Electrophysiological properties of the airway: epithelium in the murine, ovalbumin model of allergic airway disease

The electrophysiological properties of cultured tracheal cells (CTCs) were examined in a murine (C57BL/6J), ovalbumin (OVA)-induced model of allergic airway disease (AAD) at early (3-day OVA-aerosol) and peak (10-day OVA-aerosol) periods of inflammation. Transepithelial potential difference, short-circuit current (Isc), and resistance (RT) were lower in CTCs from 10-day OVA-aerosol animals compared to CTCs from na?ve mice. In cells cultured for 5 weeks, RT was greater in naive CTCs than in 10-day OVA-aerosol CTCs at all times (P < 0.01). The Isc response to mucosal amiloride (10(-4) mol/L) was increased in CTCs from 10-day OVA-aerosol mice compared to na?ve mice (6.0 +/- 0.37 microA/cm2 versus 1.8 +/- 0.56 microA/cm2; P < 0.001) with intermediate values for CTCs from 3-day OVA-aerosol mice. The cAMP-induced increase in Isc was blunted in 10-day OVA-aerosol animals compared to CTCs from na?ve mice (9 +/- 12% versus 39 +/- 7%; P < 0.01) with intermediate values for CTCs from 3-day OVA-aerosol mice. There was no difference in mannitol flux in na?ve compared to 10-day OVA-aerosol CTCs. Similar results were found using intact tracheas mounted in a perfusion chamber. These data demonstrate changes in airway epithelial cell function in the OVA-induced model of AAD that may contribute to the pathogenesis of airway inflammation.     

Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma

BACKGROUND: Epidemiological evidence underlines the impact of prenatal environmental factors on the development of postnatal allergies. In this regard an inverse correlation between lipopolysaccharide (LPS) exposure and development of childhood allergy has been found. OBJECTIVE: To assess the impact of prenatal LPS exposure on the development of postnatal respiratory allergies in a mouse model of experimental asthma. METHODS: Female BALB/c mice were exposed to LPS before conception and during pregnancy. Several weeks after birth offspring were sensitized to ovalbumin (OVA) followed by aerosol allergen challenges. RESULTS: Prenatal, maternal LPS-exposure enhanced neonatal IFN-gamma, but not IL-4 and IL-2 production. OVA sensitization of prenatally LPS-exposed mice was accompanied by a marked suppression in anti-OVA IgG1 and IgE as well as unchanged IgG2a antibody responses, paralleled by a significant reduction in IL-5 and IL-13 levels following mitogenic stimulation of splenic leucocytes. Assessment of bronchoalveolar lavage fluids following allergen challenges revealed a marked reduction in eosinophils and macrophages in these mice. Surprisingly, development of airway hyper-responsiveness, a hallmark of bronchial asthma, was not affected. CONCLUSION: This study provides first experimental evidence that LPS may already operate in prenatal life in order to modulate the development of allergies in the offspring.     

B cell subsets are modulated during allergic airway inflammation but are not required for the development of respiratory tolerance in a murine model

Allergic asthma is a widespread chronic inflammatory disease of the airways. The role of different B cell subsets in developing asthma and respiratory tolerance is not well known. Especially regulatory B (Breg) cells are proposed to be important in asthma regulation. Using wild‐type (WT) and B cell‐deficient (μMT) mice we investigated how B cells are affected by induction of allergic airway inflammation and respiratory tolerance and whether they are necessary to develop these conditions. WT mice with an asthma‐like phenotype, characterized by increased airway hyper reactivity, eosinophilic airway inflammation, mucus hypersecretion and elevated Th2 cytokines, exhibited increased MHCII and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen, which contributed to allergen‐specific T cell proliferation in vitro. Germinal center B cell numbers were elevated and associated with increased production of allergen‐specific immunoglobulins especially in bLN. In contrast, respiratory tolerance clearly attenuated these B cell alterations and directly enhanced marginal zone precursor B cells, which induced regulatory T cells in vitro. However, μMT mice developed asthma‐like and tolerized phenotypes like WT mice. Our data indicate that although B cell subsets are affected by asthma‐like and respiratory tolerant phenotypes, B cells are not required for tolerance induction.     

Chimerism but not neonatal antigen exposure induces transplant tolerance

Acquired transplant tolerance could be readily induced during foetal or neonatal period through donor cell infusion, but it is not the case in adults. This phenomenon has been attributed to the variation of immune system development in neonatal and adult periods. To investigate the role of immature immune system and chimerism in neonatal transplant tolerance, irradiated spleen cells or cell fraction from F1 (BALB/c × C57BL/6) or GFP-F1 mice were injected intravenously into neonatal C57BL/6 mice to induce tolerance. Irradiated cells or cell fraction could not induce chimerism and transplant tolerance in neonatal mice, even increasing the dose of donor cells to 5 × 10(7). Living donor cells induced tolerance in neonatal mice, and the quantity of living cells was correlated with the degree of chimerism and tolerance. At the amount of 3 × 10(7) F1 spleen cells, skin grafts were survived permanently in more than 80% of treated mice. However, the amount of 0.7 × 10(7) F1 spleen cells could only slightly prolong allografts' survival. The more donor cells were infused, the higher level of chimerism was achieved, and the higher frequency of alloreactive T cells was deleted. Chimerism is prerequisite for the induction and maintenance of tolerance. Chimerism in long-term tolerant mice was significantly higher than that in chronic graft rejected mice, with 6.48 ± 4.02% versus 1.41 ± 0.77%. It implies that transplant tolerance depends on the establishment of chimerism, but not on antigen exposure to immature immune system in foetus or neonates.     

屋尘螨在诱导BALB/c小鼠混合型气道炎症中的作用及致病机制探讨

目的 探讨屋尘螨(HDM)抗原在小鼠模型中诱导混合型气道炎症中的作用及其机理,为支气管哮喘的临床诊断和治疗提供理论依据.方法 BALB/c小鼠于实验第0天、7天、14天、21天、28天和35天进行PBS或HDM提取液(50μg或100 μg)滴鼻.采用头体积描记法测量小鼠的气道反应性;对支气管肺泡灌洗液(BAL)进行细胞计数和分类;酶联免疫法(ELISA)检测BAL中CXCL1、CXCL2、CCL11 (eotaxin)、IL-5、IFNγ、IL-10和IL-17的含量及血清总IgE,HDM特异性IgG1、IgG2a;采用实时荧光定量PCR检测肺组织中相关基因mRNA表达;并对肺组织PAS染色后进行病理学观察.结果 HDM抗原引起了以中性粒细胞和嗜酸性粒细胞为主的混合型气道炎症、血清HDM特异性IgG1的升高及高脚杯细胞增生(GCH)等组织学变化,其混合型气道炎症可能与CXCL1和IL-5等细胞因子的分泌增多有关,是固有免疫和适应性免疫共同活化的结果.这种炎症表型在经高浓度HDM(100 μg)致敏的小鼠中表现得更为显著.结论 HDM过敏原在小鼠模型中诱导了中性粒细胞和嗜酸性粒细胞的共同活化.     

An antigen-independent but not antigen-specific T(H)1 response provides protection in the murine airway inflammation model

BACKGROUND: Atopic disorders are associated with an imbalanced T(H) cell response biased toward a strong T(H)2 type, resulting in excessive production of IgE antibodies, eosinophil recruitment and activation, and mast cell degranulation. Restoring the T(H)1-T(H)2 balance by increasing the antigen-specific T(H)1 response has been pursued for specific allergy immunotherapy. Synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG) are strong T(H)1 adjuvants and are being investigated for allergy immunotherapy. OBJECTIVE: This study was designed to investigate the protective role of antigen-specific T(H)1 responses induced by epidermal powder immunization with ovalbumin (OVA) and CpG in a murine airway inflammation model. METHODS: An allergy model was used in which BALB/c mice were sensitized and then challenged with OVA. Mice received prophylactic or therapeutic immunizations with OVA, CpG, or both. After challenge, pulmonary inflammation and cell infiltration were measured on the basis of BAL cell counts and lung histology. Immune response was determined by measuring the levels of lavage cytokines and serum antibodies. RESULTS: Coadministration of OVA and CpG by means of subcutaneous injection or epidermal powder immunization, although inducing a strong T(H)1 response, neither suppressed T(H)2 cytokines nor offered protection against pulmonary eosinophilia and histopathology in a mouse challenge model. However, when CpG was used as a stand-alone treatment of previously sensitized animals, protection against allergic airway inflammation was observed. After challenge with OVA, eosinophilia was suppressed in the lungs of the CpG-treated mice. CONCLUSION: This finding argues against the approach of boosting an allergen-dependent T(H)1 response and favors induction of an antigen-independent T(H)1 response for allergy immunotherapy.     

Lipocalin2 protects against airway inflammation and hyperresponsiveness in a murine model of allergic airway disease

Background Allergen‐induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering different inflammatory pathways. Objective The aim of this study was to identify possible mediators of airway inflammation (AI) in a model of allergic AI via microarray comparisons and to analyse one of these mediators, Lipocalin2 (Lcn2), for its role in a murine model of allergic airway disease. Methods Gene microarrays were used to identify genes with at least a twofold increase in gene expression in the lungs of two separate mouse strains with high and low allergic susceptibility, respectively. Validation of mRNA data was obtained by Western blotting, followed by functional analysis of one of the identified genes, Lcn2, in mice with targeted disruption of specific gene expression. Epithelial cell cultures were undertaken to define induction requirements and possible mechanistic basis of the results observed in the Lcn2 knock‐out mice. Results Lcn2 was up‐regulated upon allergen sensitization and airway challenges in lung tissues of both mouse strains and retraced on the protein level in bronchoalveolar lavage fluids. Functional relevance was assessed in mice genetically deficient for Lcn2, which showed enhanced airway resistance and increased AI associated with decreased apoptosis of lung inflammatory cells, compared with wild‐type controls. Similarly, application of Lcn2‐blocking antibodies before airway challenges resulted in increased inflammation and reduced apoptosis. Conclusion These data indicate a protective role for Lcn2 in allergic airway disease, suggesting a pro‐apoptotic effect as the underlying mechanism. Cite this as: A. M. Dittrich, M. Krokowski, H.‐A. Meyer, D. Quarcoo, A. Avagyan, B. Ahrens, S. M. Kube, M. Witzenrath, C. Loddenkemper, J. B. Cowland and E. Hamelmann, Clinical & Experimental Allergy, 2010 (40) 1689–1700.     

Hyperresponsiveness of bronchial but not tracheal smooth muscle in a murine model of allergic bronchial asthma

Objective: To determine a change in airway smooth muscle contractility in a murine model of allergic asthma, the responsiveness of airway smooth muscles isolated from ovalbumin (OA)-sensitized and -challenged mice was compared with that from control animals.Methods: Actively sensitized mice were repeatedly challenged by ovalbumin (OA) antigen inhalation. Twenty-four h after the last antigen challenge, tracheal and bronchial smooth muscle responsiveness to acetylcholine (ACh) and endothelin-1 (ET-1) were measured. Airway microvascular leakage and histochemistry were also determined as indices of airway inflammation.Results: Both the ACh and ET-1 responsiveness of bronchial, but not tracheal, smooth muscles were significantly augmented in OA-challenged mice, whereas no significant change in the expression levels of M₂, M₃ and ET_B receptors was observed. The Evans blue dye extravasation in the main bronchial, but not tracheal, tissue of OA-challenged mice was significantly increased as compared with that of sensitized control animals. A marked inflammatory cells infiltration was also observed in bronchial but not tracheal tissues of OA-challenged mice.Conclusion: Repeated antigen challenge to sensitized mice caused a hyperresponsiveness of bronchial, but not tracheal, smooth muscle accompanied with bronchial tissue inflammation.Received 22 April 2004; returned for revision 10 June 2004; accepted by M. Katori 9 July 2004     

L-Selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma

BACKGROUND: Airway inflammation and airway hyperresponsiveness (AHR) are fundamental features of asthma. Migration of inflammatory cells from the circulation into the lungs is dependent on adhesion molecule interactions. The cell surface adhesion molecule L-selectin has been demonstrated to mediate leukocyte rolling on inflamed and noninflamed pulmonary endothelium. However, its role in the development of airway inflammation and AHR in asthma has not been examined. OBJECTIVE: We sought to characterize the role of L-selectin in the recruitment of inflammatory cells to the airway-lung and the development of AHR in a murine model of asthma. METHODS: An ovalbumin (OVA)-induced allergic airway disease model of asthma was applied to L-selectin-deficient (LKO) mice and C57BL/6 wild-type (WT) control mice. The development of airway inflammation was assessed by examining leukocyte influx into bronchoalveolar lavage (BAL) fluid and the lung. Total and differential BAL leukocyte counts were determined, and the immunophenotype of BAL lymphocytes was assessed by means of flow cytometry. The development of AHR was assessed by means of whole-body plethysmography. RESULTS: Airway-lung inflammation was equivalent in LKO and WT mice sensitized-challenged with OVA, as measured by total and differential BAL cell counts and histologic analysis of lung tissue. Numbers of eosinophils, neutrophils, lymphocytes, and monocytes in BAL fluid were equivalent in LKO and WT mice. However, phenotypic analysis of BAL lymphocytes demonstrated significantly reduced CD3(+) populations and increased B220(+) populations in LKO compared with WT mice (P <.05). Remarkably, despite a fulminant inflammatory response in the airway-lung in LKO mice sensitized-challenged with OVA, AHR was completely abrogated. CONCLUSION: L-selectin plays a crucial role in the development of AHR but not allergic inflammation in an animal model of asthma. L-selectin represents a potential target for novel asthma therapies specifically aimed at controlling AHR.     

Chronic allergic airway disease in the sheep model: functional and lung-lavage features

We developed an animal model of chronic allergic airway disease by repeatedly exposing nine sheep to tracheal instillation of ascaris antigen until stable increase in lung resistance at three times control in six reactive sheep (group C) was obtained. They were then compared to the three nonreactive sheep (group B) and a control group of eight sheep exposed to saline only (group A) in terms of pulmonary function tests and bronchoalveolar lavage (BAL) analyses. Lung resistance was 1.5 +/- 0.3 cm H2O/L/sec in group A, 1.8 +/- 0.3 in group B, and 5.9 +/- 1.3 in group C. Trapping volume (functional residual capacity by plethysmography and by helium rebreathing technique) was 0 +/- 0.1 L in group A, 0.05 +/- 0.1 in group B, and 0.51 +/- 0.17 in group C. Upstream resistance at peak flow did not differ between any two groups, but upstream resistance near residual volume was 1.8 +/- 0.3 cm H2O/L/sec in A, 6.2 +/- 1.0 in B, and 28 +/- 6 in C. In BAL, total cells were 25 +/- 5 X 10(4)/ml in A, 35 +/- 8 in B, and 31 +/- 6 in C. Macrophages in BAL were 16 +/- 2 in A, 27 +/- 9 in B, and 24 +/- 4 in C. Neutrophils were 0.5 +/- 0.2 in A, 3.4 +/- 2.5 in B, 2.8 +/- 1.5 in C. Eosinophils were 0.1 +/- 0.1 in A, 0.5 +/- 0.2 in B, and 0.9 +/- 0.3 in C (p less than 0.05 group C versus group A). Total proteins, albumin, alkaline phosphatase, and fibronectin did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous immunoglobulin attenuates airway hyperresponsiveness in a murine model of allergic asthma

Background Intravenous immunoglobulin (IVIG) has potent anti‐inflammatory and immune‐modulating properties. IVIG has been utilized as a steroid‐sparing agent in severe asthma, but the results of clinical trials have been conflicting. Objective To determine whether IVIG is able to attenuate bronchial reactivity, pulmonary inflammation and T cell function using a murine model of allergic airways disease. Methods BALB/c or C57BL/6 mice were sensitized to ovalbumin (OVA) or a phosphate‐buffered saline control using local nasal sensitization, and then received five intranasal challenges on days 28–32 before sacrifice. Mice were treated intraperitoneally with either IVIG (1–2 g/kg) or equivalent human serum albumin 24 h before the first OVA challenge. Bronchial reactivity to methacholine was examined using the FlexiVent small animal ventilator. We evaluated pulmonary histology, mRNA from lung digests for T‐helper type 2 (Th2)‐related genes and bronchoalveolar lavage for cell counts and cytokines. Splenocytes were utilized to study OVA‐induced cell proliferation, cytokine production and dendritic cell maturation. Results IVIG markedly attenuated the perivascular and peribronchial pulmonary inflammation, and decreased bronchial hyperresponsiveness to methacholine. IVIG treatment of splenocytes from sensitized animals diminished cellular proliferation to OVA, whereas IVIG treatment in vivo markedly attenuated OVA‐driven splenocyte proliferation. This is accompanied by diminished IL‐13 and TNF‐α levels in splenocyte culture, decreased expression of Jagged‐1, increased Delta‐4 and decreased GATA‐3 mRNA levels, signs that IVIG has suppressed the expected Th2 response that accompanies repeated allergen exposure. Increased regulatory T cells were found in draining pulmonary lymph nodes in IVIG‐treated mice but not in controls. Conclusions and Clinical Relevance IVIG was effective in ameliorating allergic airway disease in our model. IVIG may be a promising adjunct therapy requiring further study for patients with severe asthma. Cite this as: G. N. Kaufman, A. H. Massoud, S. Audusseau, A.‐A. Banville‐Langelier, Y. Wang, J. Guay, J. A. Garellek, W. Mourad, C. A. Piccirillo, C. McCusker and B. D. Mazer, Clinical & Experimental Allergy, 2011 (41) 718–728.     

Rapid activation of nuclear factor-kappaB in airway epithelium in a murine model of allergic airway inflammation

Bronchiolar epithelium is postulated to play a critical role in the orchestration of responses to inhaled allergens, and may contribute to the pathogenesis of asthma. Using a murine model of allergic airway inflammation and hyperresponsiveness, we demonstrate in mice sensitized with ovalbumin (OVA) that following a single challenge with nebulized OVA, a rapid and protracted activation of inhibitor of kappa B kinase (IKK) occurred in lung tissue. IKK activation was followed by nuclear localization of nuclear factor (NF)-kappaB within the bronchiolar epithelium and increased luciferase activity in lungs of mice containing a NF-kappaB-dependent reporter gene. Challenge of sensitized mice with OVA also induced mRNA expression of the chemokines, macrophage inflammatory protein-2 (MIP-2) and eotaxin in lung tissue, which corresponded temporally with the observed influx of neutrophils and eosinophils, respectively, into the airspaces. Using laser capture microdissection and quantitative polymerase chain reaction, we demonstrated that MIP-2 and eotaxin were predominantly expressed in bronchiolar epithelium, in contrast to distal regions of the lungs, which expressed lower or undetectable levels of these mRNAs. These studies strengthen the potential importance of the bronchiolar epithelial cell as a source of production of NF-kappaB-dependent mediators that play a role in asthma.     

Dissemination bottleneck in a murine model of inhalational anthrax

Inhalational anthrax is caused by the sporulating bacterium Bacillus anthracis. A current model for progression in mammalian hosts includes inhalation of bacterial spores, phagocytosis of spores in the nasal mucosa-associated lymphoid tissue (NALT) and lungs by macrophages and dendritic cells, trafficking of phagocytes to draining lymph nodes, germination of spores and multiplication of vegetative bacteria in the NALT and lymph nodes, and dissemination of bacteria via the bloodstream to multiple organs. In previous studies, the kinetics of infection varied greatly among mice, leading us to hypothesize the existence of a bottleneck past which very few spores (perhaps only one) progress to allow the infection to proceed. To test this hypothesis, we engineered three strains of B. anthracis Sterne, each marked with a different fluorescent protein, enabling visual differentiation of strains grown on plates. Mice were infected with a mixture of the three strains, the infection was allowed to proceed, and the strains colonizing the organs were identified. Although the inoculum consisted of approximately equal numbers of each of the three strains, the distal organs were consistently colonized by a majority of only one of the three strains, with the dominant strain varying among animals. Such dominance of one strain over the other two was also found at early time points in the cervical lymph nodes but not in the mediastinal lymph nodes. These results support the existence of a bottleneck in the infectious process.     

Acute exercise decreases airway inflammation, but not responsiveness, in an allergic asthma model

Previous studies have suggested that the asthmatic responses of airway inflammation, remodeling, and hyperresponsiveness (AHR) are interrelated; in this study, we used exercise to examine the nature of this interrelationship. Mice were sensitized and challenged with ovalbumin (OVA); mice were then exercised via running on a motorized treadmill at a moderate intensity. Data indicate that, within the lungs of OVA-treated mice, exercise attenuated the production of inflammatory mediators, including chemokines KC, RANTES, and MCP-1 and IL-12p40/p80. Coordinately, OVA-treated and exercised mice displayed decreases in leukocyte infiltration, including eosinophils, as compared with sedentary controls. Results also show that a single bout of exercise significantly decreased phosphorylation of the NFkappaB p65 subunit, which regulates the gene expression of a wide variety of inflammatory mediators. In addition, OVA-treated and exercised mice exhibited decreases in the levels of Th2-derived cytokines IL-5 and IL-13 and the prostaglandin PGE(2), as compared with sedentary controls. In contrast, results show that a single bout of exercise had no effect on AHR in OVA-treated mice challenged with increasing doses of aerosolized methacholine (0-50 mg/ml) as compared with sedentary mice. Exercise also had no effect on epithelial cell hypertrophy, mucus production, or airway wall thickening in OVA-treated mice as compared with sedentary controls. These findings suggest that a single bout of aerobic exercise at a moderate intensity attenuates airway inflammation but not AHR or airway remodeling in OVA-treated mice. The implication of these findings for the interrelationship between airway inflammation, airway remodeling, and AHR is discussed.     

Inhibition of murine allergic airway disease by Bordetella pertussis

Whole-cell pertussis vaccines have been shown to selectively induce T helper 1 (Th1)-type responses in human and animals. In this study, we investigated whether whole-cell B. pertussis could inhibit allergic airway reactions in a murine model of asthma induced by ovalbumin (OVA). Systemic administration of whole-cell B. pertussis strongly inhibited allergic airway reactions such as eosinophil recruitment into the airway, lung inflammation, and airway hyperresponsiveness to methacholine. The inhibitory effect of whole-cell B. pertussis was mediated by chromosomal DNA and pretreatment of DNA with CpG methylase or DNase I resulted in a loss of the inhibitory effect. Treatment of animals with B. pertussis DNA significantly decreased the Th2 cytokine (interleukins IL-4 and IL-5) concentrations in the airways without increasing Th1 cytokines. These results suggest that B. pertussis DNA containing unmethylated CpG appears to be responsible for the inhibitory effect of whole cell B. pertussis on the allergic airway reactions through inhibition of the Th2 response.     

The effect of allergen-induced airway inflammation on airway remodeling in a murine model of allergic asthma

OBJECTIVE AND DESIGN: We examined the effect of airway inflammation on airway remodeling and bronchial responsiveness in a mouse model of allergic asthma. MATERIALS AND METHODS: BALB/c mice were sensitized to ovalbumin (OA), and exposed to aerosolized OA (0.01, 0.1 and 1%). Twenty-four hours after the final antigen challenge, bronchial responsiveness was measured, and bronchoalveolar lavage (BAL) and histological examinations were carried out. RESULTS: Repeated antigen exposure induced airway inflammation, IgE/IgG1 responses, epithelial changes, collagen deposition in the lungs, subepithelial fibrosis associated with increases in the amount of transforming growth factor (TGF)-beta1 in BAL fluid (BALF), and bronchial hyperresponsiveness to acetylcholine. The number of eosinophils in BALF was significantly correlated with TGF-beta1 production in BALF and the amount of hydroxyproline. Furthermore, significant correlations were found between these fibrogenic parameters and the bronchial responsiveness. CONCLUSION: These findings demonstrated that in this murine model airway eosinophilic inflammation is responsible for the development of airway remodeling as well as bronchial hyperresponsiveness in allergic bronchial asthma.     

Characteristic features of allergic airway inflammation in a murine model of infantile asthma

BACKGROUND: The pathophysiology of infantile asthma may differ from that in older children or in adults, partly because of the different immune response depending upon maturation. In adult mice, the sensitizing dose of antigen is known to be critical to the polarized development of helper T cell subsets and allergic airway inflammation. We wanted to know the characteristics of allergic airway inflammation of infantile asthma by developing a murine model. METHODS: BALB/C mice at different stages of maturation (juvenile: 3 days after birth; adult: 8 weeks of age) were sensitized with 10 or 1,000 microg ovalbumin (OVA) or vehicle. The animals were then challenged with aerosolized OVA or saline once a day during 6 consecutive days. After the final challenge, bronchial hyperresponsiveness (BHR), bronchoalveolar lavage fluid (BALF), histological changes in the airways and immunological status were examined. RESULTS: In both juvenile and adult animals, sensitization with 10 microg OVA induced the T helper 2 response (elevated IL-4 and decreased IFN-gamma levels). BHR, airway eosinophilia, the inflammatory cell infiltration, goblet cell metaplasia (GCM), and IgE antibody production were more prominent in animals given this dose than 1,000 microg OVA. Among these responses, GCM as well as BALF IL-4, and BHR were comparable between juvenile and adult animals, whereas other parameters were lower in juvenile animals, especially in those given 1,000 microg OVA. CONCLUSION: GCM and, consequently, airway mucus hypersecretion may be an important component of allergic airway inflammation in infantile asthma.