| Objective:Bronchial asthma (asthma), characterized by reversible airflow obstruction, is chronic airway inflammatory diseases involving a variety of inflammatory cells and cellular components. The most distinctive feature of asthma is inflammation, airway remodeling and airway hyperresponsiveness. AHR is an important feature of asthma, mainly caused by excessive contraction of airway smooth muscle (ASM).It usually cause cough, chest tightness, dyspnea, wheezing and other symptoms. Generally believed that the presence of inflammatory mediators and inflammatory factors in asthma airway may cause airway hyperresponsiveness., leading airway smooth muscle (ASM) contraction and inducing acute asthma or severe asthma attacks.β2adrenergic agonist therapy has been the classic treatment protocol of asthma and can relieve symptoms rapidly. The mechanism of β2adrenergic agonist is that it can bind ASM-adrenergic receptor activate a series of signaling pathways, causing ASM relaxation. The long-term repeated use of β2AR agonists can cause reduced sensitivity to adrenergic receptors and weakened bronchodilator effect. Various mechanisms have been discussed. Some researchers believe that inflammatory cytokines contribute to β2agonist increased efficacy of ASM contraction, however the others speculate on the the direct effect of inflammatory cytokines that cause β2receptor weaken relaxant effect of ASM or inflammatory cytokines can reduce the amount of mem-P2receptors and weaken its relaxing effect. M.Kudo believed that inflammatory cytokines like interleukin-17(interleukin17, IL-17) contributed to the contraction of ASM effect of the β2agonist efficacy. Recently, many inflammatory cytokines associated with AHR have been found including IL-17.Interleukin-17(interleukin17, IL-17) is secreted by Thl7cells, and related to occurrence and development of many inflammatory and autoimmune diseases. Early studies found that IL-17concentration in serum, sputum and bronchoalveolar lavage fluid (B ALF) of asthma patients was significantly higher than normal, and their expression levels parallel with disease severity and airway responsiveness. Our study aims to investigate whether IL-17leads to decreased-sensitivity and attenuated β2R-agonist bronchodilation in asthma mice.Methods:Establishing a mouse model of acute asthma and the tracheal rings were dissected. Then ISO of different concentration was added to four thermostat by Cumulative dose dosing method, observing the tracheal rings and their tracheal ring contractility was measured. Primary cultured smooth muscle cells of mice. IL-17co-cultured with ASMC, in presence of the inhibitor of ERK, p38, PKA and PKA activator. WB was used to detect ERK1/2, p38phosphorylation levels and β2receptor expression levels (total membrane volume and surface volume), and ELISA was to detect PKA activity cell lysate. Results:Tracheal tension measurements showed IL-17may weaken the effect of β2-agonists relaxation of asthma mice bronchial smooth muscle, and this effect can be reversed by PKA inhibitor. IL-17could reduce the expression of ASMC surface P2receptors, and this effect can be suppressed by ERK, p38, PKA inhibitor, and PKA activators can also reduce the expression of the membrane surface β2receptors, indicating the result of β2receptor reduction is achieved by PKA.Conclusion:Through the ERK/p38,PKA pathway, IL-17mediated the down-regulation of β2receptor sensitivity by reduced expression of ASMC membrane receptors. Thereby β2-agonist bronchodilator effect were weaken in asthma mice model. |
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