New perspectives on the mechanical basis for airway hyperreactivity and airway hypersensitivity in asthma.

We revisit the airway wall model of Lambert et. al. (Lambert RK, Wiggs BR, Kuwano K, Hogg JC, and Pare PD. J Appl Physiol 74: 2771-2781, 1993). We examine in detail the notion of a general airway bistability such that the airway lumen can suddenly decrease from a relatively open to a relatively closed condition without needing additional increase in active airway smooth muscle (ASM) tension during the stimulation. The onset of this bistability is an emergent consequence of the balance of forces associated with airway wall properties, parenchymal tissue properties, maximum lung elastic recoil, and the maximum stress that the ASM can generate. In healthy lungs, we find that all these properties reside in conditions that largely prevent the emergence of the bistability even during maximum ASM stimulation. In asthmatic airways, however, the airway wall and ASM remodeling conditions can tip the balance so as to promote the onset of the bistability at a lower dose of ASM stimulation (enhanced sensitivity) and then work to amplify the maximum constriction reached by each airway (enhanced reactivity). Hence, a larger fraction of asthmatic airways can display overall airway hyperreactivity. Simulations studies examine the role of increasing ASM maximum tension, airway wall stiffening, reduced lung volume, and decreased parenchymal tethering. Results predict that the single most important factor causing this airway hyperreactivity is amplified maximum ASM tension and not a thickening of the airway wall per se.     

Anticytokine therapy of allergic asthma

Bronchial asthma is a chronic inflammatory disease of the airways that is characterized by episodes of shortness of breath, expiratory dyspnea, cough, wheezing, and pulmonary emphysema. At the present time, asthma is a global public health problem and affects about 5% of the worldwide population. Although a wide range of anti-inflammatory drugs is available, uncontrolled or poorly controlled asthma is still a problem, requiring the development of novel therapeutic approaches. Intense studies of the molecular mechanisms of asthma in transgenic animals performed since the 1990s implicated cytokines, such as IL-4, IL-5, and IL-13, and their receptors in the initiation and maintenance of asthma. These findings led to anticytokine therapy as a novel approach for bronchial asthma treatment. To date, many preclinical and clinical studies have been performed in this field especially with drugs based on humanized monoclonal antibodies, soluble receptors, peptide inhibitors, etc. The review summarizes the data from preclinical and clinical studies of anti-cytokine therapeutics in humans.     

肠道菌群与过敏性哮喘

近年来随着过敏性哮喘发病率的持续升高,人们开始注意到环境、生活方式的改变可能会影响过敏性哮喘的发生。流行病学调查显示,过敏性哮喘的发生和发展与生命早期肠道菌群的紊乱密切相关。本研究主要综述近年来肠道菌群对过敏性哮喘发生的影响及机制,探讨影响肠道菌群定植的主要因素,以及微生态调节剂在过敏性哮喘等变应性疾病中的预防和治疗作用。     

Glycopeptide in sputum from allergic asthma patients

The glycopeptide and glycosaminoglycan content of sputa from allergic asthma, bronchiectasis, and common cold patients was assayed. The glycopeptide content was higher in sputum from allergic asthma patients than that in bronchiectasis and common cold patients, while no significant difference in the glycosaminoglycan content was detected among these materials. Fractionation of the glycopeptide by DEAE-cellulose column chromatography yielded four glycopeptide fractions at concentrations of 0.05 to 0.3 M NaCl from the allergic asthma samples, whereas it yielded three fractions at concentrations of 0.05 to 0.2 M NaCl from the bronchiectasis and common cold samples. They were characterized by increases in sialic acid and sulfate as the molarity of NaCl increased. Hexose was the main component and hexosamine was the next in each fraction from all materials. The increase in sputum glycopeptide in the allergic asthma samples was due to a large increase in sialic acid- and sulfate-rich glycopeptide.     

Food allergy enhances allergic asthma in mice

Background

Atopic march refers to the typical transition from a food allergy in early childhood to allergic asthma in older children and adults. However the precise interplay of events involving gut, skin and pulmonary inflammation in this process is not completely understood.

Objectives

To develop a mouse model of mixed food and respiratory allergy mimicking the atopic march and better understand the impact of food allergies on asthma.

Methods

Food allergy to ovalbumin (OVA) was induced through intra-peritoneal sensitization and intra-gastric challenge, and/or a respiratory allergy to house dust mite (HDM) was obtained through percutaneous sensitization and intra-nasal challenges with dermatophagoides farinae (Der f) extract. Digestive, respiratory and systemic parameters were analyzed.

Results

OVA-mediated gut allergy was associated with an increase in jejunum permeability, and a worsening of Der f-induced asthma with stronger airway hyperresponsiveness and pulmonary cell infiltration, notably eosinophils. There was overproduction of the pro-eosinophil chemokine RANTES in broncho-alveolar lavages associated with an enhanced Th2 cytokine secretion and increased total and Der f-specific IgE when the two allergies were present. Both AHR and lung inflammation increased after a second pulmonary challenge.

Conclusion

Gut sensitization to OVA amplifies Der f-induced asthma in mice.     

Involvement of CCL18 in allergic asthma

Allergic asthma is associated with a pulmonary recruitment of Th type 2 cells, basophils, and eosinophils, mainly linked to chemokine production. CCL18 is a chemokine preferentially expressed in the lung, secreted by APCs, induced by Th2-type cytokines, and only present in humans. Therefore, CCL18 may be involved in allergic asthma. PBMC from asthmatics allergic to house dust mite cultured in the presence of Dermatophagoides pteronyssinus 1 (Der p 1) allergen secreted CCL18, 48 and 72 h after stimulation, whereas those from healthy donors did not. Part of CCL18 was directly derived from Der p 1-stimulated plasmacytoid dendritic cells, whereas the other part was linked to monocyte activation by IL-4 and IL-13 produced by Der p 1-stimulated T cells. In bronchoalveolar lavages from untreated asthmatic allergic patients, CCL18 was highly increased compared with controls. Functionally, CCL18 preferentially attracted in vitro-polarized Th2 cells and basophils, but not eosinophils and Th1 cells, and induced basophil histamine and intracellular calcium release. These data show a new function for CCL18, i.e., the recruitment of Th2 cells and basophils, and suggest that CCL18 may play a predominant role in allergic asthma.     

Cyclooxygenase enzymes in allergic inflammation and asthma

The cyclooxygenase enzyme system produces eicosanoids which mediate many important physiological and pathological functions. Experimental and clinical data suggest a role for this enzyme system in the pathogenesis of allergic inflammation and asthma. This article focuses on the function of this pathway in the lung, reviews evidence implicating the involvement of this pathway in asthma and allergic airway inflammation, and discusses implications for the treatment of asthmatics with cyclooxygenase inhibitors.     

Regulatory T cells and allergic asthma

Because of the characteristic airway inflammation observed in allergic asthma, the pathogenesis of this disease may be due, in part, to a lack of anti-inflammatory and immune suppressive mechanisms. Here, we discuss the possible involvement and therapeutic use of T regulatory cells and their soluble factors in this multifactorial disease.     

Long-lived Th2 memory in experimental allergic asthma

Although life-long immunity against pathogens is beneficial, immunological memory responses directed against allergens are potentially harmful. Because there is a paucity of information about Th2 memory cells in allergic disease, we established a model of allergic asthma in BALB/c mice to explore the generation and maintenance of Th2 memory. We induced disease without the use of adjuvants, thus avoiding Ag depots, and found that unlike allergic asthma in mice immunized with adjuvant, immunizing with soluble and aerosol OVA resulted in pathological lung lesions resembling human disease. To test memory responses we allowed mice with acute disease to recover and then re-exposed them to aerosol OVA a second time. Over 400 days later these mice developed OVA-dependent eosinophilic lung inflammation, airway hyperresponsiveness, mucus hypersecretion, and IgE. Over 1 year after recuperating from acute disease, mice had persistent lymphocytic lung infiltrates, Ag-specific production of IL-4 and IL-5 from spleen and lung cells in vitro, and elevated IgG1. Moreover, when recuperated mice were briefly aerosol challenged, we detected early expression of Th2 cytokine RNA in lungs. Taken together, these data demonstrate the presence of long-lived Th2 memory cells in spleen and lungs involved in the generation of allergic asthma upon Ag re-exposure.     

Seasonal allergic asthma and non-specific bronchial responsiveness

Summary Bronchial responsiveness to methacoline (PD20 FEV1 mcg) was measured in 64 non smoker asthmatic patients with baseline FEV190% predicted. Patients underwent skin prick tests (SPT) and RAST.Allergic patients had: SPT3+ and RAST-score>II class to the same antigen and correlation with asthmatic symptoms; non allergic patients had negative SPT and RAST. We divided patients in four groups: 1st) allergic seasonal asthmatics before pollen season; 2nd) allergic seasonal asthmatics during pollen season; 3rd) allergic perennial asthmatics; 4th) non-allergic perennial asthmatics.A significant difference in log PD20 was observed between 1st and 2nd group (p<0.0005); between 1st and 3rd group (p<0.0005); between 1st and 4th group (p<0.0005). In allergic seasonal asthmatics before pollen season 10/20 subjects were non-responsive to methacholine (PD201600 mcg), while in 2nd, 3rd and 4th group no subjects were non-responsive.The authors conclude that non-specific bronchial hyperresponsiveness to methacoline is not constant in seasonal allergic asthmatics out of pollen season.     

Arthropod-derived histamine-binding protein prevents murine allergic asthma

Because histamine receptor type I blockade attenuates allergic asthma, we asked whether complete neutralization of histamine by an arthropod-derived, high affinity histamine-binding protein (EV131) would prevent allergic asthma. Intranasal administration of EV131 given before Ag challenge in immunized mice prevented airway hyperreactivity by 70%, and abrogated peribronchial inflammation, pulmonary eosinophilia, mucus hypersecretion, and IL-4 and IL-5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The inhibitory effect of EV131 on bronchial hyperreactivity was comparable to that of glucocorticosteroids. These results demonstrate that histamine is a critical mediator of allergic asthma. Therefore, complete neutralization of histamine, rather than specific histamine receptor blockade, may have a profound effect on allergic asthma.     

Diagnostic significance of immunoglobulins in infectious allergic bronchial asthma

In 100 patients with infectious allergic bronchial asthma the levels of IgM. IgG and IgA were determined by Mancini's method and the levels of IgE, tissue and microbial antibodies by the Prausnitz - Küstner test before and after combined treatment carried out under conditions of the microclimate of the salt mines in the village of Solotvino. The data on the content of immunoglobulins in the blood serum allowed the authors to establish 3 types of immediate hypersensitivity. THe decreased content of IgM in the blood serum indirectly revealed the role of immune complexes in the pathogenesis of infectious allergic bronchial asthma. The high content of IgE suggested that atopy could take some part in the infectious process.