Volume 125, Issue 5 , Pages 993-994, May 2010
The Editors' Choice
Article Outline
- Morbidity of respiratory illness in children with asthma
- A potentially effective anti-inflammatory strategy for chronic obstructive pulmonary disease
- Both sputum eosinophils and neutrophils, but not either alone, in more severe asthma
- Tissue remodeling in Chinese patients with chronic rhinosinusitis or expression of mediators associated with tissue remodeling in Chinese patients with chronic rhinosinusitis
- Platelet-activating factor receptor on human lung mast cells might be a good therapeutic target for anaphylaxis
- Taking the brakes off the allergic response
- Copyright
Morbidity of respiratory illness in children with asthma
Exacerbations of childhood asthma and rhinovirus infections both peak during the spring and fall, suggesting that viral infections are major contributors to seasonal asthma morbidity. Kim and Olenec et al (p 1001) evaluated rhinovirus infections during peak seasons in children with asthma and analyzed relationships between viral infection and illness severity. Viral samples were provided by the subjects weekly, irrespective of symptoms. Diaries of symptoms, medication use, and peak flows were also kept by the subjects. Viruses were identified through use of multiplex PCR and partial sequencing of viral genomes. Viruses, the majority of which were rhinoviruses, were detected in almost half of all specimens. The strains of rhinovirus detected differed dramatically from season to season and year to year, with no strains found in more than 2 collection periods. All but 2 children had a respiratory tract infection at some point during the evaluation. Although viral infection appeared to be nearly universal, the atopic children experienced more frequent and severe virus-induced illnesses when compared with those children without evidence of allergen-specific IgE; conversely, nonatopic children were twice as likely to have asymptomatic infections (see Figure). The authors conclude that the combination of viral infection and allergy increases the morbidity of respiratory tract illnesses in children with asthma.
Effect of sensitization on symptoms associated with viral infections.
A potentially effective anti-inflammatory strategy for chronic obstructive pulmonary disease
The persistent lung inflammation of patients with chronic obstructive pulmonary disease (COPD) is central to the progression of the disease. Currently available treatments, including glucocorticoids, are not very effective at controlling this inflammatory response. In this issue Marwick et al (p 1146) show that the Akt/phosphoinositide 3-kinase (PI3K) signaling pathway is activated in lung macrophages of patients with COPD and that the inhibition of a specific signaling protein isoform of PI3K, PI3Kδ, but not the closely related PI3Kγ, restores the anti-inflammatory action of glucocorticoids in patients with COPD (see Figure). However, although PI3Kγ does not appear to have a role in glucocorticoid function in patients with COPD, along with PI3Kδ, it is widely recognized as an important regulator of both the innate and adaptive immune responses, both of which play an important role in the progression of the disease. Consequently, the authors propose that dual PI3Kδ/γ inhibitors in combination with an inhaled glucocorticoid could present an attractive therapeutic strategy against the chronic lung inflammation seen in patients with COPD by not only enabling a more effective use of glucocorticoids but also directly suppressing innate and adaptive responses. The relatively restricted expression of the PI3Kδ/γ isoforms to leukocytes coupled with local delivery of these agents to the lung might minimize the risk of potential side effects.
Restoration of glucocorticoid function by PI3Kδ inhibition (A) but not PI3Kγ inhibition (B).
Both sputum eosinophils and neutrophils, but not either alone, in more severe asthma
Investigations of either sputum eosinophils or neutrophils have linked each separately to severe, poorly controlled asthma. In a large, comprehensively characterized group of subjects representing a broad range of asthma severity from the National Heart, Lung, and Blood Institute Severe Asthma Research Program, Hastie et al (p 1028) found that the subgroup of asthmatic subjects who displayed both increased eosinophil counts and increased neutrophil counts in sputum were characterized by lower lung function, persistent symptoms, worse asthma control, and increased health care use. Subjects with increased eosinophil counts, with or without increased neutrophil counts, had increased exhaled nitric oxide levels, increased serum eosinophil counts, and greater frequency of daily β-agonist use, whereas those subjects with increased neutrophil counts, with or without increased eosinophil counts, had more frequent urgent health care visits in the past year. Protein microarrays identified 25 to 28 novel inflammatory proteins associated with increased neutrophil counts. Brain-derived neurotrophic factor, IL-1β, and macrophage inflammatory protein 3α were confirmed by means of ELISA and showed positive association with increased neutrophil counts in sputum. These proteins are typical of TH1 inflammation, although macrophage inflammatory protein 3α is linked to activation of TH2 inflammatory cells. These data indicate complex overlapping pathologies contributing to asthma severity and heterogeneity.
Tissue remodeling in Chinese patients with chronic rhinosinusitis or expression of mediators associated with tissue remodeling in Chinese patients with chronic rhinosinusitis
To date, there has been no information on the expression of mediators associated with tissue remodeling in Asian patients with chronic rhinitis with (CRSwNP) or without (CRSsNP) nasal polyps. As reported in this issue of the Journal, Li et al (p 1061) studied the expression of TGF-β1, matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), collagen, and regulatory T cells in Chinese patients with CRSwNP and CRSsNP. The patients with CRSwNP showed significantly lower concentrations of TGF-β1, TIMP-1, TIMP-4, forkhead box protein 3, and collagen than were seen in the patients with CRSsNP (see Figure). The concentrations of MMP-7 and MMP-9 in patients with CRSwNP and CRSsNP were significantly increased in comparison with those in control subjects. The authors show that the remodeling patterns seen in Chinese patients with chronic rhinosinusitis resemble those reported in white subjects and that differences in TGF-β and MMP/TIMP concentrations are probably integral to the remodeling in patients with chronic rhinosinusitis with or without nasal polyps. Furthermore, these data suggest that the differences in these mediators are predominantly integral to the development of nasal polyps, and thus appropriate manipulation of these mediators might lead to better management of patients with nasal polyps.
Picrosirius red staining for collagen in patients with chronic rhinosinusitis.
Platelet-activating factor receptor on human lung mast cells might be a good therapeutic target for anaphylaxis
In human subjects platelet-activating factor (PAF) concentrations are markedly increased in plasma after anaphylactic reactions, and these correlate strongly with the severity of the response. The mechanism for the systemic spread of mast cell activation in patients with anaphylaxis is often assumed to relate to the hematogenous spread of allergen, but this is perhaps implausible, and amplification mechanisms need to be considered. In this issue of the Journal, Kajiwara et al (p 1137) show for the first time that human lung mast cells express a functional PAF receptor that induces rapid degranulation in response to PAF (see Figure A). The immunohistochemical analysis of human lung specimens showed that the PAF receptor was expressed on mast cells in vivo (see Figure B). Others have shown that in the skin neural reflexes activate mast cells after the administration of PAF. These findings support the presence of 2 pathways for a PAF-amplification loop in the generation of anaphylaxis, the first provided by the direct activation of airway mast cells contributing to bronchospasm and laryngeal edema and perhaps mast cells in other organs, such as the heart, and the second mediated through neural reflexes in the skin. Blocking the PAF receptor on human lung mast cells might offer a novel approach to the prevention and treatment of anaphylaxis.
Functional expression of PAF receptor in human lung mast cells.
Taking the brakes off the allergic response
The IL-4/IL-13/IL-4 receptor (IL-4R) axis plays a key role in the pathogenesis of allergic diseases. In this issue Tachdjian et al (p 1128) demonstrate that fine tuning of the signal amplitude of this axis is controlled by an immunoreceptor tyrosine-based inhibitory motif (ITIM) present in the cytoplasmic domain of the IL-4Rα chain. On receptor activation, the ITIM binds the protein phosphatase SHP-1, which in turn attenuates receptor signaling. The authors examined the consequences of ITIM inactivation, effected by gene knockin mutagenesis, on the in vivo allergic response in mice. ITIM mutagenesis augmented the activation of the downstream transcription factor signal transducer and activator of transcription 6, and it intensely amplified in vivo allergic responses, especially those dependent on IL-13, such as allergic airway inflammation (see Figure). Thus perturbations in receptor signaling resulting from failed negative regulation, such as those induced by some disease-associated human IL-4Rα chain polymorphisms, might have a profound influence on the magnitude of the allergic response in vivo.
Intense allergic airway inflammation and goblet cell metaplasia in IL-4Rα chain ITIM mutant mice.
PII: S0091-6749(10)00577-4
doi:10.1016/j.jaci.2010.03.031
© 2010 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 125, Issue 5 , Pages 993-994, May 2010
