Disease relevance of Bhr1

• Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure [1].
• T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice [2].
• We have used two models of murine pulmonary inflammation to investigate the signals responsible for the resolution of bronchial hyperresponsiveness (BHR) [3].
• This has been further supported by data from IL-9-transgenic mice in which the overexpression of IL-9 in the lung causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness [4].
• Viral respiratory infections can cause bronchial hyperresponsiveness and exacerbate asthma [5].

High impact information on Bhr1

• Since airway responsiveness failed to segregate as a mendelian trait, we show significant linkage at two loci, Bhr1 (lod = 3.0) and Bhr2 (lod = 3.7) on chromosomes 2 and 15 [6].
• Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium [1].
• Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way [1].
• In asthma, although activated T cells play a role in the initiation and maintenance of airway inflammation, the importance of T cell costimulation in bronchial hyperresponsiveness had not been characterized [7].
• Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness [2].

Chemical compound and disease context of Bhr1

• RESULTS: The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness [2].
• The inhibitory effect of FTY720 on airway inflammation, induction of bronchial hyperresponsiveness, and goblet cell hyperplasia could be confirmed in an actively Ag-sensitized murine asthma model, clearly indicating that Th2 cell-driven allergic diseases such as asthma could benefit from such treatment [8].
• Inhaled fluticasone propionate reduces concentration of Mycoplasma pneumoniae, inflammation, and bronchial hyperresponsiveness in lungs of mice [9].
• IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil alpha4 integrin [10].
• Allergen exposure induced bronchial hyperresponsiveness to methacholine as measured by the concentration of methacholine needed to increase pulmonary resistance by 200% (PC200), eosinophilia in bronchoalveolar lavage fluid and increase in airway smooth muscle area and goblet cell hyperplasia [11].

Biological context of Bhr1

• Thus, this segment of the genome represents a candidate region for genes that determine susceptibility to bronchial hyperresponsiveness and atopy in animal models [12].
• Increases in the initial component of this transduction system (the beta(2)AR) are sufficient to markedly alter signaling and airway smooth muscle function to the extent that bronchial hyperresponsiveness is ablated, consistent with an anti-asthma phenotype [13].
• However, IL-3 levels in model A closely correlated with the rate of leukocyte clearance by apoptosis and were observed concomitant with a decline in BHR [3].
• Differences in kinetics of lung eosinophilia/BHR were shown to be independent of IgE levels and IL-4 or IL-5 [3].
• Bronchial hyperresponsiveness was measured, bronchoalveolar lavage (BAL) fluid was collected, and lungs were harvested for histology 24 h after the last challenge [14].

Anatomical context of Bhr1

• Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13 [2].
• Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness [15].
• Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE [16].
• Tc2 cells respond to soluble antigen in the respiratory tract and induce lung eosinophilia and bronchial hyperresponsiveness [17].
• FP treatment of infected mice reduced neutrophils in bronchoalveolar lavage fluid (BALF), lung inflammation, and BHR [9].

Associations of Bhr1 with chemical compounds

• Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation [18].
• Both pranlukast and SB210661 significantly attenuated BHR induced by eotaxin with logPC(50), which is the concentration of acetylcholine needed to increase baseline insufflation pressure by 50%, from -0.43 +/- 0.16 to 0.39 +/- 0.10 and from -0.22 +/- 0.10 to 0.53 +/- 0.10, respectively (p < 0.05) [19].
• The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness [20].
• Bronchial hyperresponsiveness (BHR) was assessed by methacholine challenge and was significantly heightened in the infected mice compared with saline controls at Days 3, 7, and 14 [21].
• alpha4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice [10].

Regulatory relationships of Bhr1

• Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in mice [22].

Other interactions of Bhr1

• Experimental ABPA was associated with severe peribronchial eosinophilia, bronchial hyperresponsiveness, and augmented IL-13 and IgE levels [23].
• Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergen-induced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod = 4. 2) and Abhr2 (lod = 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice [24].
• The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract [2].
• 4. Subcutaneously administered cyclosporin A (30 mg kg(-1)) and dexamethasone (10 mg kg(-1)) inhibited antigen-induced mRNA expression of IL-2 and IL-5, increase of BALF eosinophils and bronchial hyperresponsiveness of FJ17-transferred mice in vivo [25].
• 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 [26].

Analytical, diagnostic and therapeutic context of Bhr1

• Administration of anti-IL-12p35 or anti-IL-12p40 mAb to previously OVA-sensitized BALB/c mice concomitantly with exposure to nebulized OVA, abolished both the development of bronchial hyperresponsiveness to metacholine as well as the eosinophilia in bronchoalveolar lavage fluid and peripheral blood [27].
• Most importantly, Th-modified IL-5 DNA vaccination restores normal bronchial hyperresponsiveness to beta-methacholine [28].
• Chronic airway inflammation, mucus hypersecretion, reversible airway constriction, and bronchial hyperresponsiveness are important pathogenic features of asthma [29].
• The meeting followed hard on the heels of a report suggesting that eosinophils might be redundant in late-phase responses in asthma, inasmuch as treatment of asthmatic patients with humanized anti-IL-5 in clinical trials failed to modify bronchial hyperresponsiveness [30].
• The aim of this study was to examine associations among MCAF/MCP-1, BALF cells and spirometry parameters and bronchial hyperresponsiveness in patients with atopic asthma and chronic bronchitis [31].

References