Allergic airway inflammation

Several genes, including ADAM33, DPP10, PHF11, GPRA, and TIM-1, have been implicated in the pathogenesis and susceptibility to atopy and asthma. Advances have been made in defining the mechanism for the control of allergic airway inflammation in response to inhaled antigens. There is growing evidence that associates asthma with a systemic propensity for allergic type 2 T-cell cytokines. Disordered coagulation and fibrinolysis could also exacerbate asthma symptoms. Major emphasis on immunotherapy for asthma during the past decade has been to direct the immune response to a type 1 response. Recent literature supports the pivotal role of plasmacytoid dendritic cells and allergen-specific T-regulatory cells in the development of tolerance to allergens. In this review article, we discuss the current information on the pathogenesis of allergic airway inflammation and potential allergen immunotherapies, which could be beneficial in the treatment of airway inflammation, allergy, and asthma.     

Effect of interferon-gamma on allergic airway responses in interferon-gamma-deficient mice

Interferon (IFN)-gamma reduces airway responses after allergen challenge in mice. The mechanisms of this effect are not clear. These studies investigate whether IFN-gamma can reverse prolonged airway responses after allergen challenge in IFN-gamma-deficient (IFN-gammaKO) mice. Sensitized mice (IFN-gammaKO and wild-type [WT]) were challenged with ovalbumin. Airway responsiveness, eosinophils in bronchoalveolar lavage fluid, and lung lymphocyte subsets (CD4(+) and CD8(+)) were measured 24 hours and 8 weeks after challenge. In further experiments, we treated IFN-gammaKO mice with recombinant IFN-gamma starting 4 weeks after the challenge for 1 week or 4 weeks. Airway responsiveness, bronchoalveolar lavage eosinophils, and lung CD4(+) cells were increased 8 weeks after challenge in IFN-gammaKO but not WT mice. IFN-gamma treatment returned lung CD4(+) cell numbers to values obtained in unchallenged mice. One week of IFN-gamma treatment also returned airway responsiveness to baseline levels; however, 4-week treatment with IFN-gamma failed to decrease airway responsiveness below levels observed in untreated animals. This suggests that IFN-gamma plays an essential role in reversing allergen-induced airway inflammation and hyperresponsiveness and that it may have dual actions on the latter. Observations that IFN-gamma reverses airway responses, even when administered after challenge, suggests that IFN-gamma treatment could control allergic disease, including asthma.     

Influence of lipopolysaccharide exposure on airway function and allergic responses in developing mice

Exposure to endotoxin has been associated with an exacerbation of asthmatic responses in humans and animal models. However, recent evidence suggests that microbial exposure in early life may protect from the development of asthma and atopy. In this study, we sought to evaluate the effects of lipopolysaccaride (LPS) on airway function in developing mice. In addition, we evaluated the influence of LPS on subsequent allergen sensitization and challenge. Under light anesthesia, 2-3-week-old Balb/c mice received a single intranasal instillation of LPS or sterile physiologic saline. Measurements of airway function were obtained in unrestrained animals, using whole-body plethysmography. Airway responsiveness was expressed in terms of % enhanced pause (Penh) increase from baseline to aerosolized methacholine (Mch). In additional studies, we assessed the functional and cellular responses to ovalbumin sensitization and challenge following prior exposure to LPS.We found that exposure to LPS induced transient airway hyperresponsiveness to Mch. These functional changes were associated with the recruitment of neutrophils and lymphocytes into the bronchoalveolar lavage (BAL) fluid. Airway responsiveness after allergen sensitization and challenge was decreased by prior exposure to LPS. The analysis of BAL cells and cytokines (interferon-gamma and interleukin-4) did not reveal alterations in the overall Th1/Th2 balance.Our findings suggest that LPS leads to airway hyperresponsiveness in developing mice, and may protect against the development of allergen-driven airway dysfunction.     

Novel recombinant interleukin-13 peptide-based vaccine reduces airway allergic inflammatory responses in mice

RATIONALE: Interleukin (IL)-13 plays a pivotal role in the pathogenesis of allergic asthma. Passive administration of its monoclonal antibody or soluble receptor to block overproduced IL-13 has been proven to be effective in controlling airway allergic responses in animal models, but these approaches have disadvantages of short half-lives, high costs, and possible adverse effects. OBJECTIVES: We sought to develop a novel therapeutic strategy through constructing an IL-13 peptide-based vaccine for blocking IL-13 on a persistent effect basis and to evaluate its in vivo effects using a murine model. METHODS: To break self-tolerance, truncated hepatitis B core antigen was used as a carrier. Vaccine was prepared by inserting a peptide derived from the receptor binding site of mouse IL-13 into the immunodominant epitope region of the carrier using gene recombination methods. Mice received vaccine subcutaneously three times, and then subjected to intraperitoneal sensitization and intranasal challenge with ovalbumin. Control animals received carrier or saline in place of vaccine. MEASUREMENTS AND MAIN RESULTS: The vaccine presented as virus-like particles and induced sustained and high titered IL-13-specific IgG without the use of conventional adjuvant. Vaccination significantly suppressed ovalbumin-induced inflammatory cell number, and IL-13 and IL-5 levels in bronchoalveolar lavage fluids. Serum total and ovalbumin-specific IgE were also significantly inhibited. Moreover, allergen-induced goblet cell hyperplasia, lung tissue inflammatory cell infiltration, and pulmonary hyperresponsiveness to inhaled methacholine were significantly suppressed in vaccinated mice. CONCLUSIONS: Our data indicate that IL-13 peptide-based vaccines could be an effective therapeutic approach in the treatment of asthma.     

Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

Recent research links diet-induced obesity (DIO) with impaired immunity, although the underlying mechanisms remain unclear. We find that the induction of inducible NO synthase (iNOS) and cytokines is suppressed in mice with DIO and in bone marrow macrophages (BMMΦ) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMMΦ from lean mice pre-treated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMMΦ from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMMΦ from mice with DIO. This reduction is responsible for diminished NF-κB activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMMΦ from DIO mice whereas carboxy-terminal modulator protein (CTMP), a known suppressor of Akt phosphorylation, is elevated. This elevation stems from defective TLR2 signaling. In BMMΦ from lean mice, both FFAs and TNF-α—via separate pathways—induce an increase in CMTP. However, in BMMΦ from DIO mice, TLR2 can no longer inhibit the TNF-α-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMMΦ from DIO mice. Thus, feeding mice a high-fat diet over time elevates the CTMP intracellular pool, initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-α-induced CTMP. These findings unveil a link between obesity and innate immunity.     

Allergic bronchial asthma: airway inflammation and hyperresponsiveness

The international consensus report on diagnosis and treatment of asthma was published in 1992 (Clin Exp Allergy 22: 1-72). According to the report, asthma is a chronic inflammatory disorder of the airways in which many cells play a role, including mast cells and eosinophils. Airway inflammation causes various symptoms of asthma which are usually associated with widespread but variable airflow obstruction and causes an associated increase in airway responsiveness to a variety of stimuli. The definition of asthma, provided in this report, is an epoch-making revision of the conventional recognition of asthma based on respiratory physiology and does not contradict the empirical knowledge that asthma responds well to steroid therapy. One reason, which led airway inflammation to be understood as a major factor in the pathophysiology of asthma is the technological advance and the widespread use of bronchoscopes. The use of bronchoscopy as a research tool has markedly improved the understanding of the pathology of asthma. It became also possible to link biopsy findings to autopsy findings in patients who died of asthma. However, it is relatively difficult to repeat a biopsy of the airway mucosal membranes in individual asthmatic patients. Here, animal models of asthma play a significant role. Findings from animal models can provide a clue for the development of new anti-asthmatic drugs. This paper will deal with the paradigm of allergic asthma and focus on recent topics of interleukin (IL)-4 and IL-5, which seem to play a central role in allergic asthma. The causative relationship between airway inflammation and hyperresponsiveness will be discussed.     

过敏性哮喘与骨髓反应

过敏性哮喘是以嗜酸细胞在气道浸润为主的慢性炎症 ,激活的嗜酸细胞可分泌多种前炎性蛋白和脂质介质 ,在白三烯 (ＬＴＢ4 )和血小板激活因子 (ＰＡＦ)刺激下 ,它还可释放基质蛋白酶、嗜酸细胞阳离子蛋白、嗜酸细胞神经毒素等引起气道上皮破坏、平滑肌痉挛 ,粘液分泌增多[1 ] ,形成慢性气道炎症和气道高反应性 ,介导迟发性哮喘反应 (ＬＡＲ) [2 ] ;在哮喘患者外周血和气道中嗜酸细胞及其祖细胞明显增多 ,最近发现 ,由于抗原刺激气道后引起炎性介质释放或气道中炎细胞趋化至骨髓 ,引起骨髓中炎细胞的祖细胞 (主要是嗜酸 /嗜碱细胞祖细胞 )扩增…     

Allergic airway hyperresponsiveness and eosinophil infiltration is reduced by a selective iNOS inhibitor, 1400W, in mice

Nitric oxide (NO) hyperproduction has been reported in asthmatic airways and may contribute to airway inflammatory responses. The purpose of this study was to examine the role of NO via inducible NO synthase (iNOS) in allergic airway inflammation using a selective iNOS inhibitor, N-[3-(aminomethyl)benzyl] acetamidine (1400W), in ovalbumin (OVA)-sensitized Balb/c mice. Sensitized animals were challenged with aerosolized 0.5% OVA for 1 h on two occasions 4 h apart. 1400W or the vehicle was administered by osmotic mini-pump from 2 h before to 24 h after OVA challenge. Twenty-four hours after OVA challenge, the vehicle-treated mice showed a significant airway hyperresponsiveness to intravenous methacholine (P<0.05) as well as an influx of eosinophils into the airways (P<0.05). iNOS immunoreactivity was obvious in the epithelial and, to a lesser extent, the infiltrated inflammatory cells. iNOS protein in the airway assessed by Western blotting also increased. Pretreatment with 1400W almost completely abolished the OVA-induced airway hyperresponsiveness and to a lesser extent eosinophil accumulation into the airways. These results suggest that NO synthesized by iNOS may participate in airway hyperresponsiveness and eosinophil infiltration into the airways after allergic reaction.     

Allergic responses to biting and stinging insects

Biting and stinging insects are classified under the major division of arthropods. The arthropods consist of eighty-five per cent of the animal kingdom. Since we share so much of this earth's surface with these small creatures, it is evident that they must often affect our lives. Man may be helped by some activities or hindered by others. On the positive side, arthropods help in the pollination of plants, destroying the dead animals and plants, and help to return the organic materials to the soil. The value of bee products such as honey and wax is estimated to be as high as fifty million dollars each year in the United States. On the negative side, arthropods can cause disease and varied allergic reactions. This article will deal chiefly with the allergic responses. Most of the allergic reactions are minor annoyances, but some are serious and can result in death.     

Chitin induces steroid-resistant airway inflammation and airway hyperresponsiveness in mice

BackgroundPrevious reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1β in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models.MethodsWe developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX.ResultsThe numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1β levels in BAL fluids and the numbers of IL-1β-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1β was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1β production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin.ConclusionsThese results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1β. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.     

Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D

Muscarinic cholinergic signaling plays an essential role in the control of the normal airway functions and in the development of pulmonary pathologies including asthma. In this paper we demonstrate that the airways of mice deficient in a cAMP-specific phosphodiesterase (PDE4D) are no longer responsive to cholinergic stimulation. Airway hyperreactivity that follows exposure to antigen was also abolished in PDE4D(-/-) mice, despite an apparently normal lung inflammatory infiltration. The loss of cholinergic responsiveness was specific to the airway, not observed in the heart, and was associated with a loss of signaling through muscarinic receptors with an inability to decrease cAMP accumulation. These findings demonstrate that the PDE4D gene plays an essential role in cAMP homeostasis and cholinergic stimulation of the airway, and in the development of hyperreactivity. In view of the therapeutic potentials of PDE4 inhibitors, our findings provide the rationale for novel strategies that target a single PDE isoenzyme.     

An exploration of obese observational learning in modifying selected eating responses of obese children

The present study investigated the effects of two observational learning paradigms in modifying the eating behavior of obese children. A total of 18 subjects ranging in age from seven to 12 years and in weight from 74 to 160 lb (33 to 72 kg) were randomly assigned to three conditions. Intervention consisted of four sessions in which subjects viewed videotapes of their baseline eating behaviors compared with a model eating at a reduced speed. Based on the assumption that children may acquire their parents' eating behaviors, one condition included videotapes of a same-sex adult model. In order to maximize model-observer similarity, subjects in a second treatment condition observed videotapes of themselves eating at a reduced speed. Subjects in the control condition viewed only their baseline eating behavior videotapes. Dependent measures of eating behavior were found to be significantly affected by both model treatments, while no significant differences were evidenced in the control group.     

Biomarkers of airway and systemic inflammation in obese asthmatic paediatric patients

BackgroundIt is thought that airway inflammation is more common in obese asthmatic patients because inflammation is harder to control and does not respond well to glucocorticoid treatment.ObjectiveThis study's aim was to investigate the effect of obesity on airway and systemic inflammation in children with asthma and to identify the biomarkers that play a role in this inflammation.MethodsThe study included patients aged 6–16 years who were diagnosed with asthma in the paediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. Complete blood count parameters were compared between three groups: obese asthmatic (n = 43), obese non-asthmatic (n = 45), and non-obese non-asthmatic (control group, n = 30). Levels of high-sensitive CRP (hs-CRP), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and matrix metalloproteinase-9 (MMP-9), and 25(OH)-vitamin D were compared between the groups.ResultsNo statistically significant differences were observed in 25(OH)-vitamin D, NGAL, OPN, hs-CRP, and MMP-9 levels between groups. There was a statistically significant negative correlation between FEV1/FVC and NGAL and MMP-9.ConclusionThis is the first study to investigate levels of hs-CRP, NGAL, OPN, MMP-9, and 25(OH)-vitamin D in obese asthmatic children. Larger studies with sputum and BAL examinations are required to determine the potential of biomarkers for identifying inflammation in obese asthmatic children.     

Effects of montelukast and budesonide on airway responses and airway inflammation in asthma

Inhaled corticosteroids are effective antiinflammatory therapy for asthma; however, they do not completely abolish allergen-induced airway inflammation. Leukotriene modifiers attenuate both early and late allergen responses and have antiinflammatory properties. We reasoned that treatment with budesonide and montelukast in combination might provide greater antiinflammatory effects than either drug alone, and the purpose of this study was to compare the effects of treatment with budesonide and montelukast, alone or in combination, on outcome variables after allergen inhalation. Ten subjects with asthma with dual responses after allergen inhalation were included in this randomized, double-blind, crossover study. Outcomes included early and late asthmatic responses, and changes in airway responsiveness and sputum eosinophilia, measured before and after challenge. Treatment with montelukast attenuated the maximal early asthmatic response compared with placebo (p < 0.001) and budesonide (p = 0.002). Both budesonide and montelukast, alone and in combination, attenuated the maximal late asthmatic response compared with placebo (p < 0.01). Budesonide and montelukast, alone and in combination, afforded protection against allergen-induced airway hyperresponsiveness (p < 0.05), although the treatment effect of budesonide was greater than that of montelukast (p < 0.05). Treatment with budesonide and montelukast, alone and in combination, also attenuated allergen-induced sputum eosinophilia. Thus, montelukast and budesonide attenuated allergen-induced asthmatic responses, airway hyperresponsiveness, and sputum eosinophilia, although combination treatment did not provide greater antiinflammatory effects than either drug alone.