Type 2 Cytokines in the Pathogenesis of Sustained Airway Dysfunction and Airway Remodeling in Mice (original) (raw)
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Clinical & Experimental Allergy, 2007
T-helper type 2 (Th2)-derived cytokines such as IL-4, IL-5, IL-9 and IL-13 play an important role in the synthesis of IgE and in the promotion of allergic eosinophilic inflammation and airway wall remodelling. We determined the importance of IL-13 alone, and of the four Th2 cytokines together, by studying mice in which either IL-13 alone or the Th2 cytokine cluster was genetically disrupted. The knock-out mice and their BALB/c wild-type (wt) counterparts were sensitized and repeatedly exposed to ovalbumin (OVA) aerosol. Bronchial responsiveness measured as the concentration of acetylcholine aerosol needed to increase baseline lung resistance by 100% (PC100) was decreased in IL-13-/-, but increased in IL-4/5/9/13-/- mice. Chronic allergen exposure resulted in airway hyperresponsiveness (AHR) in wt mice but not in both genetically modified mice. After allergen exposure, eosinophil counts in bronchoalveolar lavage fluid and in airways mucosa, and goblet cell numbers were not increased in IL-4/5/9/13-/- mice, and were only attenuated in IL-13-/- mice. Airway smooth muscle (ASM) hyperplasia after allergen exposure was prevented in both IL-13-/- and IL-4/5/9/13-/- mice to an equal extent. Similarly, the rise in total or OVA-specific serum IgE levels was totally inhibited. IL-13 is mainly responsible for AHR, ASM hyperplasia and increases in IgE, while IL-4, -5 and -9 may contribute to goblet cell hyperplasia and eosinophilic inflammation induced by chronic allergen exposure in a murine model. Both redundancy or complementariness of Th2 cytokines can occur in vivo, according to specific aspects of the allergic response.
American Journal of Respiratory Cell and Molecular Biology, 2002
The mechanisms underlying airway hyperresponsiveness recurves), hyperreactivity (increased slope of these curves), main unclear, although airway inflammation and remodeling and a greater maximum degree of induced bronchoconstricare likely important contributing factors. We hypothesized that tion. However, the pathophysiologic mechanisms underlyairway physiology would differ between mice subjected to brief ing these abnormalities remain unclear. T helper type 2 or chronic allergen exposure, and that these differences would (Th2) inflammation of the airways is believed to be central be associated with characteristic inflammatory markers and inin the pathogenesis of asthma (4-6), although the exact dices of airway remodeling. BALB/c mice were sensitized to contribution of airway inflammation to airway dysfunction ovalbumin and studied at several time points following brief remains ill-defined (7). While some studies have shown that or chronic allergen challenge protocols. By measuring airway the extent of airway eosinophilia in asthmatic subjects was responses to methacholine, we demonstrated increases in maximal inducible bronchoconstriction that persisted for 8 wk fol-related to the degree of their AHR (4, 8), the observation lowing either brief or chronic allergen challenge; we also obthat profound AHR is sustained in asthma, despite prolonged served increases in airway reactivity, although it was only in treatment with anti-inflammatory corticosteroids (9-12), sugchronically challenged mice that these changes persisted begests that other mechanisms likely account for a major yond the resolution of allergen-induced inflammation. Using component of AHR. airway morphometry, we further demonstrated that increases Evidence suggests that chronic structural changes in the in maximal bronchoconstriction were associated with increases airway, often termed airway remodeling, may be at least in in airway contractile tissue in both models, and that chronic, part responsible for sustained AHR (12-16). These changes but not brief, allergen challenge resulted in subepithelial fibroinclude thickening of the airway wall, subepithelial fibrosis, sis. Our observations that different aspects of sustained airway hyperplasia and hypertrophy of smooth muscle cells, and dysfunction and remodeling persist beyond the resolution of acute inflammatory events support the concept that remodel-hyperplasia of myofibroblasts and goblet cells (17-22). ing occurs as a consequence of allergic airway inflammation, Mathematical modeling studies postulating that both inand that these structural changes contribute independently to creased muscle mass and, to a lesser extent, airway wall the persistence of airway hyperresponsiveness.
T-cell-mediated inflammation does not contribute to the maintenance of airway dysfunction in mice
Journal of Applied Physiology, 2004
T cell mediated airway inflammation is considered to be critical in the pathogenesis of airway hyperresponsiveness. We have described a mouse model in which chronic allergen exposure results in sustained airway hyperresposiveness (AHR) and aspects of airway remodeling, and here sought to determine whether eliminating CD4 + and CD8 + cells, at a time when airway remodeling had occurred, would attenuate this sustained AHR. Sensitized BALB/c mice were subjected to either brief or chronic periods of allergen exposure, and studied 24 hours after brief or 4 weeks after chronic allergen exposure. In both models, mice received three treatments with anti-CD4 and CD8 monoclonal antibodies during the 10 days prior to outcome measurements. Outcomes included in vivo airway responsiveness to intravenous methacholine, CD4 + and CD8 + cell counts of lung and spleen using flow cytometric analysis, and airway morphometry using a computer-based image analysis system. Compared to saline control mice, brief allergen challenge resulted in AHR, which was eliminated by antibody treatment. Chronic allergen challenge resulted in sustained AHR and indices of airway remodeling. This sustained AHR was not reversed by antibody treatment, even though CD4 + and CD8 + cells were absent in lung and spleen. These results indicate that T cell mediated inflammation is critical for development of airway hyperresponsiveness associated with brief allergen exposure, but is not necessary to maintain sustained AHR.
Is Interleukin-13 Critical in Maintaining Airway Hyperresposiveness in Allergen-challenged Mice?
American Journal of Respiratory and Critical Care Medicine, 2004
Interleukin (IL)-13 is regarded as being a central effector in the pathophysiology of airway hyperresponsiveness. We have described a mouse model in which chronic allergen exposure results in sustained airway hyperresponsiveness and aspects of airway remodeling, and here sought to demonstrate that this component of airway hyperresponsiveness is independent of biologically active IL-13. Sensitized mice were subjected to either brief or chronic periods of allergen exposure and studied 24 hours after brief or 4 weeks after chronic allergen inhalation. A soluble murine anti-IL-13 receptor fusion protein that specifically binds to and neutralizes IL-13 was given daily during the 4 days before the day of outcome measurements in both protocols. Outcome measurements included airway responses to intravenous methacholine, bronchoalveolar lavage fluid cell counts, and airway morphometry. Compared with the saline control, brief allergen challenge resulted in airway hyperresponsiveness, which was prevented by anti-IL-13 treatment. Chronic allergen challenge resulted in sustained airway hyperresponsiveness and indices of airway remodeling; IL-13 blockade failed to reverse this sustained airway hyperresponsiveness. These results confirm that IL-13 is critical for the development of airway hyperresponsiveness associated with brief allergen exposure, but is not necessary to maintain the sustained airway hyperresponsiveness associated with airway remodeling.
Allergen-induced airway disease is mouse strain dependent
American journal of physiology. Lung cellular and molecular physiology, 2003
We investigated the development of airway hyperreactivity (AHR) and inflammation in the lungs of nine genetically diverse inbred strains of mice [129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ] after sensitization and challenge with ovalbumin (OVA). At 24, 48, and 72 h post-OVA exposure, the severity of AHR and eosinophilic inflammation of the mouse strains ranged from relatively unresponsive to responsive. The severity of the airway eosinophilia of some strains did not clearly correlate with the development of AHR. The temporal presence of T helper type 2 cytokines in lung lavage fluid also varied markedly among the strains. The levels of IL-4 and IL-13 were generally increased in the strains with the highest airway eosinophilia at 24 and 72 h postexposure, respectively; the levels of IL-5 were significantly increased in most of the strains with airway inflammation over the 72-h time period. The differences of physiological and biological res...
Journal of Allergy and Clinical Immunology, 2007
Background: Pathologic changes, including inflammation and remodeling, occur in the asthmatic airway. However, their relative contribution to the components of airway hyperresponsiveness (AHR) remains unclear. Objective: Attempting to delineate AHR into discrete immunemediated and structural remodeling components, we performed a detailed time course of the development, progression, and persistence of maximal respiratory system resistance, airway reactivity, and airway sensitivity. Methods: Mice exposed to increasing durations of persistent allergen were assessed for airway function, morphometry, and inflammation. Results: Allergen exposure resulted in increases for all indices of AHR that persisted for at least 4 weeks after chronic allergen exposure (P < .01 for all values). Early increases in AHR were associated with increases in immune-mediated events, including airway eosinophils (P < .01), whereas sustained AHR was associated with structural remodeling events. Increased maximal respiratory system resistance, evident by 6 weeks postallergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, was associated with an increase in collagen deposition (P < .01). Increased airway reactivity and sensitivity, each evident by 1 week after allergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, were associated with an increase in airway smooth muscle area (P < .01). Conclusion: Our novel observation of distinct temporal relationships in the development, progression, and persistence of the individual indices of AHR supports our hypothesis that multiple underlying factors contribute to airway dysfunction. Clinical implications: These findings illustrate the importance of clearly addressing specific components of airway dysfunction to provide greater insight into specific pathophysiologic mechanisms in airway disease. (J Allergy Clin Immunol 2007;119:848-54.)
Impaired mucus clearance exacerbates allergen-induced type 2 airway inflammation in juvenile mice
The Journal of allergy and clinical immunology, 2016
Type 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. Recently, we demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile β-epithelial Na(+) channel (Scnn1b)-transgenic (Tg) mice. We sought to determine the role of impaired mucus clearance in the pathogenesis of allergen-induced type 2 airway inflammation and identify cellular sources of the signature cytokine IL-13. We challenged juvenile Scnn1b-Tg and wild-type mice with Aspergillus fumigatus and house dust mite allergen and compared the effects on airway eosinophilia, type 2 cytokine levels, goblet cell metaplasia, and airway hyperresponsiveness. Furthermore, we determined cellular sources of IL-13 and effects of genetic deletion of the key type 2 signal-transducing molecule signal transducer and activator of transcription 6 (STAT6) and evaluate...
Journal of Korean medical science, 2007
During the course of establishing an animal model of chronic asthma, we tried to elucidate the time sequence of airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and associated cytokines. Seven-week-old female BALB/c mice were studied as a chronic asthma model using ovalbumin (OVA). After sensitization, mice were exposed twice weekly to aerosolized OVA, and were divided into three groups depending on the duration of 4 weeks, 8 weeks, and 12 weeks. At each time point, airway responsiveness, inflammatory cells, cytokines in bronchoalveolar lavage fluids (BALF), serum OVA-specific IgE, IgG1, IgG2a, and histological examination were carried out. AHR to methacholine, increased levels of OVA-specific IgG1 and IgG2a, and goblet cell hyperplasia were continuously sustained at each time point of weeks. In contrast, we observed a time-dependent decrease in serum OVA-specific IgE, BALF eosinophils, BALF cytokines such as IL-13, transforming growth factor-beta1, and a ti...
Differential Effects of Allergen Challenge on Large and Small Airway Reactivity in Mice
PLoS ONE, 2013
The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways disease to induce inflammation and remodelling and determine whether in vivo hyperresponsiveness to methacholine is consistent with in vitro reactivity of trachea and small airways. Balb/C mice were sensitised (days 0, 14) and challenged (3 times/week, 6 weeks) with ovalbumin. Airway reactivity was compared with saline-challenged controls in vivo assessing whole lung resistance, and in vitro measuring the force of tracheal contraction and the magnitude/rate of small airway narrowing within lung slices. Increased airway inflammation, epithelial remodelling and fibrosis were evident following allergen challenge. In vivo hyperresponsiveness to methacholine was maintained in isolated trachea. In contrast, methacholine induced slower narrowing, with reduced potency in small airways compared to controls. In vitro incubation with IL-1/TNFa did not alter reactivity. The hyporesponsiveness to methacholine in small airways within lung slices following chronic ovalbumin challenge was unexpected, given hyperresponsiveness to the same agonist both in vivo and in vitro in tracheal preparations. This finding may reflect the altered interactions of small airways with surrounding parenchymal tissue after allergen challenge to oppose airway narrowing and closure.
Allergen-induced Th2-independent production of IL-4 in the airways of mice
Matters (Zürich), 2016
It is thought that release of cytokines from allergen-damaged epithelial cells induces production of an innate source of IL-4 and IL-13 that are important in initiating adaptive T-helper type II (Th2)-mediated allergic responses. However, detecting innate production of IL-4 or IL-13 in vivo is difficult due to high levels of adaptive production of IL-4 and IL-13 by Th2 cells. The IL-4 receptor (IL-4R) and the IL-4/13 co-receptor (IL-13R) share a common receptor subunit (IL-4Ra). Consequently, both IL-4 and IL-13 signal via the IL-4Ra-associated signaling molecule, signal transducer and activator of transcription factor 6 (STAT6). STAT6 signaling in T-cells, B-cells, and airway epithelial cells is essential for Th2 differentiation, isotype class switching to IgE, and mucus production, respectively. Therefore, Epi-STAT6 mice (STAT6-/-mice with airway epithelial-specific transgenic STAT6 expression) are defective in Th2 immune responses but can produce mucus in response to IL-4 and/or IL-13 in their airways. As compared to wildtype mice, allergen-challenged Epi-STAT6 mice were deficient in IgE production and the levels of IL-13 expressed were not above appropriate controls. However, significant levels of IL-4 and mucin gene expression were detected in their lungs. These observations support the existence of an allergen-responsive, non-Th2-derived source of IL-4 in the airways of mice.