Biomedical subjects

Paul S Foster

Publications and source records attributed to Paul S Foster.

At least 19 recordsLinked to original sources

PubMed2007

Comparative roles of IL-4, IL-13, and IL-4Ralpha in dendritic cell maturation and CD4+ Th2 cell function.

IL-4 and IL-13 play key roles in Th2 immunity and asthma pathogenesis. Although the function of these cytokines is partially linked through their shared use of IL-4Ralpha for signaling, the interplay between these cytokines in the development of memory Th2 responses is not well delineated. In this investigation, we show that both IL-4 and IL-13 influence the maturation of dendritic cells (DC) in the lung and their ability to regulate secretion of IFN-gamma and Th2 cytokines by memory CD4(+) T cells. Cocultures of wild-type T cells with pulmonary DC from allergic, cytokine-deficient mice demonstrated that IL-4 enhanced the capacity of DC to stimulate T cell secretion of Th2 cytokines, whereas IL-13 enhanced the capacity of DC to suppress T cell secretion of IFN-gamma. Because IL-4Ralpha is critical for IL-4 and IL-13 signaling, we also determined how variants of IL-4Ralpha influenced immune cell function. T cells derived from allergic mice expressing a high-affinity IL-4Ralpha variant produced higher levels of IL-5 and IL-13 compared with T cells derived from allergic mice expressing a low-affinity IL-4Ralpha variant. Although DC expressing different IL-4Ralpha variants did not differ in their capacity to influence Th2 cytokine production, they varied in their capacity to inhibit IFN-gamma production by T cells. Thus, IL-4 and IL-13 differentially regulate DC function and the way these cells regulate T cells. The affinity of IL-4Ralpha also appears to be a determinant in the balance between Th2 and IFN-gamma responses and thus the severity of allergic disease.

Animals↗

PubMed2007

Laterality, region, and type of motor dysfunction correlate with cognitive impairment in Parkinson's disease.

We studied the relationship between two screening cognitive measures and off motor Unified Parkinson's Disease Rating Scale (UPDRS) scores in 108 Parkinson's disease patients. Multiple regressions were conducted to examine the UPDRS subscores' unique contributions to cognitive function. When including bradykinesia, rigidity, and postural/gait instability subscores, only bradykinesia predicted Mini Mental Status Examination (MMSE), normalized beta = -0.57, t(104) = -3.31, P < 0.01, and Dementia Rating Scale-2 (DRS-2), normalized beta = -0.45, t(104) = -2.55, P < 0.05. Tremor was not included in the regression analyses because it did not correlate with cognitive function. When including axial and appendicular subscores, only the axial subscore predicted MMSE, normalized beta = -0.39, t(105) = -3.19, P < 0.01, and DRS-2 scores, normalized beta = -0.40, t(106) = -3.28, P < 0.01. When including left-sided and right-sided subscores, only the right-sided symptoms predicted DRS-2 scores, normalized beta = -0.28, t(105) = -2.45, P < 0.05, and showed a trend toward predicting MMSE scores, normalized beta = -0.22, t(105) = -1.95, P = 0.054. We therefore found that right-sided symptoms (for laterality), axial symptoms (for region), and bradykinesia (for type of symptoms) were the best predictors of cognitive function.

Aged↗

PubMed2006

Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness.

Increased arginase I activity is associated with allergic disorders such as asthma. How arginase I contributes to and is regulated by allergic inflammatory processes remains unknown. CD4+ Th2 lymphocytes (Th2 cells) and IL-13 are two crucial immune regulators that use STAT6-dependent pathways to induce allergic airways inflammation and enhanced airways responsiveness to spasmogens (airways hyperresponsiveness (AHR)). This pathway is also used to activate arginase I in isolated cells and in hepatic infection with helminths. In the present study, we show that arginase I expression is also regulated in the lung in a STAT6-dependent manner by Th2-induced allergic inflammation or by IL-13 alone. IL-13-induced expression of arginase I correlated directly with increased synthesis of urea and with reduced synthesis of NO. Expression of arginase I, but not eosinophilia or mucus hypersecretion, temporally correlated with the development, persistence, and resolution of IL-13-induced AHR. Pharmacological supplementation with l-arginine or with NO donors amplified or attenuated IL-13-induced AHR, respectively. Moreover, inducing loss of function of arginase I specifically in the lung by using RNA interference abrogated the development of IL-13-induced AHR. These data suggest an important role for metabolism of l-arginine by arginase I in the modulation of IL-13-induced AHR and identify a potential pathway distal to cytokine receptor interactions for the control of IL-13-mediated bronchoconstriction in asthma.

Animals↗

PubMed2006

Lewy body dementia and creativity: case report.

BACKGROUND: We studied a visual artist with Lewy body dementia (LBD) to learn how this disease influenced his paintings during the course of the disease. METHODS: Study 1 evaluated two paintings of the same subject matter, one that the patient painted before his illness and the other after the onset of this disease. Study 2 evaluated a collection of his paintings from the time before he was ill (1994) until the time he stopped painting when he was suffering with LBD (2002). To learn how the onset and progression of LBD affected his paintings we had judges score the following qualities: aesthetic-beauty, closure completeness, evocative impact, novelty, technique and representational quality. RESULTS: In Study 1 we found that the representational ratings for the picture he painted when he had LBD was significantly lower than the picture he painted before he developed LBD. In Study 2, we found that all the artistic qualities measures temporally declined except novelty. We also found that the paintings that were judges as having the highest quality representations were significantly more novel than those that had poorer representations. In addition, we conducted a forward stepwise regression analysis using quality measures as predictor of year. This analysis revealed that only representational quality significantly predicted painting year. CONCLUSIONS: Our results suggest that as LBD progresses, except for novelty there is a gradual degradation of the ability to visually express artistic subject matter. It possible that the preserved ability to paint novel picture is related to relative preservation of frontal lobe function, but the degradation of other artistic qualities might be related to deterioration of the parietal lobes which either impairs the brain's iconic representations or the knowledge needed to portray these representations.

Adult↗

PubMed2006

Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function?

The discovery of small "noncoding" or "nonmessenger" RNA molecules that are repressors of translation (microRNAs) has provided the opportunity to specifically suppress a gene or clusters of genes. Moreover, the recent employment of synthetic analogs of these small RNA molecules termed "antagomirs" has shown that microRNAs of interest can be specifically targeted. Understanding the role of microRNAs in fundamental processes associated with complex diseases such as asthma, chronic obstructive pulmonary disease, cancer, chronic infections, and immune disorders may aid in disease diagnosis and prognosis and potentially identify new therapeutic targets.

Gene Expression Regulation↗

PubMed2006

Interleukin-5 does not influence differential transcription of transmembrane and soluble isoforms of IL-5R alpha in vivo.

UNLABELLED: Interleukin-5 (IL-5) promotes signal transduction and expansion of eosinophil colonies in bone marrow via interactions with its heterodimeric receptor (IL-5R). Two variants encoding soluble forms of the alpha subunit (sIL-5R alpha) have been described, although the signals promoting and/or limiting differential transcription remain to be clarified. OBJECTIVES: Our intent was to explore the role of IL-5 in regulating differential transcription of these splice variants in vivo. METHODS: We have designed a quantitative reverse transcriptase-polymerase chain reaction assay to detect transcripts encoding the transmembrane, soluble 1 and 2 forms of IL-5R alpha in two strains of wild-type (BALB/c and C57BL/6) and corresponding IL-5 gene-deleted mice. Wild-type mice respond to S. mansoni infection with a gradual increase in serum IL-5 and eosinophilia, which is not observed in IL-5 gene-deleted mice. RESULTS AND CONCLUSIONS: We find that IL-5 is not necessary for differential splicing to occur in vivo, as all three forms of the IL-5R alpha are detected in both strains of IL-5 gene-deleted mice, with ratios of transcript expression (transmembrane : soluble 1 : soluble 2) that were indistinguishable from their wild-type counterparts. Differential splicing does vary markedly between strains, potentially because of local effects of strain-specific polymorphisms.

Alternative Splicing↗

PubMed2006

Airway hyperreactivity in exacerbation of chronic asthma is independent of eosinophilic inflammation.

We have developed an animal model to investigate the mechanisms underlying an acute exacerbation of chronic asthma. Sensitized BALB/c mice were exposed to aerosolized ovalbumin, either as chronic low-level challenge (mass concentration approximately 3 mg/m(3)) for 4 wk, a single moderate-level challenge (approximately 30 mg/m(3)), or chronic low-level followed by single moderate-level challenge (the acute exacerbation group). Compared with animals receiving chronic challenge alone, mice in the acute exacerbation group exhibited a more marked inflammatory response, with involvement of intrapulmonary airways and lung parenchyma, and increased numbers of lymphocytes and eosinophils in bronchoalveolar lavage fluid. They also developed airway hyperreactivity (AHR) to methacholine, demonstrable as increased transpulmonary resistance and decreased compliance. This pattern of AHR was absent in chronically challenged animals, but was also present in animals given single moderate-level challenge. However, compared with animals receiving a single moderate-level challenge, inflammation and AHR were induced more rapidly in the acute exacerbation group. Eosinophil-deficient GATA1 Deltadbl mice exhibited undiminished AHR in the acute exacerbation model. We conclude that in mice with pre-existing airway lesions resembling mild chronic asthma, exposure to a moderately high concentration of inhaled antigen induces features of an acute exacerbation. The inflammatory response involves distal airways and is associated with a distinct pattern of AHR, which develops independent of the enhanced eosinophilic inflammation.

Animals↗

PubMed2006

Schistosoma mansoni infection in eosinophil lineage-ablated mice.

We explore the controversial issue of the role of eosinophils in host defense against helminthic parasites using the established Schistosoma mansoni infection model in 2 novel mouse models of eosinophil lineage ablation (DeltadblGATA and TgPHIL). No eosinophils were detected in bone marrow of infected DeltadblGATA or TgPHIL mice, despite the fact that serum IL-5 levels in these infected mice exceeded those in infected wild type by approximately 4-fold. Liver granulomata from infected DeltadblGATA and TgPHIL mice were likewise depleted of eosinophils compared with those from their respective wild types. No eosinophil-dependent differences in granuloma number, size, or fibrosis were detected at weeks 8 or 12 of infection, and differential accumulation of mast cells was observed among the DeltadblGATA mice only at week 12. Likewise, serum levels of liver transaminases, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) increased in all mice in response to S mansoni infection, with no eosinophil-dependent differences in hepatocellular damage observed. Finally, eosinophil ablation had no effect on worm burden or on egg deposition. Overall, our data indicate that eosinophil ablation has no impact on traditional measures of disease in the S mansoni infection model in mice. However, eosinophils may have unexplored immunomodulatory contributions to this disease process.

Animals↗

PubMed2006

ICAM-1-dependent pathways regulate colonic eosinophilic inflammation.

Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal (EGID) diseases. Central to eosinophil migration into the gastrointestinal tract are the integrin-mediated interactions with adhesion molecules. Although the mechanisms regulating eosinophil homing into the small intestine have begun to be elucidated, the adhesion pathways responsible for eosinophil trafficking into the large intestine are unknown. We investigated the role of adhesion pathways in eosinophil recruitment into the large intestine during homeostasis and disease. First, using a hapten-induced colonic injury model, we demonstrate that in contrast to the small intestine, eosinophil recruitment into the colon is regulated by a beta7 -integrin addressin cell adhesion molecule-1-independent pathway. Characterization of integrin expression on colonic eosinophils by flow cytometry analysis revealed that colonic CC chemokine receptor 3+ eosinophils express the intercellular adhesion molecule-1 (ICAM-1) counter-receptor integrins alphaL, alphaM, and beta2. Using ICAM-1-deficient mice and anti-ICAM-1 neutralizing antibodies, we show that hapten-induced colonic eosinophilic inflammation is critically dependent on ICAM-1. These studies demonstrate that beta2 -integrin/ICAM-1-dependent pathways are integral to eosinophil recruitment into the colon during GI inflammation associated with colonic injury.

Animals↗

PubMed2006

Magnitude of cerebral asymmetry at rest: covariation with baseline cardiovascular activity.

The cerebral regulation of cardiovascular functioning varies along both a lateral and a longitudinal axis. The parasympathetic and sympathetic nervous systems are lateralized to the left and right cerebral hemispheres, respectively. Further, the frontal lobes are known to be inhibitory in nature, whereas the temporal lobes are excitatory. However, no systematic investigation has been conducted to determine the nature and strength of the relationship between the left and right frontal and temporal lobes in regulating cardiovascular activity. The present investigation sought to examine these relationships by testing the hypothesis that negative correlations would be found between baseline heart rate and blood pressure and asymmetry of alpha magnitude across the frontal lobes. Further, positive correlations were hypothesized to exist across the temporal lobes. A total of 20 women were asked to relax with their eyes closed while heart rate and blood pressure as well as quantitative electroencephalography data were obtained. The results indicated that, as hypothesized, significant negative correlations existed across the frontal lobes and significant positive correlations existed across the temporal lobes. The results provide further support for a division of responsibility between the left and right frontal and temporal lobes in the regulation of heart rate and blood pressure.

Adolescent↗

PubMed2006

Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study.

BACKGROUND: Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. OBJECTIVE: To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. DESIGN: Double-masked, placebo-controlled, parallel-group, single-center trial. PATIENTS: Two experimental groups: patients with PD who were receiving either TT or placebo. INTERVENTIONS: Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. MAIN OUTCOME MEASURES: The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. RESULTS: Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). CONCLUSIONS: Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.

Affect↗

PubMed2006

Mechanistic analysis of experimental food allergen-induced cutaneous reactions.

Individuals with food allergy often present with uritcaria and atopic dermatitis. Indeed, susceptibility to food allergy may predispose to the development of these cutaneous allergic disorders. Recently, we developed a model of food allergy, whereby oral consumption of food [pea Pisum sativum L.; expressing alpha-amylase inhibitor-1 (alphaAI) from the common bean Phaseolus vulgaris L. cv Tendergreen (pea-alphaAI)] promotes a T helper cell type 2 (Th2) inflammatory response and predisposes to cutaneous allergic reactions following subsequent food allergen (alphaAI) exposure. To delineate the kinetics of food allergen-induced cutaneous reactions and examine the inflammatory mechanisms involved in this allergic reaction, we used interleukin (IL)-13-, IL-4 receptor alpha-, and eotaxin-1-deficient mice and performed serum transfer and CD4+ T cell depletion studies. We demonstrate that consumption of pea-alphaAI promotes an alphaAI-specific immunoglobulin G1 (IgG1) and IgE antibody response. Furthermore, we show that subsequent food allergen (alphaAI) challenge in the skin induced an early (3 h)- and late-phase (24 h) cutaneous allergic reaction. The early-phase response was associated with mast cell degranulation and the presence of Ig, whereas the late-phase response was characterized by a lymphoid and eosinophilic infiltrate, which was critically regulated by CD4+ T cells, IL-13, and eotaxin-1. Collectively, these studies demonstrate that food allergy can predispose to cutaneous inflammatory reactions, and these processes are critically regulated by Th2 immune factors.

Allergens↗

PubMed2006

Interferon-gamma as a possible target in chronic asthma.

The role of interferon-gamma (IFN-gamma) in asthma is controversial. However, this cytokine has been proposed to play a role both in acute severe asthma and chronic stable asthma. We have shown that in a chronic low-level challenge model of allergic asthma in mice, which replicates characteristic features of airway inflammation and remodelling, the mechanisms of airway hyperreactivity (AHR) are markedly different to those in short-term high-level challenge models. Notably, AHR is independent of various Th2 cytokines and their signalling pathways. However, administration of a neutralising antibody to IFN-gamma suppresses AHR. More recently, we have found that following chronic allergen challenge, but not acute challenge, IFN-gamma-producing CD4+ T cells are demonstrable in peribronchial lymph nodes, both in wild-type mice and in STAT6-/-mice. Treatment with anti-IFN-gamma decreases the number of IFN-gamma-producing CD4+ T cells in both wild-type and gene-targeted mice, providing a possible explanation for the ability of anti-IFN-gamma to inhibit AHR in the setting of chronic challenge. These data further strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a co-operative interaction between Th2 and Th1 cytokines. This may be particularly relevant to acute exacerbations of asthma, in which setting there may be justification for therapeutic inhibition of IFN-gamma.

Animals↗

PubMed2005

Transgenic expression of bean alpha-amylase inhibitor in peas results in altered structure and immunogenicity.

The development of modern gene technologies allows for the expression of recombinant proteins in non-native hosts. Diversity in translational and post-translational modification pathways between species could potentially lead to discrete changes in the molecular architecture of the expressed protein and subsequent cellular function and antigenicity. Here, we show that transgenic expression of a plant protein (alpha-amylase inhibitor-1 from the common bean (Phaseolus vulgaris L. cv. Tendergreen)) in a non-native host (transgenic pea (Pisum sativum L.)) led to the synthesis of a structurally modified form of this inhibitor. Employing models of inflammation, we demonstrated in mice that consumption of the modified alphaAI and not the native form predisposed to antigen-specific CD4+ Th2-type inflammation. Furthermore, consumption of the modified alphaAI concurrently with other heterogeneous proteins promoted immunological cross priming, which then elicited specific immunoreactivity of these proteins. Thus, transgenic expression of non-native proteins in plants may lead to the synthesis of structural variants possessing altered immunogenicity.

Animals↗

PubMed2004

The Ruff Figural Fluency Test: heightened right frontal lobe delta activity as a function of performance.

Research has indicated that the Ruff Figural Fluency Test [RFFT; Ruff, R. M., Light, R. H., & Evans, R. W. (1987). The Ruff Figural Fluency Test: A normative study with adults. Developmental Neuropsychology, 3, 37-51] is sensitive to right frontal lobe functioning. Indeed, research has differentiated between patients with left or right frontal lobe lesions using performance on the RFFT [Ruff, R. M., Allen, C. C., Farrow, C. E., Niemann, H., & Wylie, T. (1994). Figural fluency: Differential impairment in patients with left versus right frontal lobe lesions. Archives of Clinical Neuropsychology, 9, 41-55]. The present investigation used quantitative electroencephalography to test further whether the RFFT was sensitive to right frontal lobe functioning among a group of individuals with no history of head injury. To meet this objective, the RFFT was administered to a group of 45 right-handed men with no history of significant head injury or cerebral dysfunction. Delta magnitude (muV) at three right frontal electrode sites (FP2, F4, F8) was then used to compare those who performed the best (High Fluency) with those who performed the worst (Low Fluency) on the RFFT. The findings indicated heightened right frontal delta magnitude for the Low Fluency group relative to the High Fluency group at the F2 and F8 right frontal electrode sites. Thus, the present findings provide further support for the contention that the RFFT is sensitive to right frontal lobe functioning, even among those with no history of head injury.

Adolescent↗

PubMed2004

Effects of anticytokine therapy in a mouse model of chronic asthma.

The relative contribution of Th2 and Th1 cytokines to the pathogenesis of lesions of chronic asthma remains poorly understood. To date, therapeutic inhibition of Th2 cytokines has proved disappointing. We used a clinically relevant model of chronic allergic asthma in mice to compare the effects of administering neutralizing antibodies to interleukin (IL)-13, IL-5, and interferon-gamma (IFN-gamma) to animals with established disease. As has been observed in clinical studies, anti-IL-5 inhibited both inflammation and remodeling but had no effect on airway responsiveness to methacholine. Anti-IL-13 effectively suppressed eosinophil recruitment and accumulation of chronic inflammatory cells in the airways. This treatment also partially suppressed changes of airway wall remodeling, including goblet cell hyperplasia/metaplasia and subepithelial fibrosis, but had limited ability to inhibit airway hyperreactivity (AHR). In contrast, treatment with anti-IFN-gamma markedly suppressed AHR. This antibody inhibited accumulation of chronic inflammatory cells but did not affect eosinophil recruitment or changes of remodeling. We conclude that inhibition of IL-5 is beneficial and that inhibition of IL-13 has considerable potential as a therapeutic strategy in chronic asthma, that IFN-gamma may play an important role in the pathogenesis of AHR, and that co-operative interaction between Th2 and Th1 cytokines contributes to the pathogenesis of the lesions of chronic asthma.

Animals↗

PubMed2004

Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase.

The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.

Animals↗

PubMed2004

Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen.

Eosinophil degranulation is thought to play a pivotal role in the pathogenesis of allergic disorders. Although mouse models of allergic disorders have been used extensively to identify the contribution of eosinophils to disease, ultrastructural evidence of active granule disassembly has not been reported. In this investigation, we characterized the degree of eosinophil activation in the bone marrow, blood, lung tissue, and airways lumen [bronchoalveolar lavage fluid (BALF)] of ovalbumin-sensitized and aero-challenged wild-type and interleukin-5 transgenic mice. Degranulation was most prominent in and primarily compartmentalized to the airways lumen. Eosinophils released granule proteins by the process of piecemeal degranulation (PMD). Accordingly, recruitment and activation of eosinophils in the lung correlated with the detection of cell-free eosinophil peroxidase in BALF and with the induction of airways hyper-reactivity. As in previous studies with human eosinophils, degranulation of isolated mouse cells did not occur until after adherence to extracellular matrix. However, higher concentrations of exogenous stimuli appear to be required to trigger adherence and degranulation (piecemeal) of mouse eosinophils when compared with values reported for studies of human eosinophils. Thus, mouse eosinophils undergo PMD during allergic inflammation, and in turn, this process may contribute to pathogenesis. However, the degranulation process in the allergic lung of mice is primarily compartmentalized to the airway lumen. Understanding the mechanism of eosinophil degranulation in the airway lumen may provide important insights into how this process occurs in human respiratory diseases.

Animals↗