Hua Xiaoyang, Chason Kelly D, Fredholm Bertil B, Deshpande Deepak A, Penn Raymond B, Tilley Stephen L
Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Allergy Clin Immunol. 2008 Jul;122(1):107-13, 113.e1-7. doi: 10.1016/j.jaci.2008.03.026. Epub 2008 May 9.
The mechanisms responsible for the development of airway hyperresponsiveness in asthma are poorly understood. Adenosine levels are high in the lungs of patients with asthma, but a role for adenosine in the development of this cardinal feature of asthma has not been previously reported.
To determine the capacity of adenosine to induce airway hyperresponsiveness, and to investigate the mechanisms behind these effects of adenosine on airway physiology.
Wild-type C57BL/6 mice were exposed to aerosolized adenosine analog adenosine-5' N-ethylcarboxamide (NECA), and subsequent hyperresponsiveness to methacholine was investigated by measuring airway mechanics after anesthesia and tracheostomy. Similar experiments were conducted with A(1)-deficient, A(3)-deficient, and mast cell-deficient mice, as well as with mast cell-deficient mice engrafted with wild-type (wt) or A(3)(-/-) mast cells. The effect of NECA on methacholine-induced tension development in ex vivo tracheal rings was also examined.
Exposure of wt mice to NECA resulted in the robust induction of airway hyperresponsiveness. NECA failed to induce hyperresponsiveness to methacholine in tracheal ring preps ex vivo, and NECA-induced airway hyperresponsiveness in vivo was not affected by the genetic inactivation of the A(1) adenosine receptor. In contrast, NECA-induced airway hyperresponsiveness was abolished in A(3) adenosine receptor-deficient mice and in mice deficient in mast cells. Reconstitution of mast cell-deficient mice with wt mast cells restored hyperresponsiveness, whereas reconstitution with A(3) receptor-deficient mast cells did not.
Adenosine induces airway hyperresponsiveness indirectly by activating A(3) receptors on mast cells.
哮喘患者气道高反应性发生的机制尚不清楚。哮喘患者肺内腺苷水平较高，但腺苷在哮喘这一主要特征发生过程中的作用此前尚未见报道。
确定腺苷诱导气道高反应性的能力，并研究腺苷对气道生理作用的机制。
将野生型C57BL/6小鼠暴露于雾化的腺苷类似物5'-N-乙基甲酰胺腺苷（NECA），在麻醉和气管切开术后通过测量气道力学来研究随后对乙酰甲胆碱的高反应性。对A(1)受体缺陷、A(3)受体缺陷和肥大细胞缺陷小鼠，以及移植野生型（wt）或A(3)(-/-)肥大细胞的肥大细胞缺陷小鼠进行了类似实验。还检测了NECA对离体气管环中乙酰甲胆碱诱导的张力发展的影响。
野生型小鼠暴露于NECA后导致气道高反应性的强烈诱导。NECA在离体气管环标本中未能诱导对乙酰甲胆碱的高反应性，且NECA在体内诱导的气道高反应性不受A(1)腺苷受体基因失活的影响。相反，在A(3)腺苷受体缺陷小鼠和肥大细胞缺陷小鼠中，NECA诱导的气道高反应性被消除。用野生型肥大细胞重建肥大细胞缺陷小鼠可恢复高反应性，而用A(3)受体缺陷肥大细胞重建则不能。
腺苷通过激活肥大细胞上的A(3)受体间接诱导气道高反应性。
