lung due to the prevalence of the disease among such individuals. This study supports the theory that this is due to the inhalation of airborne diacetyl. Diacetyl is used in the manufacture of buttery flavoring for microwave popcorn. All workers in microwave popcorn production are now recommended to wear respiratory protection.
Cecile Rose, a pulmonary specialist at Denver’s National Jewish Medical and Research Center (CO, USA) has recently raised concerns that diacetyl has the potential to harm consumers of popcorn, as well as workers. Her concerns came as a result of findings in one of her patients. Of this patient, Rose said there was no “plausible explanation” for the development of bronchiolitis other than the “exposure to butter-flavored microwave popcorn from daily heavy preparation”.
Source: van Rooy F, Rooyackers J, Prokop M, Houba R, Smit L, Heederik D. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am. J. Respir. Crit. Care Med. 176, 498–504 (2007).
UVB suppresses asthma
Researchers from the University of Western Australia have found that erythemal UVB irradiation of skin suppresses airway hyper-responsiveness (AHR) and cellular responses of the airways to respiratory allergens. Using a murine asthma model, they investigated the regulatory properties of UVB irradiation of the skin and the induction of allergen-induced airway immunity. Mice were sensitized with the antigen ovalbumin (OVA) on day 0 and received a boost dose on day 14. A single erthemal dose of UVB was administered to the mice 3 days prior to sensitization. The mice were subjected to aerosolized OVA on day 21 and airway responses to this were measured.
Various measurements were taken to assess this response; AHR was measured in vivo, the lung-draining lymph nodes (LDLN) were analyzed for OVA-specific proliferative responses and cytokine production and the bronchoalveolar lavage fluid were analyzed for inflammatory cells and cytokines. To determine UVB-induced mechanisms of regulation, 5,000,000 LDLN cells from UVB-irradiated, OVA-sensitized mice were transferred into naive mice that were subsequently sensitized and challenged with OVA or a nonspecific antigen. Methacholine was used in attempt to trigger bronchial hyper-reactivity.
The results show that AHR significantly suppressed methacholine and OVA-specific responses in the LDLN and in the lung compartment. The irradiated mice and the mice with LDLN transferred from UVB-irradiated, OVA-sensitized mice had reduced OVA-specific responses. However, the OVA-sensitized mice who were not subjected to UVB irradiation exhibited no such reduction in OVA-specific responses. The authors therefore suggest that, “UVB-induced regulatory cells are responsible for many of the asthma-reducing effects of dorsal UVB exposure”. Importantly, the findings have put forward the concept of using UVB or its signaling pathway to tackle asthma. Their results could indicate that there is more than a casual link between the increase in the incidence of asthma and relatively recent public health campaigns to avoid UV radiation in order to reduce skin cancer.
UV radiation has also successfully treated other inflammatory conditions, such as psoriasis. This is the first study that has analyzed in vivo measurements of AHR and the antigen specificity of the UV-induced effects.
Source: McGlade J, Gorman S, Zosky G et al. Suppression of the asthmatic phenotype by ultraviolet B-induced, antigen-specific regulatory cells. Clin. Exp. Allergy 37(9), 1267–1276 (2007).
Worldwide increase in asthma continues
A worldwide study into the prevalence of asthma has indicated a rise in the number of children diagnosed with asthma. The results from Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC) were published in the journal Thorax. Phase III was a repeat of Phase I of the study, which was carried out 5–10 years earlier. Phase III included both centers that took part in Phase I, as well as new centers. In order to make the results from Phase I and Phase III comparable, strict protocols were given to ensure the data were collected in the same way; for example, sampling methods and questionnaires remained the same.
The researchers found no significant difference in global change in asthma prevalence between male and females, and therefore the results do not distinguish between the participants.
Across 110 centers in 58 countries, a total of 304,679 children aged 13–14 years and 193,404 children aged 6–7 years took part in Phase III of the study.
In the 13–14 years age group, the authors report that, “the mean prevalence of ‘current wheeze’ (‘Have you had wheezing or whistling in your chest in the past 12 months?’) increased only slightly from 13.2 to 13.7% (a mean increase of 0.06% per year).” Symptoms of severe asthma also remained at a similar level between the Phase I and Phase III stages. However, the distribution of the symptoms was observed to have changed. The prevalence of current wheeze in English language countries decreased by 0.51% each year, whereas Latin America, Northern and Eastern Europe, Africa and North America had an increase. A similar pattern of reduced differences between regions was also seen in those aged 6–7 years.
The number of children reported to have had asthma at some time has significantly increased; the authors suggest that this is due to greater awareness of the condition and/or changes in diagnostic procedure. The authors conclude that, “The increases in asthma symptom prevalence in Africa, Latin America and parts of Asia indicate that the global burden of asthma is continuing to rise, but the global prevalence differences are lessening.”
Source: Pearce N, Ait-Khaled N, Beasley R et al. Worldwide trends in the prevalence of asthma symptoms: Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 62, 757–765 (2007).
COPD and cell surface molecules
The limitation in airflow suffered by COPD patients may be linked to the overexpression of particular proteins in circulating neutrophils. This conclusion was drawn by Masakazu Ichinose and colleagues from the Wakayama Medical University in Japan.
The study investigated the surface expression of proteins in circulating neutrophils in order to elucidate their role, if any, in the airflow limitation of COPD.
Flow cytometry analysis was performed to measure the surface expression of Mac-1 cells (CD-11b and CD-18 cells) and chemokine receptor (CXCR)1 and CXCR2 of circulating neutrophils. Samples were taken from COPD patients and healthy individuals. An ELISA was used to measure the serum levels of IL-8.
COPD patients were found to have significantly higher levels of CD-11b and CXCR1 expression than the healthy individuals. Furthermore, the expression of these proteins showed significant negative correlation with the severity of airflow limitation. The researchers looked for background factors that may have skewed the results, such as age, smoking and BMI. Only age was found to be positively correlated with CXCR1 expression, indicating that the elevated protein expression in COPD patients is linked to the COPD rather than other factors. No significant correlation between serum IL-8 levels and the expression of any molecule was observed.
Although the findings are significant, the authors conclude that, “The precise mechanisms of the regulation of the expression of these molecules are still unclear. Further investigation will be needed to elucidate the exact mechanisms by which these molecules are upregulated and their role in the pathophysiology of COPD.”
Source: Yamagata T, Sugiura H, Yokoyama T et al. Overexpression of CD-11b and CXCR1 on circulating neutrophils. Chest 132, 890–899 (2007).
Late-breaking results presented at the European Respiratory Society Annual Congress 2007
The 2007 Annual Congress of the European Respiratory Society was held in Stockholm, from the 15 to 19th September. This is the largest annual scientific gathering in the world of respiratory medicine. The number of participants is growing each year, with attendance in 2006 reaching over 17,000.
Among the many presentations given, the first, late-breaking results from the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study, comparing two treatments (salmeterol/fluticasone propionate [SFC] and tiotropium bromide) for COPD exacerbations, were reported. The aim of the study was “to see if there was a difference in the effects of two leading medicines used for the treatment of severe COPD, to help inform our medical decisions,” explained Wisia Wedzicha (University College London, UK). Over 1300 patients with severe or very severe COPD were initially enrolled in the study and randomized to either SFC (n = 658) or tiotropium (n = 668). The multicenter, multinational, randomized, double-blind, placebo-controlled trial recruited patients from 179 centers in 20 European countries.
The initial results show that the impact of both treatments on the overall exacerbation rate is similar. However, a difference was observed in the nature of the exacerbations experienced, suggesting the two treatments work in different ways. Furthermore, over the 2-year study period, SFC was observed to give a sustained improvement in quality of life, as well as a better relative mortality risk than tiotropium. The researchers commented: “INSPIRE is the first study to show a statistically significant difference in the relative risk of dying from any cause, with a 52% risk reduction with SFC compared to tiotropium (p = 0.012).” Side effects were reported more frequently in the patients receiving SFC than those in the tiotropium group (66 vs 62%), with the most common side effect being an exacerbation of symptoms. These results could have an important bearing on the treatment choices made for COPD patients in the future.
Source: http://dev.ersnet.org
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