The Editors' Choice

Article Outline

• Psychologic factors play a pivotal role in asthma treatment
• Day-care attendance reduces the risk of wheeze at age 5 years
• Obesity associated with worse asthma outcomes
• ROG (repressor of GATA) as a therapeutic target for asthma
• Surfactant protein D: How does this soap keep the lungs clean?
• ALOX15: A novel asthma gene?
• Copyright

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Psychologic factors play a pivotal role in asthma treatment 

Both depressive (or negative) affect and treatment nonadherence predict poorly controlled asthma. The study by Bender and Zhang (p 490) examines for the first time the relationships between both variables and asthma symptom control, employing a new approach to study the link between negative affect and symptoms by controlling for adherence while utilizing a lagged analysis. Child affect was measured with the Children's Depression Inventory and the Revised Children's Manifest Anxiety Scale, and parent affect was measured with the Center for Epidemiologic Studies Depression Scale. Low treatment adherence (which averaged 40% across 4 months) predicted increased prednisone bursts. In contrast, negative affect in either the child or the parent predicted higher symptom scores, which were a composite of self-reported wheezing, tightness of chest, shortness of breath, coughing from exercising, coughing from other causes, and nighttime symptoms (see Figure [showing regression lines]). The authors assert that the relationship between negative affect and self-reported symptoms may reflect a tendency to over-perceive and over-report asthma symptoms when feeling distressed. These findings, in turn, suggest a need for physicians to consider a patient's emotional state when inquiring about disease control both in practice and clinical trials.

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• Associations between child-reported symptom scores and measures of negative affect.

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Day-care attendance reduces the risk of wheeze at age 5 years 

Children who attend daycare in early life may be at lower risk of developing asthma than children who are cared for at home, consequent to high microbial exposure in day-care centers. However, studies investigating the associations between day-care attendance and wheezing have produced conflicting results. Nicolaou et al (p 500) investigated the relationship between day-care attendance and number of older siblings with early childhood wheeze in more than 900 participants in a population-based birth cohort in Manchester, United Kingdom. After adjusting for confounders (see Figure), the authors concluded that day-care attendance was associated with a reduced risk of current wheeze at age 5 years and that the protective effect appeared strongest if children entered the nursery between 6 and 12 months of age. No association was observed between the presence and number of older siblings and wheezing, indicating that day-care attendance and position in sibship are the markers of different exposures. These data suggest that the timing of exposure to the day-care environment may play an important role. Further studies will need to be carried out to ascertain whether the protective effect afforded by the day-care attendance in early life applies to all children or just to a susceptible subgroup within the population.

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• Independent associates of current wheeze at age 5 years.

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Obesity associated with worse asthma outcomes 

Mosen et al (p 507) found that obese individuals (body mass index [BMI], >30 kg/m²) with persistent asthma were significantly more likely than those with normal BMI (<25 kg/m²) to report worse asthma-related quality of life, worse asthma control, and more asthma-related hospitalizations. The authors also found that being overweight (BMI, 25.0-30 kg/m²) was not as clearly associated with these asthma outcomes, though the overall data did demonstrate worse outcomes with increasing BMI. This study is unique in reporting an association of obesity with worse asthma outcomes in a large sample from 2 geographic areas of the United States while also adjusting for several covariates that are independently associated with the study outcomes. Findings from this study suggest that obese patients with asthma might need more intense monitoring and treatment to improve their asthma. Future research is needed to identify optimal pharmacologic asthma treatments for obese patients with asthma and to develop, implement, and evaluate interventions to promote weight loss within the obese asthmatic population; randomized trials will determine whether such interventions actually improve asthma outcomes.

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ROG (repressor of GATA) as a therapeutic target for asthma 

Studies of human asthma and of animal models of allergic inflammation/asthma highlight the crucial role for TH2 cells in the pathogenesis of allergic asthma. In this study, Hirahara et al (p 512) studied the regulatory roles of repressor of GATA (ROG) in the pathogenesis of TH2-driven allergic diseases, such as allergic asthma. ROG is a POZ (BTB) domain-containing Kruppel-type zinc finger family (or POK family) repressor. Three different mouse models were adopted: ROG-deficient (ROG^–/–) mice, ROG transgenic mice, and an adoptive transfer system with ROG overexpressing cells. The allergen-induced hyperproduction of mucus was dramatically enhanced in the ROG^–/– mice (see Figure). This study indicates that ROG regulates both allergic airway inflammation and airway hyperresponsiveness in a negative manner and that ROG thus might represent another potential therapeutic target for the treatment of asthma patients.

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• Hyperproduction of mucus in the absence of ROG.

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Surfactant protein D: How does this soap keep the lungs clean? 

For maintenance of a pristine, inflammation- and infection-free tissue environment, the pulmonary innate immune system fulfils a dual role: constitutive elimination of inhaled pathogenic material and prevention of a consequent chronic immune response. Through the use of gene-targeted mice, it has recently been revealed that surfactant protein D (SP-D), a lung collectin produced by type II alveolar epithelial cells and Clara cells of the airways, might mediate both functions. SP-D shares target cells with the proinflammatory cytokine TNF-α, an important autocrine stimulator of dendritic cells and macrophages in the airways, but the mechanisms by which TNF-α and SP-D interact to regulate the pulmonary innate immune system are not well understood. In this issue, Hortobagyi et al (p 521) investigated the interactions between TNF-α and SP-D. They found that TNF-α might indirectly enhance SP-D expression via the action of IL-13 in epithelial cells. Such an increase in release of the immunoprotective SP-D occurs parallel to and indeed might be responsible for resolution of the inflammatory airways response. Lack of SP-D in gene-deficient mice resulted in an accumulation of proinflammatory, myeloid dendritic cells in the airways and enhanced TNF-α production by these cells; in contrast, SP-D administration to maturing bone marrow–derived dendritic cells inhibited the maturation process and reduced cytoplasmic TNF-α expression (see Figure). The authors propose that SP-D can antagonize the proinflammatory effects of TNF-α on macrophages and dendritic cells at least partly by inhibiting production of this cytokine. Such negative feedback regulation is important for facilitating resolution of acute inflammatory changes in the respiratory tract and to prevent development of chronic conditions such as asthma.

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• Lack of SP-D enhanced and the presence of SP-D suppressed TNF-α in dendritic cells.

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ALOX15: A novel asthma gene? 

Asthma is a complex genetic disease, which implies that multiple genes and environmental factors are involved in its pathogenesis. The potential number of candidate genes involved in asthma is enormous. In this study, Tremblay et al (p 529) reasoned that genes that are over- or underexpressed in asthmatic airways in comparison with control airways are good candidates for genetic susceptibility, and they tested whether variants of these candidate genes were associated with asthma and related phenotypes. This strategy revealed the novel finding that polymorphisms in the ALOX15 gene impart protection from allergic asthma and airway hyperresponsiveness. The ALOX15 gene encodes arachidonate 15-lipoxygenase (15-LO), an enzyme expressed in several lung cell types (including human airway epithelial cells, alveolar macrophages, and neutrophils) and converts arachidonic acid into 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], a major metabolite of the 15-LO pathway. The available evidence suggests that this enzyme might have an anti-inflammatory effect, making it an attractive target for novel therapeutic approaches to allergic airway disease. Further functional investigations are required to more precisely delineate the role of this biologic pathway in asthma. Hypothesis-driven candidate gene selection from microarray experiments is a methodologic approach that improves the likelihood of finding positive as well as novel asthma associations.