Spirometry and Impulse Oscillometry in Preschool Children: Acceptability and Relationship to Maternal Smoking in Pregnancy.

BACKGROUND: Comparisons of the technical acceptability of spirometry and impulse oscillometry (IOS) and clinical correlations of the measurements have not been well studied in young children. There are no large studies focused on African American and Hispanic children. OBJECTIVES: We sought to (1) compare the acceptability of spirometry and IOS in 3- to 5-year-old children and (2) examine the relationship of maternal smoking during pregnancy to later lung function. METHODS: Spirometry and IOS were attempted at 4 sites from the Urban Environmental and Childhood Asthma Study birth cohort at ages 3, 4, and 5 years (472, 471, and 479 children, respectively). We measured forced expiratory flow in 0.5 s (forced expiratory volume in 0.5 seconds [FEV0.5]) with spirometry and area of reactance (AX), resistance and reactance at 5 Hz (R5 and X5, respectively) using IOS. RESULTS: Children were more likely to achieve acceptable maneuvers with spirometry than with IOS at age 3 (60% vs 46%, P < .001) and 5 years (89% vs 84%, P = .02). Performance was consistent among the 4 study sites. In children without recurrent wheeze, there were strong trends for higher FEV0.5 and lower R5 and AX over time. Maternal smoking during pregnancy was associated with higher AX at ages 4 and 5 years (P < .01 for both years). There was no significant difference in FEV0.5 between children with and without in utero exposure to smoking. CONCLUSION: There is a higher rate of acceptable maneuvers with spirometry compared with IOS, but IOS may be a better indicator of peripheral airway function in preschool children.

Redistribution of inhaled hyperpolarized 3He gas during breath-hold differs by asthma severity.

The purpose of this work was to quantify the redistribution of ventilation-weighted signal in the lungs of asthmatic subjects during a breath-hold using high temporal-spatial resolution hyperpolarized (HP) He-3 MRI. HP He-3 MRI was used to obtain time-resolved, volumetric images of lung ventilation during breath-hold in 39 human subjects classified as either healthy/nondiseased (n = 14), mild-to-moderate asthmatic (n = 17), or severely asthmatic (n = 8). Signals were normalized to a standard lung volume, so that voxels within the lung from all 39 subjects could be analyzed as a group to increase statistical power and enable semiautomated classification of voxels into 1 of 5 ventilation level categories (ranging from defect to hyperintense). End-inspiratory ventilation distribution and temporal rates of mean signal change for each of the five ventilation categories were compared using ANOVA. Time rates of signal change were hypothesized to represent underlying gas redistribution processes, potentially influenced by disease. We found that mild-to-moderate asthmatic subjects showed the greatest rate of signal change, even though those with severe asthma had the greatest end-inspiration ventilation heterogeneity. The observed results support the existence of local differences in airway resistances associated with the different obstructive patterns in the lungs for severe vs. mild-to-moderate asthmatic subjects.

Comparison of temporal transcriptomic profiles from immature lungs of two rat strains reveals a viral response signature associated with chronic lung dysfunction.

Early life respiratory viral infections and atopic characteristics are significant risk factors for the development of childhood asthma. It is hypothesized that repeated respiratory viral infections might induce structural remodeling by interfering with the normal process of lung maturation; however, the specific molecular processes that underlie these pathological changes are not understood. To investigate the molecular basis for these changes, we used an established Sendai virus infection model in weanling rats to compare the post-infection transcriptomes of an atopic asthma susceptible strain, Brown Norway, and a non-atopic asthma resistant strain, Fischer 344. Specific to this weanling infection model and not described in adult infection models, Sendai virus in the susceptible, but not the resistant strain, results in morphological abnormalities in distal airways that persist into adulthood. Gene expression data from infected and control lungs across five time points indicated that specific features of the immune response following viral infection were heightened and prolonged in lungs from Brown Norway rats compared with Fischer 344 rats. These features included an increase in macrophage cell number and related gene expression, which then transitioned to an increase in mast cell number and related gene expression. In contrast, infected Fischer F344 lungs exhibited more efficient restoration of the airway epithelial morphology, with transient appearance of basal cell pods near distal airways. Together, these findings indicate that the pronounced macrophage and mast cell responses and abnormal re-epithelialization precede the structural defects that developed and persisted in Brown Norway, but not Fischer 344 lungs.

Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.

The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.

Evaluation of structure-function relationships in asthma using multidetector CT and hyperpolarized He-3 MRI.

RATIONALE AND OBJECTIVES: Although multiple detector computed tomography (MDCT) and hyperpolarized gas magnetic resonance imaging (HP MRI) have demonstrated ability to detect structural and ventilation abnormalities in asthma, few studies have sought to exploit or cross-validate the regional information provided by these techniques. The purpose of this work is to assess regional disease in asthma by evaluating the association of sites of ventilation defect on HP MRI with other regional markers of airway disease, including air trapping on MDCT and inflammatory markers on bronchoscopy. MATERIALS AND METHODS: Both HP MRI using helium-3 and MDCT were acquired in the same patients. Supervised segmentation of the lung lobes on MRI and MDCT facilitated regional comparisons of ventilation abnormalities in the lung parenchyma. The percentage of spatial overlap was evaluated between regions of ventilation defect on HP MRI and hyperlucency on MDCT to determine associations between obstruction and likely regions of gas trapping. Similarly, lung lobes with high defect volume were compared to lobes with low defect volume for differences in inflammatory cell number and percentage using bronchoscopic assessment. RESULTS: There was significant overlap between sites of ventilation defect on HP MRI and hyperlucency on MDCT suggesting that sites of airway obstruction and air trapping are associated in asthma. The percent (r=0.68; P= .0039) and absolute (r=0.61; P= .0125) number of neutrophils on bronchoalveolar lavage for the sampled lung lobe also directly correlated with increased defect volume. CONCLUSIONS: These results show promise for using image guidance to assess specific regions of ventilation defect or air trapping in heterogeneous obstructive lung diseases such as asthma.

Pin1 regulates TGF-beta1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis.

Eosinophilic inflammation is a cornerstone of chronic asthma that often culminates in subepithelial fibrosis with variable airway obstruction. Pulmonary eosinophils (Eos) are a predominant source of TGF-beta1, which drives fibroblast proliferation and extracellular matrix deposition. We investigated the regulation of TGF-beta1 and show here that the peptidyl-prolyl isomerase (PPIase) Pin1 promoted the stability of TGF-beta1 mRNA in human Eos. In addition, Pin1 regulated cytokine production by both in vitro and in vivo activated human Eos. We found that Pin1 interacted with both PKC-alpha and protein phosphatase 2A, which together control Pin1 isomerase activity. Pharmacologic blockade of Pin1 in a rat asthma model selectively reduced eosinophilic pulmonary inflammation, TGF-beta1 and collagen expression, and airway remodeling. Furthermore, chronically challenged Pin1(-/-) mice showed reduced peribronchiolar collagen deposition compared with wild-type controls. These data suggest that pharmacologic suppression of Pin1 may be a novel therapeutic option to prevent airway fibrosis in individuals with chronic asthma.

A critical role for Pin1 in allergic pulmonary eosinophilia in rats.

BACKGROUND: Infiltration, accumulation, and degranulation of eosinophils in the lung are hallmarks of active allergic asthma. The pulmonary response to inhaled allergen triggers the secretion of eosinophil chemoattractants and antiapoptotic cytokines, including GM-CSF, IL-3, IL-4, IL-5, and eotaxin, among others. We recently showed that in vitro Pin1 regulated eosinophil production of and response to GM-CSF. OBJECTIVE: We sought to determine the effect of Pin1 inhibition on pulmonary eosinophilia after allergen challenge. METHODS: The Pin1 inhibitor juglone (5-hydroxy-1,4-naphthoquinone) was administered to allergen-sensitized and allergen-challenged Brown Norway rats. Bronchoalveolar lavage fluid and lungs were assessed for inflammation, cytokine expression, and Pin1 activity. RESULTS: Juglone-treated rats showed a dramatic reduction (approximately 75%) in bronchoalveolar lavage fluid and pulmonary eosinophilia but no change in lymphocyte, monocyte/macrophage, or neutrophil numbers. GM-CSF and IL-5 expression were also significantly reduced, whereas Pin1-independent cytokines, such as eotaxin or IL-4, as well as housekeeping mRNAs and proteins, including actin, were unaffected by juglone. The eosinophils present in the lung in juglone-treated rats showed significantly greater apoptosis. CONCLUSION: These data suggest that in vivo Pin1 blockade attenuates GM-CSF and IL-5 production and can selectively reduce eosinophilic allergic inflammation. CLINICAL IMPLICATIONS: Eosinophils can be selectively reduced by Pin1 blockade, despite allergen challenge.

Functional lung imaging using hyperpolarized gas MRI.

The noninvasive assessment of lung function using imaging is increasingly of interest for the study of lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Hyperpolarized gas MRI (HP MRI) has demonstrated the ability to detect changes in ventilation, perfusion, and lung microstructure that appear to be associated with both normal lung development and disease progression. The physical characteristics of HP gases and their application to MRI are presented with an emphasis on current applications. Clinical investigations using HP MRI to study asthma, COPD, cystic fibrosis, pediatric chronic lung disease, and lung transplant are reviewed. Recent advances in polarization, pulse sequence development for imaging with Xe-129, and prototype low magnetic field systems dedicated to lung imaging are highlighted as areas of future development for this rapidly evolving technology.