Showing papers by "Erwin W. Gelfand published in 2005"

The Enhancement or Prevention of Airway Hyperresponsiveness during Reinfection with Respiratory Syncytial Virus Is Critically Dependent on the Age at First Infection and IL-13 Production

Abstract: Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of postbronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.

Leukotriene B4 Receptor-1 Is Essential for Allergen-Mediated Recruitment of CD8 + T Cells and Airway Hyperresponsiveness

Abstract: Recent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8-/-) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8+ T cells or in vitro-generated effector CD8+ T cells (T(EFF)). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated T(EFF) recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8+ T cell-mediated allergic AHR and inflammation. Adoptive transfer of in vivo-primed BLT1+/+, but not BLT1-/-, CD8+ T cells into sensitized and challenged CD8-/- mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8-/- mice, in vitro-generated BLT1+/+, but not BLT1-/-, T(EFF) accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ T(EFF) recruitment into the lung and development of AHR and airway inflammation.

Importance of the personal endotoxin cloud in school-age children with asthma.

Abstract: Background A number of studies have observed associations between the amount of endotoxin in urban dust and chronic asthma severity, but a direct relationship between personal exposure to household endotoxin and acute asthma worsening has not yet been defined. Objective We sought to investigate the relationship between day-to-day changes in personal endotoxin exposure and asthma severity. Methods In the winter and spring of 1999 through 2000, endotoxin exposures were monitored in asthmatic schoolchildren by using portable, as opposed to stationary, monitors designed to measure inhalable and respirable particulate matter less than or equal to 2.5 and 10 μm in diameter. Children were followed with daily measurements of FEV 1 and asthma symptoms. Results Over a 24-hour period, median daily personal endotoxin exposures ranged from 0.08 EU/m 3 (measured at a particulate matter size range ≤2.5 μm in diameter) to 0.37 EU/m 3 (measured at a particulate matter size range ≤10 μm in diameter). Personal exposures were significantly ( P 1 values and increased symptoms. Conclusions These findings demonstrate the importance of using personal monitoring to both measure and correlate endotoxin exposure with asthma severity.

Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness.

Abstract: Rationale: Leukotriene B4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4–BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. Objectives: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. Methods: BLT1-deficient (BLT1−/−) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. Results: Compared with wild-type mice, BLT1−/− mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin...

Distribution and leukocyte contacts of γδ T cells in the lung

Abstract: Pulmonary T cells protect the lung and its functions, but little is known about their distribution in this organ and their relationship to other pulmonary cells. We now show that and T cells are distributed differently in the normal mouse lung. The T cells have a bias for nonal- veolar locations, with the exception of the airway mucosa. Subsets of T cells exhibit further vari- ation in their tissue localization. and T cells frequently contact other leukocytes, but they favor different cell-types. The T cells show an intrin- sic preference for F4/80 and major histocompat- ibility complex class II leukocytes. Leukocytes expressing these markers include macrophages and dendritic cells, known to function as sentinels of airways and lung tissues. The continuous inter- action of T cells with these sentinels likely is related to their protective role. J. Leukoc. Biol. 78: 1086-1096; 2005.

Do NHLBI lung function criteria apply to children? A cross‐sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999–2002

Abstract: Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4–18 years of age. Retrospective cross-sectional analysis was performed on all spirometries done in children at the National Jewish Medical and Research Center from 1999–2002. In total, 2,728 children performed 24,388 measures. The mean ± SD values for forced vital capacity (FVC), forced expired volume in 1 sec (FEV1), FEV1/FVC ratio, and forced expiratory flow (FEF)25–75 were 92.7 ± 16.2, 92.2 ± 18.0, 85.3 ± 9.3, and 78.0 ± 36.5 percent predicted, respectively. Seventy-seven percent of FEV1 values were ≥ 80%, 18.6% were between 60–80%, and 3.1% were <60% of predicted. FEV1 was highest in 5-year-old children; it declined thereafter, reaching a nadir at 11 years, followed by a partial recovery from 12–18 years. Expressed in liters, FEV1 values were lower than expected at every age, with the greatest difference at 18 years. FEV1/FVC ratios declined through childhood, suggesting impaired airway but not lung growth in children with asthma. In conclusion, the majority of asthmatic children attending a tertiary care facility had FEV1 values within normal range. With increasing age, the increase in FEV1 lags behind that of nonasthmatics, so that by 18 years, maximum FEV1 is impaired. The NHLBI FEV1 cutoff values do not appear to accurately stratify pediatric asthma, and no useful FEV1 cutoff could be generated. Pediatr Pulmonol. 2005; 39:311–317. © 2005 Wiley-Liss, Inc.

Quantitative computed tomography detects peripheral airway disease in asthmatic children

Abstract: The aim of this study was to compare air-trapping as quantified by high-resolution computed tomography (HRCT) of the chest with measures of lung function and airway inflammation in children with mild to moderate asthma. Plethysmography indices, respiratory resistance, and reactance before and after bronchodilator with impulse oscillation (IOS), exhaled nitric oxide (eNO), total eosinophil count (TEC), and serum eosinophil cationic protein (ECP) levels were measured in 21 subjects. A single-cut HRCT image at end-expiration was obtained. Air-trapping was quantified and expressed in terms of the pixel index (PI) by determining the percentage of pixels in lung fields below -856 and -910 Hounsfeld units (HU). Pairwise linear correlations between PI and other parameters were evaluated. Subjects had only mild airflow limitation based on prebronchodilator forced expiratory volume in 1 sec (FEV(1)), but were hyperinflated and had air-trapping based on elevated total lung capacity (TLC) and residual volume (RV)/TLC ratio, respectively. The PI at -856 HU was positively correlated with % predicted TLC, total gas volume (TGV), and ECP level, and was inversely correlated with FEV(1)/forced vital capacity (FVC) and % predicted forced expiratory flow between 25-75% FVC (FEF(25-75)). The PI at -910 HU correlated similarly with these variables, and also correlated positively with IOS bronchodilator reversibility. This data suggest that quantitative HRCT may be a useful tool in the evaluation of peripheral airflow obstruction in children with asthma.

Hepatocyte growth factor attenuates airway hyperresponsiveness, inflammation, and remodeling.

Abstract: Hepatocyte growth factor (HGF) is known to influence a number of cell types and their production of regulatory cytokines. We investigated the potential of recombinant HGF to regulate not only the development of allergic airway inflammation and airway hyperresponsiveness (AHR), but also airway remodeling in a murine model. Administration of exogenous HGF after sensitization but during ovalbumin challenge significantly prevented AHR, as well as eosinophil and lymphocyte accumulation in the airways; interleukin (IL)-4, IL-5, and IL-13 levels in bronchoalveolar lavage (BAL) fluid were also significantly reduced. Further, treatment with HGF significantly suppressed transforming growth factor-beta (TGF-beta), platelet-derived growth factor, and nerve growth factor levels in BAL fluid. The expression of TGF-beta, the development of goblet cell hyperplasia and subepithelial collagenization, and the increases in contractile elements in the lung were also reduced by recombinant HGF. Neutralization of endogenous HGF resulted in increased AHR as well as the number of eosinophils, levels of Th2 cytokines (IL-4, IL-5, and IL-13) and TGF-beta in BAL fluid. These data indicate that HGF may play an important role in the regulation of allergic airway inflammation, hyperresponsiveness, and remodeling.

Virus-Induced Airway Dysfunction: Pathogenesis and Biomechanisms

Abstract: Background: Viral respiratory tract infections cause significant morbidity and mortality. Respiratory viruses are suspected to play a role in the inception of asthma early in life. Respiratory syncytial virus (RSV) is the most common cause of infant bronchiolitis, which is associated with the development of childhood wheezing and asthma. However, it is not clear whether this association is causal or circumstantial. Methods: Animal models have been pivotal in studying the pathophysiology of viral respiratory infections. Various approaches to assessing airway inflammation and function have been used to define the mechanisms of virus-induced airway dysfunction and to address clinically relevant questions regarding the role of RSV in wheezing and asthma after bronchiolitis. Results: Viral lower respiratory tract infections alter airway function in humans and animals. The extent and duration of the alterations may depend on the virus itself, host factors and environmental factors. Animal studies demonstrated that viral infection induces airway hyperresponsiveness and enhances this alteration in the allergen-sensitized and exposed host. This altered airway function is mediated by immune and neurogenic inflammatory mechanisms. Recent studies in mice show that neonatal RSV infection sensitizes the newborn to develop an asthma-like phenotype on reinfection, providing further opportunities to investigate the role of RSV in postbronchiolitis wheezing and asthma in this animal model. Conclusions: Further studies are needed to fully establish the mechanisms underlying the pathophysiology of viral respiratory tract infections and to clarify their role in the inception and/or progression of chronic airway diseases such as asthma. The results of ongoing therapeutic studies promise to minimize the impact of such viral infections.

Ozone Exposure in Vivo and Formation of Biologically Active Oxysterols in the Lung

Abstract: Ozone toxicity in the lung is thought to be mediated by products derived from the reaction of ozone with components of the lung epithelial lining fluid. Cholesterol is an abundant component of this epithelial lining fluid, and it is susceptible to ozonolysis, yielding several stable products including 3β-hydroxy-5-oxo-5,6-secocholestan-6-al and 5β,6β-epoxycholesterol. Both 5β,6β-epoxycholesterol and its metabolite, cholestan-6-oxo-3,5-diol, have been shown to cause cytotoxicity in vitro, suggesting that they may be potential mediators of ozone toxicity in vivo. An ozone-sensitive mouse strain, C57BL/6J, was exposed to varying concentrations of ozone (0.5-3.0 ppm), and subsequently the levels of these cholesterol ozonolysis products were quantitated by electrospray ionization mass spectrometry in bronchoalveolar lavage fluid, lavaged cells, and lung homogenate. An ozone dose-dependent formation of these biologically active oxysterols was observed in vivo, supporting a role for these compounds in ozone toxicity. Since the 5β,6β-epoxycholesterol metabolite, cholestan-6-oxo-3,5-diol, was isobaric with other cholesterol ozonolysis products, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al and its aldol condensation product, 3β-hydroxy-5β-hydroxy-B-norcholestan-6β-carboxaldehyde, detailed mass spectral analysis using electron impact ionization was utilized to differentiate these isobaric cholesterol ozonolysis products. The specific detection of cholestan-6-oxo-3,5-diol in lung homogenate after ozone exposure established formation of 5β,6β-epoxycholesterol within the lung after exposure to 0.5 ppm ozone.

Immunoglobulin replacement therapy in primary antibody deficiency diseases--maximizing success.

Abstract: Antibody or humoral immunodeficiencies comprise the largest group of primary immunodeficiency diseases. Since the first description of patients with low gammaglobulin levels more than four decades ago

Alteration of airway neuropeptide expression and development of airway hyperresponsiveness following respiratory syncytial virus infection.

Abstract: The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of...

Physiologic assessment of allergic rhinitis in mice: Role of the high-affinity IgE receptor (FcɛRI)

Abstract: Background There have been few reports using animal models to study the development of allergic rhinitis. Characterization of such a model in mice would be advantageous given the availability of reagents and gene-manipulated strains. Objective We sought to develop a murine model of allergic rhinitis in the absence of lower airway changes. Methods After sensitization and challenge, both wild-type and FcɛRI-deficient mice were studied for their ability to develop early- and late-phase nasal responses. In the invasive approach, direct measurements of nasal airway resistance (R NA ) were obtained; in the noninvasive approach using whole-body plethysmography, respiratory frequency and expiratory and inspiratory times were monitored. In both approaches, nasal responses were determined either acutely after challenge (early phase) or 24 hours after challenge (late phase). Results After challenge of sensitized mice, R NA significantly increased. In parallel, respiratory frequency significantly decreased and was highly correlated with the increases in R NA . Sensitized wild-type mice had an early-phase nasal response and persistent nasal blockage (late-phase response) after allergen challenge. In contrast, sensitized and challenged FcɛRI α-chain–deficient mice did not have an early-phase nasal reaction and exhibited reduced nasal blockage and lower IL-13 levels in nasal tissue homogenates. Conclusions These data indicate that FcɛRI is essential to development of an early-phase nasal response and contributes to the development of the late-phase nasal response. These invasive and noninvasive approaches provide new opportunities to evaluate the mechanisms underlying the development of nasal responses to allergen and to assess various therapeutic interventions.

Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors

Abstract: In this work we present evidence that the p53 tumor suppressor protein and NF-κB transcription factors could be related through common descent from a family of ancestral transcription factors regulating cellular proliferation and apoptosis. P53 is a homotetrameric transcription factor known to interact with the ankyrin protein 53BP2 (a fragment of the ASPP2 protein). NF-κB is also regulated by ankyrin proteins, the prototype of which is the IκB family. The DNA binding sequences of the two transcription factors are similar, sharing 8 out of 10 nucleotides. Interactions between the two proteins, both direct and indirect, have been noted previously and the two proteins play central roles in the control of proliferation and apoptosis. Using previously published structure data, we noted a significant degree of structural alignment between p53 and NF-κB p65. We also determined that IκBα and p53 bind in vitro through a specific interaction in part involving the DNA binding region of p53, or a region proximal to it, and the amino terminus of IκBα independently or cooperatively with the ankyrin 3 domain of IκBα In cotransfection experiments, κBα could significantly inhibit the transcriptional activity of p53. Inhibition of p53-mediated transcription was increased by deletion of the ankyrin 2, 4, or 5 domains of IκBα Co-precipitation experiments using the stably transfected ankyrin 5 deletion mutant of κBα and endogenous wild-type p53 further support the hypothesis that p53 and IκBα can physically interact in vivo. The aggregate results obtained using bacterially produced IκBα and p53 as well as reticulocyte lysate produced proteins suggest a correlation between in vitro co-precipitation in at least one of the systems and in vivo p53 inhibitory activity. These observations argue for a mechanism involving direct binding of IκBα to p53 in the inhibition of p53 transcriptional activity, analogous to the inhibition of NF-κB by κBα and p53 by 53BP2/ASPP2. These data furthermore suggest a role for ankyrin proteins in the regulation of p53 activity. Taken together, the NFκB and p53 proteins share similarities in structure, DNA binding sites and binding and regulation by ankyrin proteins in support of our hypothesis that the two proteins share common descent from an ancestral transcriptional factor.

Mismatched Antigen Prepares γδ T Cells for Suppression of Airway Hyperresponsiveness

Abstract: Gammadelta T cells suppress airway hyperresponsiveness (AHR) induced in allergen-challenged mice but it is not clear whether the suppression is allergen specific. The AHR-suppressive cells express TCR-Vgamma4. To test whether the suppressive function must be induced, we adoptively transferred purified Vgamma4(+) cells into gammadelta T cell-deficient and OVA-sensitized and -challenged recipients (B6.TCR-Vgamma4(-/-)/6(-/-)) and measured the effect on AHR. Vgamma4(+) gammadelta T cells isolated from naive donors were not AHR-suppressive, but Vgamma4(+) cells from OVA-stimulated donors suppressed AHR. Suppressive Vgamma4(+) cells could be isolated from lung and spleen. Their induction in the spleen required sensitization and challenge. In the lung, their function was induced by airway challenge alone. Induction of the suppressors was associated with their activation but it did not alter their ability to accumulate in the lung. Vgamma4(+) gammadelta T cells preferentially express Vdelta4 and -5 but their AHR-suppressive function was not dependent on these Vdeltas. Donor sensitization and challenge not only with OVA but also with two unrelated allergens (ragweed and BSA) induced Vgamma4(+) cells capable of suppressing AHR in the OVA-hyperresponsive recipients, but the process of sensitization and challenge alone (adjuvant and saline only) was not sufficient to induce suppressor function, and LPS as a component of the allergen was not essential. We conclude that AHR-suppressive Vgamma4(+) gammadelta T cells require induction. They are induced by allergen stimulation, but AHR suppression by these cells does not require their restimulation with the same allergen.

Barometric whole body plethysmography in mice

Abstract: There has been significant utilization of the technique described by Hamelmann et al. (Am J Respir Crit Care Med 156: 766–775, 1997) in which a parameter, enhanced pause (Penh), related to airways ...

S-carboxymethylcysteine normalises airway responsiveness in sensitised and challenged mice

Abstract: S -carboxymethylcysteine ( S -CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S -CMC on allergic airway inflammation has not yet been defined. In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S -CMC (5–100 mg·kg −1 ) was administered from 2 days before the secondary challenge through to the day of assay. Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S -CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S -CMC. In BAL fluid, increased levels of interferon-γ, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected. In conclusion, the data indicate that S -carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.

Pediatric allergic rhinitis: Factors affecting treatment choice

Abstract: Allergic rhinitis is the most prevalent chronic allergic disease in children. Although it is not life-threatening, it can have a significantly detrimental effect on a child's quality of life, and it may exacerbate a number of common comorbidities, including asthma and sinusitis. The Allergic Rhinitis and its Impact on Asthma guidelines, an evidence-based algorithm for the treatment of allergic rhinitis, advocate the use of antihistamines for the treatment of the broad spectrum of the disease. However, first-generation antihistamines are associated with a number of adverse events, including central nervous system impairment and anticholinergic and cardiovascular effects. Moreover, these agents have not been rigorously tested in the pediatric population. Nevertheless, first-generation antihistamines remain the most frequently prescribed agents in this class of drugs. This is despite the fact that the second-generation antihistamines are largely free of the undesirable side effects associated with their predecessors and the fact that they have been shown to be effective in relieving allergic rhinitis symptoms in children in a number of large-scale clinical trials. Therefore, when selecting an antihistamine for a child, it would be prudent to consider the full range of antihistamines and to base the selection of a particular drug on its efficacy, onset and duration of action, and safety profile.

Critical decisions in selecting an intravenous immunoglobulin product.

Abstract: Use of intravenous immunoglobulin (IVIG) therapy has expanded enormously in the past two to three decades, targeting a large number of autoimmune and inflammatory disorders as well as primary immunodeficiency disease, human immunodeficiency virus, and Kawasaki disease. Increased use, particularly at higher doses and in older patients, has presented certain challenges related to safety and tolerability. All IVIGs are not the same. They differ in manufacturing processes, methods of virus elimination, and final composition. Carefully evaluating patient risk factors and matching them to potential IVIG product risks and benefits are becoming increasingly important in the selection of a particular IVIG.

Airway Hyperresponsiveness in the Absence of CD4+ T Cells after Primary but Not Secondary Challenge

Abstract: CD4+ T cells have been shown to play a role in the development of airway hyperresponsivness (AHR) and airway eosinophilia in mice using ablation as well as adoptive transfer experiments. However, as other T cell subsets (CD8, NKT) may play a role in these models, we examined the responses of sensitized CD4-deficient mice after either primary or secondary airway allergen challenge. After sensitization, CD4-deficiency in mice was not associated with airway eosinophilia, allergen-specific IgE, or elevated levels of interleukin (IL)-4 or IL-13. Increases in lung CD8 T cells and IL-5 were observed and shown to be essential for AHR as demonstrated after CD8 T cell depletion or anti-IL-5 treatment. In contrast to the response of sensitized CD4-deficient mice to primary allergen challenge, they failed to develop AHR after secondary allergen challenge. Although the importance of this CD4+ T cell-independent pathway in normal mice is unclear at this time, these studies identify the diversity of the cellular pathway, which may contribute to the development of AHR after primary allergen exposure of sensitized mice.

Methods of using nucleic acid vector-lipid complexes

Abstract: This invention relates to a vaccine and a method for immune activation which is effective for eliciting both a systemic, non-antigen specific immune response and a strong antigen-specific immune response in a mammal. The method is particularly effective for protecting a mammal from a disease including cancer, a disease associated with allergic inflammation, an infectious disease, or a condition associated with a deleterious activity of a self-antigen. Also disclosed are therapeutic compositions useful in such a method.