The Editors' Choice

Article Outline

• Who are the responders to leukotriene modifier therapy?
• Are alveolar macrophages relevant in children with poorly controlled asthma?
• Asthma exacerbations during pregnancy increase the risk of congenital malformations
• A BAFFability: Mechanism of B-cell responses in chronic rhinosinusitis with nasal polyps
• Gene modifications inhibit ADAM33 production in bronchial epithelial cells
• Finally … Unravelling a function for a disintegrin and metalloprotease 33
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Who are the responders to leukotriene modifier therapy? 

Although cysteinyl leukotrienes (CysLTs) are important mediators of asthma in children, predictors of susceptibility to CysLT effects and to therapy with CysLT modifiers have not been developed. In the study by Rabinovitch et al (p 1365), 27 schoolchildren predominantly taking inhaled corticosteroids (ICSs) were followed for 5 months with measurements of urinary leukotriene E₄ (LTE₄), cotinine, and fractional exhaled nitric oxide (FENO) and monitoring of albuterol use. After a baseline run-in, children were randomized to receive daily montelukast or placebo without change in their current controller medications. At baseline, a significant positive association was observed between LTE₄ levels and albuterol use 2 days later. LTE₄-related albuterol usage (ie, change per interquartile increase in LTE₄) declined significantly after montelukast treatment but not placebo. Declines in LTE₄-related albuterol usage tended to be greater in girls and were highest among children with elevated cotinine levels. Children with high LTE₄ levels relative to FENO demonstrated significant declines in LTE₄-related albuterol usage when taking montelukast (see Figure). Among subsets of children with asthma on ICS therapy, tobacco smoke exposure and gender are most related to susceptibility to montelukast treatment. Montelukast susceptibility may be predicted by high LTE₄-to-FENO ratios.

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• Differential responder subgroups to CysLT effects and montelukast therapy.

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Are alveolar macrophages relevant in children with poorly controlled asthma? 

Children with poorly controlled asthma have an altered response to respiratory infection characterized by severe lower airway inflammation and prolonged respiratory symptoms. Given the important role of alveolar macrophages (AMs) in innate immune defense, Fitzpatrick et al (p 1372) studied whether the phagocytic and apoptotic functions of AMs were impaired in children with moderate and severe poorly controlled asthma. Compared with healthy adults and nonasthmatic children with chronic cough, children with poorly controlled asthma had a 2.5-fold decrease in baseline and lipopolysaccharide-stimulated phagocytosis of inactive fluorescent Staphylococcus aureus (see Figure). This finding was accompanied by increased external binding of S aureus to the AM surface (without internalization) and a 2-fold increase in apoptosis. These data suggest that the functional abilities of AMs are compromised in children with poorly controlled asthma and may contribute to an impaired immune response to respiratory pathogens. The findings from this study may offer some insight into the mechanisms associated with respiratory infection and symptom response in children with poorly controlled asthma.

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• Representative images of AM internalization of S aureus (green particles).

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Asthma exacerbations during pregnancy increase the risk of congenital malformations 

Asthma is one of the most common chronic conditions during pregnancy. Uncontrolled maternal asthma during pregnancy has been thought by some to be a cause of congenital malformations, though there are few published studies on this topic. Blais et al (p 1379) reconstructed a cohort of 4344 pregnancies in asthmatic women and the children born of them from the linkage of health care and pharmacy records to study the association between moderate to severe asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations. They found that women who had an asthma exacerbation (a filled prescription of oral corticosteroids, an emergency department visit, or a hospitalization for asthma) during the first trimester of their pregnancies were at a 48% (95% CI, 1.04-2.09) greater risk of having a child born with a congenital malformation. These findings emphasize the necessity to keep asthma under control during pregnancy and the importance of continued controller therapy for pregnant asthmatic women to reduce this risk. Recent research reassures about the safety of low to moderate doses of inhaled corticosteroids during pregnancy, and health professionals should encourage pregnant asthmatic women to continue their recommended doses once they know they are pregnant.

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A BAFFability: Mechanism of B-cell responses in chronic rhinosinusitis with nasal polyps 

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases in adults in the United States. The polypoid form of CRS (CRSwNP) can be resistant to medical therapy and therefore often requires surgical intervention for treatment. Nasal polyps are well known to contain large quantities of eosinophils, B lymphocytes, and immunoglobulins, suggesting that activation and accumulation of eosinophils and B cells may play a pathogenic role in CRSwNP. In this issue, Kato et al (p 1385) investigated the role of B cell–activating factor of the TNF family (BAFF) in CRS. They found that BAFF was significantly increased in nasal polyps, especially in mucosal epithelial cells and infiltrated cells in the lamina propria, from patients with CRSwNP (see Figure). Importantly, expression of BAFF in sinus tissue was strongly correlated with markers of B cells—namely, CD20 and transmembrane activator and CAML interactor, one of BAFF's receptors. The Northwestern group also found that IgA, an immunoglobulin isotype known to activate eosinophils, was significantly elevated in the polypoid tissue. The authors conclude that overproduction of BAFF in nasal polyps may contribute to the pathogenesis of CRSwNP. Thus, the study provides a potentially novel insight into the mechanism of activation of B cells and, indirectly, eosinophils in polypoid CRS.

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• BAFF expression in nasal polyps from a patient with CRSwNP.

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Gene modifications inhibit ADAM33 production in bronchial epithelial cells 

A disintegrin and metalloprotease 33 (ADAM33) is an asthma and chronic obstructive pulmonary disease (COPD) susceptibility gene. Small changes in the sequence of the gene (single nucleotide polymorphisms) are associated with asthma and bronchial hyperresponsiveness (twitchy airways) and also with more rapid decline in lung function in patients with COPD. Although ADAM33 was thought to be exclusively present in mesenchymal cells such as smooth muscle cells, fibroblasts, and myofibroblasts, recent reports have suggested that ADAM33 is present in epithelial cells in severe asthma. This raised the possibility that dysregulated expression of ADAM33 may contribute to disease pathogenesis. In this issue of the Journal, Yang et al (p 1393) have elegantly demonstrated that the promoter region of the ADAM33 gene is epigenetically modified (hypermethylated) in epithelial cells and inhibits expression of ADAM33. In fibroblasts, the promoter is not modified (hypomethylated) and therefore allows ADAM33 expression. The lack of ADAM33 expression in epithelial cells was also confirmed in patients with severe asthma. This finding is important because it now seems unlikely that the pathologic effect of ADAM33 is a result of aberrant expression in epithelial cells. Other research by the same group, also reported in this issue, describes for the first time a biological role for ADAM33 that may help focus further research into its contribution to airway disease.

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• Chemical demethylation (5-aza-dC treatment) induces ADAM33 expression in epithelial cells.

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Finally … Unravelling a function for a disintegrin and metalloprotease 33 

The discovery of a disintegrin and metalloprotease 33 (ADAM33) as an asthma susceptibility gene back in 2002 sparked great interest in the scientific community. ADAM33 is expressed selectively in mesenchymal cells, fueling speculation that it plays a role in airway remodeling. Despite the interest, the biological and pathologic function of the ADAM33 protein has remained elusive. Even the ADAM33 knockout mouse had no loss of function phenotype and yielded no clues about function after allergen challenge. In this issue of JACI, Puxeddu et al (p 1400) report the first functional role for ADAM33. The authors show that soluble recombinant forms of ADAM33 containing the metalloprotease domain are proangiogenic. ADAM33 is shown to cause endothelial cell differentiation, and when applied to chick egg chorioallantoic membranes or to human lung explants, it induces blood vessel growth. Furthermore, the release of soluble ADAM33 from the full-length membrane-anchored form of the molecule can be augmented by TGF-β₂. These findings inject fresh knowledge into the understanding of ADAM33. The authors postulate that under pathologic conditions the aberrant release of soluble ADAM33 results in a “gain of function” to cause increased vascularity and airway remodeling. Therefore, compounds targeting ADAM33 activity may be of interest as potential disease-modifying therapeutics.

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• Proteolytically active (A33Pro-MP) but not inactive (A33Pro-MPE346A) ADAM33 induces angiogenesis.