Penh is not a validated technique for measuring airway function in mice.
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Animals↗
Biomedical subjects
Peter D Sly
Publications and source records attributed to Peter D Sly.
Broadband frequency dependence of respiratory impedance in rats.
Past studies in humans and other species have revealed the presence of resonances and antiresonances, i.e., minima and maxima in respiratory system impedance (Zrs), at frequencies much higher than those commonly employed in clinical applications of the forced oscillation technique (FOT). To help understand the mechanisms behind the first occurrence of antiresonance in the Zrs spectrum, the frequency response of the rat was studied by using FOT at both low and high frequencies. We measured Zrs in both Wistar and PVG/c rats using the wave tube technique, with a FOT signal ranging from 2 to 900 Hz. We then compared the high-frequency parameters, i.e., the first antiresonant frequency (far,1) and the resistive part of Zrs at that frequency [Rrs(far,1)], with parameters obtained by fitting a modified constant-phase model to low-frequency Zrs spectra. The far,1 was 570 +/- 43 (SD) Hz and 456 +/- 16 Hz in Wistar and PVG/c rats, respectively, and it did not shift with respiratory gases of different densities (air, heliox, and a mixture of SF(6)). The far,1 and Rrs(far,1) were relatively independent of methacholine-induced bronchoconstriction but changed significantly with increasing transrespiratory pressures up to 20 cmH(2)O, in the same way as airway resistance but independently of changes to tissue parameters. These results suggest that, unlike the human situation, the first antiresonance in the rat is not primarily dependent on the acoustic dimensions of the respiratory system and can be explained by interactions between compliances and inertances localized to the airways, but this most likely does not include airway wall compliance.
Acoustics↗
Developmental changes in airway and tissue mechanics in mice.
Most studies using mice to model human lung diseases are carried out in adults, although there is emerging interest in the effects of allergen, bacterial, and viral exposure early in life. This study aims to characterize lung function in BALB/c mice from infancy (2 wk) through to adulthood (8 wk). The low-frequency forced oscillation technique was used to obtain impedance data, partitioned into components representing airway resistance, tissue damping, tissue elastance, and hysteresivity (tissue damping/tissue elastance). Measurements were made at end-expiratory pause (transrespiratory system pressure = 2 cmH2O) and during relaxed slow expiration from 20 to 0 cmH2O. Airway resistance decreased with age from 0.63 cmH2O x ml(-1) x s at 2 wk to 0.24 cmH2O x ml(-1) x s at 8 wk (P < 0.001). Both tissue damping and tissue elastance decreased with age (P < 0.001) from 2 to 5 wk, then plateaued through to 8 wk (P < 0.001). This pattern was seen both in measurements taken at end-expiratory pause and during expiration. There were no age-related changes seen in hysteresivity when measured at end-expiratory pause, but the pattern of volume dependence did differ with the age of the mice. These changes in respiratory mechanics parallel the reported structural changes of the murine lung from the postnatal period into adulthood.
Adaptation, Physiological↗
Pediatric lung disease: from proteinases to pulmonary fibrosis.
One distinctive outcome of interstitial lung diseases in childhood is the abnormal accumulation of pulmonary extracellular matrix. The clinical consequence of such excessive connective tissue accumulation is known as pulmonary fibrosis. While numerous aspects of its pathogenesis have become familiar, many key events involved in its inception and progression still remain unclear. There is now compelling evidence that lung damage due to uncontrolled proteolysis may help drive critical processes that regulate fibrotic matrix remodeling. In this regard, a number of proteinases have been implicated in promoting both the initial lung injury and the fibroproliferative repair that follows. This review summarizes the knowledge of how different matrix-targeting enzymes may act to influence the development of pediatric pulmonary fibrosis. Understanding the scientific basis of this complex process may highlight opportunities to limit unwanted proteolysis and the intensity of its fibrotic sequelae.
Child↗
Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies.
The term asthma refers to a spectrum of wheezing syndromes resulting from airways inflammation triggered by a range of environmental stimuli, the most important of which are aeroallergens and viruses. We describe below a model for the cause of atopic asthma in which discrete sets of developmental factors governing the postnatal maturation of the immune and respiratory systems play central and complementary roles in disease causality. Within the immune system, the relevant developmental processes involve maturation of TH1 and associated innate immune functions that combat infection and concomitantly antagonize the early programming of TH2-polarized immunologic memory against inhalant allergens. Within the respiratory system, the relevant developmental processes involve intensive lung growth and airway remodeling during infancy. We hypothesize that delayed maturation of TH1-associated functions during early postnatal life increases the risk for sensitization to aeroallergens and for severe respiratory infection, resulting in airway inflammation at a crucial stage in lung development and precipitating changes in lung growth that are the harbingers of susceptibility to persistent asthma. We further hypothesize that protection of the growing lung against the effects of inflammation during infancy and early childhood has unique potential as a generic strategy for asthma prophylaxis.
Asthma↗
Support for 2 variants of eczema.
BACKGROUND: Studies investigating the natural history and risk factors for eczema have historically considered eczema as a single entity, without regard for the individual's atopic status. The association between atopy and eczema is complex, and as many as (2/3) of patients with eczema are not atopic. OBJECTIVE: To investigate the risk factors for eczema in relation to the child's atopic status in a cohort of high-risk children. METHODS: A prospective birth cohort of 263 children was followed for 5 years and closely examined for eczema. Antenatal and postnatal data on environmental exposures were collected by interview. Skin prick test to define atopic status was performed at 6 months and 2 and 5 years of age. RESULTS: Of the subjects, 66.1% had eczema in the first 5 years, and the majority (85.5%) reported onset of rash in the first year. A third of those with eczema were not atopic (nonatopic/intrinsic eczema). Children with atopic eczema (extrinsic eczema) were more likely to be male, to have been breast-fed longer, and to have a history of food allergies, allergic rhinitis, and current wheeze. Nonatopic eczema was more common in girls, and an association was found with early daycare attendance. CONCLUSION: This study supports the presence of 2 variants of eczema: atopic eczema occurring early in childhood and nonatopic eczema with early daycare attendance. It is likely that environmental factors have a different effect on these 2 variants of eczema, and future studies should thus consider eczema as 2 variants in determining the effect of attributable risks.
Age Distribution↗
The role of the neonatal intensive care nurse in decision-making: advocacy, involvement in ethical decisions and communication.
Neonatal intensive care unit (NICU) nurses are often faced with complex clinical and ethical problems. Little is known about the role of the NICU nurse in ethical decision-making, or processes that inform decision-making in this setting. The purpose of this study was to explore and describe nurses' perceptions of their role as patient advocate, clinical situations that cause them concern and the extent of their involvement in ethical decision-making. A combined quantitative and qualitative research design was used. A questionnaire was administered to nurses working in the NICU of the sole perinatal tertiary referral centre of Western Australia, Australia. Findings showed that NICU nurses saw their role in ethical decision-making primarily as advocating for the best interests of the infant and family, that they used clinical knowledge and experience to guide ethical decision-making, they were able to clearly articulate ethical problems and respond to them according to the clinical scenario and, while being primarily assertive in presenting their views, some nurses took a more passive approach. These findings support the need for development of a multidisciplinary model for ethical decision-making, where the view of all team members are considered.
Australia↗
Inflammatory profile in nasal secretions of infants hospitalized with acute lower airway tract infections.
OBJECTIVE: The aim of this study was to determine whether the regulatory immune response (interleukin (IL)-10 response) differed between children hospitalized with acute respiratory infections and wheezing. METHODOLOGY: Infants with signs and symptoms of acute viral respiratory infection, admitted during winter 2000 to Princess Margaret Hospital for Children, Perth, WA, Australia, were enrolled in this study. Nasopharyngeal aspirates were collected in the first 48 h of admission. Total cell count and differential cell counts were assessed. Samples were tested for the presence of respiratory viruses. The concentrations of the anti-inflammatory cytokine IL-10, and pro-inflammatory cytokines IL-8, interferon-gamma, and IL-11 were determined by ELISA. RESULTS: Children with acute bronchiolitis (AB; n = 36), recurrent wheeze (RW; n = 17) and upper respiratory infection (URI; n = 18) were enrolled. Respitory syncytial virus was the most commonly detected virus in all groups. IL-10 concentrations were significantly increased in AB (median, 0.019 ng/mL) when compared to URI (median, 0.006 ng/mL) or to RW (median, 0.007 ng/mL; P < 0.05). Neutrophils were the predominant cells in the cytological analysis in all subjects. CONCLUSION: These data argue that host-response factors are important in determining the clinical phenotype, independent of the causative virus.
Acute Disease↗
Th2-associated local reactions to the acellular diphtheria-tetanus-pertussis vaccine in 4- to 6-year-old children.
Acellular vaccines against diphtheria-tetanus-pertussis (acellular pertussis) (DTaP) are being progressively introduced into vaccination programs worldwide, with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis (whole-cell pertussis) (DTwP) vaccine. The DTaP vaccine has an improved safety profile in infants, but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses. We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4- to 6-year-old children primed during infancy with DTaP (n = 30) or DTwP (n = 16) and by correlating these parameters, in particular cytokine responses, with expression of local side effects at the injection site. Large local reactions (> or =50-mm diameter) 24 to 72 h after receiving the DTaP booster occurred in 43% of exclusively DTaP-primed children, in contrast to 6% of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 (IL-5), IL-6, and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically "high Th2 responders" as detected by in vitro responsiveness to polyclonal mitogen. Our findings suggest that priming during infancy with DTaP promotes stable, boostable Th2-polarized immunity against vaccine antigens, which in a significant subset of children is subsequently associated with local reactions at the booster site. The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory.
Antibody Formation↗
Partitioning of airway and parenchymal mechanics in unsedated newborn infants.
The recent trend toward development of noninvasive methods that can accurately evaluate the lung periphery has particular relevance for the predominantly parenchymal nature of neonatal respiratory disease. Concerns regarding the safety of sedating newborn (especially preterm) infants have also stimulated a drive toward measurements obtained during natural sleep. This study aimed to adapt existing methodology for the low-frequency forced oscillation technique to obtain partitioned measurements of airway and parenchymal mechanics during unsedated, quiet sleep in newborn infants without a history of previous respiratory disease. A face mask was positioned over the infant's mouth and nose and a brief (4-5 s) breathing pause was induced by evoking the Hering-Breuer reflex via end-inspiratory occlusion at raised lung volume (airway opening occluded at 2 kPa). Airway opening pressure and flow were measured while a pseudorandom noise (2-14 Hz) was applied to the airway. Acceptable pulmonary impedance data were collected in 11 of the 12 infants studied (34.1-42.6 wk postmenstrual age, 1.9-3.9 kg body weight) on 17 (total of 20) occasions. Airway parameters (resistance and inertance) and respiratory tissue parameters were calculated from the resultant impedance spectra. Tissue resistance and tissue elastance decreased with increasing body length albeit at different rates such that hysteresivity (tissue resistance/tissue elastance) also decreased. There was a trend toward reduction in airway resistance with increasing length. Measurements of lung function are feasible in the unsedated newborn infant using low-frequency forced oscillations and confirm the important contribution of tissue resistance to lung mechanics in the developing lung.
Airway Resistance↗
Impact of postnatal glucocorticoids on early lung development.
Inhaled glucocorticoid treatment during the first 2 yr of life is controversial because this is a period of major structural remodeling of the lung. Rabbits received aerosolized budesonide (Bud; 250 microg/ml) or injected dexamethasone (Dex; 0.05 mg.ml(-1).kg(-1)) between 1 and 5 wk of age. Treatment with Bud caused specific growth retardation of the lung. Dex but not Bud affected the mechanical properties of the lung parenchyma, when corrected for lung volume. Small peripheral airway walls in both glucocorticoid groups were thinner and had fewer alveolar attachment points with greater distance between attachments than controls, but collagen content was not affected by glucocorticoids. Dex led to reduced body weight, lung volume, alveolar number, and surface area. The alveolar size and number and elastin content, when related to lung volume, was not affected by Bud, suggesting normal structural development but inhibition of total growth. Arterial wall thickness and diameter were affected by Bud. This study demonstrates that developing lungs are sensitive to inhaled glucocorticoids. As such, the use of glucocorticoids in young infants and children should be monitored with caution and only the lowest doses that yield significant clinical improvement should be used.
Administration, Inhalation↗
The pattern of methacholine responsiveness in mice is dependent on antigen challenge dose.
BACKGROUND: Considerable variation exists in the protocols used to induce hyperresponsiveness in murine models of allergic sensitisation. We examined the effect of varying the number of antigen exposures at challenge on the development of methacholine responsiveness in systemically sensitised mice. METHODS: BALB/c mice were sensitised with ovalbumin (OVA), challenged with 1, 3 or 6 OVA aerosols. Lung function was measured using low frequency forced oscillations and partitioned into components representing the airways (Raw) and lung parenchyma (tissue damping (G) and tissue elastance (H)). Responsiveness to inhaled methacholine (MCh), inflammatory cell profile and circulating IgE were assessed 24 and 48 hours after challenge. The threshold dose of MCh required to elicit a detectable response (sensitivity) and response to 30 mg x mL(-1) (maximal response) were determined for each compartment. RESULTS: Sensitivity; All three OVA protocols resulted in an increased sensitivity to MCh in Raw but not in G or H. These responses where present at 24 and 48 hrs, except 1 OVA aerosol in which changes had resolved by 48 hrs. Maximal response; 1 OVA aerosol increased maximal responses in Raw, G and H at 24 hrs, which was gone by 48 hrs. Three OVA aerosols increased responses in H at 48 hrs only. Six OVA challenges caused increases in Raw, G and H at both 24 and 48 hrs. Eosinophils increased with increasing antigen challenges. IgE was elevated by OVA sensitisation but not boosted by OVA aerosol challenge. CONCLUSIONS: The pattern of eosinophilia, IgE and MCh responsiveness in mice was determined by antigen dose at challenge. In this study, increased sensitivity to MCh was confined to the airways whereas increases in maximal responses occurred in both the airway and parenchymal compartments. The presence of eosinophilia and IgE did not always coincide with increased responsiveness to inhaled MCh. These findings require further systematic study to determine whether different mechanisms underlie airway and parenchymal hyperresponsiveness post antigen challenge.
Animals↗
Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens.
A number of laboratories have reported cord blood T cell responses to ubiquitous environmental Ags, including allergens, by proliferation and cytokine secretion. Moreover, the magnitude of these responses has been linked with risk for subsequent expression of allergy. These findings have been widely interpreted as evidence for transplacental priming and the development of fetal T memory cells against Ags present in the maternal environment. However, we present findings below that suggest that neonatal T cell responses to allergens (and other Ags) differ markedly from those occurring in later life. Notably, in contrast to allergen-responsive adult CD4(+) T cell cultures, responding neonatal T cell cultures display high levels of apoptosis. Comparable responses were observed against a range of microbial Ags and against a parasite Ag absent from the local environment, but not against autoantigen. A notable finding was the appearance in these cultures of CD4(+)CD25(+)CTLA4(+) T cells that de novo develop MLR-suppressive activity. These cells moreover expressed CD45RA and CD38, hallmarks of recent thymic emigrants. CFSE-labeling studies indicate that the CD4(+)CD25(+) cells observed at the end of the culture period were present in the day 0 starting populations, but they were not suppressive in MLR responses. Collectively, these findings suggest that a significant component of the reactivity of human neonatal CD4(+) T cells toward nominal Ag (allergen) represents a default response by recent thymic emigrants, providing an initial burst of short-lived cellular immunity in the absence of conventional T cell memory, which is limited in intensity and duration via the parallel activation of regulatory T cells.
Allergens↗
Prevention of bronchoconstriction in sensitized guinea pigs: efficacy of common prophylactic drugs.
Efficacy of beta2-agonists (B2), anticholinergics, corticosteroids, anti-inflammatory drugs or antihistamines against methacholine, histamine, or allergen-induced lung constriction was tested in ovalbumin sensitized guinea pigs. Airway resistance (Raw) and parenchymal damping (G) and elastance (H) were determined from low-frequency forced oscillatory input impedance (ZL). ZL was measured under control conditions, during iv infusions of methacholine, and following iv boluses of histamine or ovalbumin. In decreasing potency, ipratropium, salmeterol, fluticasone or cromoglycate reduced the methacholine-induced increases in Raw and G. Only antihistamines had any effects on the histamine-induced increased in Raw, G, and H. The ovalbumin-induced increases in Raw, G and H in the control animals (120 +/- 90%, 201 +/- 126%, 86 +/- 71%) were markedly reduced by pretreatments with antihistamines (18 +/- 11%, 13 +/- 9%, 3+/- 3%) and cromoglycate (29 +/- 13%, 35 +/- 22%, 18 +/- 10%). Bronchoconstriction induced by muscarinic receptor stimulation is inhibited by anticholinergic, anti-inflammatory or beta2-agonist pretreatment; antihistaminic or anti-inflammatory premedication is beneficial if the release of histamine via an exposure to allergen is responsible for the fall in lung function.
Adrenergic Agonists↗
Variability in preterm lamb lung mechanics after intra-amniotic endotoxin is associated with changes in surfactant pool size and morphometry.
Antenatal exposure to intra-amniotic (i.a.) endotoxin initiates a complex series of events, including an inflammatory cascade, increased surfactant production, and alterations to lung structure. Using the low frequency forced oscillation technique as a sensitive tool for measurement of respiratory impedance, we aimed to determine which factors contributed most to measured changes in lung mechanics. Respiratory impedance data obtained from sedated preterm lambs exposed to either i.a. injection with saline or 20 mg of endotoxin 1, 2, 4, and 15 days before delivery at 125 days gestation were studied, and association with indexes of standard lung morphometry, inflammatory response, and alveolar surfactant-saturated phosphatidylcholine (Sat PC) pool size was demonstrated. Reduction in tissue impedance with increasing interval between exposure and delivery was evident as early as 4 days after i.a. endotoxin injection, coinciding with resolution of inflammatory reaction, increased alveolar surfactant pools, and contribution of alveolar ducts to the parenchymal fraction, and a later decrease in the tissue component of the parenchymal fraction. Decreases in tissue damping (resistance) were more marked than decreases in tissue elastance. Log alveolar Sat PC accounted for most variability in tissue damping (88.9%) and tissue elastance (73.4%), whereas tissue fraction contributed 2 and 6.4%, respectively. The alveolar Sat PC pool size was the sole factor contributing to change in tissue hysteresivity. No changes were observed in airway resistance. Despite the complex cascade of events initiated by antenatal endotoxin exposure, variability in lung tissue mechanics is associated primarily with changes in alveolar Sat PC pool and lung morphology.
Animals↗
Lung function, bronchial responsiveness, and asthma in a community cohort of 6-year-old children.
KEYWORDS: Children as young as 6 years old can perform spirometry, yet the relationship between current asthma, lung function, and bronchial responsiveness has not been described at this age; 2,537 children from a community-based birth cohort were assessed at 6 years of age, with history (n = 2,141), physical examination (n = 1,995), standard spirometry (n = 1,735), and a random sample (n = 711) offered methacholine challenge. Males had greater values of FVC and FEV(1) but not of mean forced expiratory flow during the middle half of the FVC or FEV(1)/FVC than females. The greatest influences on lung function at 6 years were height, sex, birth weight, and wheezing in the first year of life. Children with current asthma had small but significant deficits in lung function and were more sensitive to methacholine. The optimal cutpoint for determining heightened bronchial responsiveness was found to be a 15% fall in FEV(1) at a dose of 1.8 mg/ml. A negative test could be useful in excluding a diagnosis of asthma (negative predictive value of 92%). Lung function testing, including methacholine challenge, is feasible in 5- to 7-year-old children and has the potential to contribute to the clinical management of children with asthma.
Age Factors↗
High IFN-gamma production by CD8+ T cells and early sensitization among infants at high risk of atopy.
BACKGROUND: High genetic risk (HR) of atopy among unstratified populations of infants is associated with attenuated IFN-gamma responses. However, the role of IFN-gamma in progression from HR status to active disease is less clear. OBJECTIVE: To identify immune function markers in neonates with HR that are associated with positive atopic outcomes at 2 years. METHODS: Cord blood mononuclear cells (CBMCs) were collected from 175 children with HR and cryopreserved. The children were assessed for atopy by skin prick at 0.5 and 2 years. CBMCs were thawed and stimulated with allergens and mitogens PHA and staphylococcal enterotoxin B (SEB), and cytokine responses were determined. RESULTS: No correlations were observed between allergen-specific CBMC responses and atopic outcomes. In contrast, sensitization was strongly associated with polyclonal IFN-gamma responses to both PHA (P=.002) and SEB (P=.005), and also with SEB-induced IL-5 (P =.05), IL-10 (P =.02), and IL-13 (P =.01). Logistic regression analysis identified elevated PHA-induced IFN-gamma and SEB-induced IL-13 responses as the strongest independent predictors of atopy development. Cell separation studies confirmed CD8+ T cells as the source of approximately 90% of IFN-gamma production. CONCLUSIONS: IFN-gamma produced by CD8+ T cells may synergize with T(H)2 cytokines in driving atopy development in children with HR.
Allergens↗
Relationship of asthma, atopy, and bronchial responsiveness to serum eosinophil cationic proteins in early childhood.
BACKGROUND: The relationship between atopy, asthma, and eosinophilic inflammation is less clear in early childhood than later in life. OBJECTIVE: We sought to determine the relationships between asthma, atopy, and serum eosinophil cationic protein (ECP), a biomarker of eosinophil activation, in 6-year-old children. METHODS: Serum ECP levels were available from 968 six-year-old children who were part of a longitudinal birth cohort being assessed for asthma and atopy. Detailed clinical history and examination, lung function testing, methacholine challenge, and skin prick testing to 4 common allergens were undertaken. Subgroups of the children were compared by using t tests, ANOVA, chi 2 tests, and regression analysis. RESULTS: One hundred ninety-one (19.7%) children had current asthma, with 114 (59.7%) of these being atopic. The mean serum ECP level for the entire group was 18.0 mug/L (range, 2.0-146.0 mug/L), with no difference between male and female patients. Serum ECP was higher in atopic children (20.5 +/- 18.4), those with asthma (22.4 +/- 19.6), and those with asthma and atopy (26.6 +/- 22.4; all P < .001 compared with children with no asthma or atopy [16.1 +/- 15.9]). Serum ECP levels were highest in children with severe asthma ( P < .001), especially in those with concurrent atopy. Severity of atopy, judged on the basis of wheal size or derived variables combining wheal size and the number of positive skin tests, was a major determinant of serum ECP. Heightened methacholine responsiveness was not associated with increased serum ECP levels. CONCLUSION: The higher serum ECP levels seen in 6-year-old children with current asthma and more severe atopy suggest that atopy and eosinophilic inflammation are important in driving this clinical phenotype and that this might represent asthma that persists.
Asthma↗