Grunstein M M, Hakonarson H, Maskeri N, Kim C, Chuang S
Division of Pulmonary Medicine, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Am J Physiol Lung Cell Mol Physiol. 2000 Jun;278(6):L1154-63. doi: 10.1152/ajplung.2000.278.6.L1154.
Cell adhesion molecules (CAMs) have been importantly implicated in the pathobiology of the airway responses in allergic asthma, including inflammatory cell recruitment into the lungs and altered bronchial responsiveness. To elucidate the mechanism of CAM-related mediation of altered airway responsiveness in the atopic asthmatic state, the expressions and actions of intercellular adhesion molecule-1 (ICAM-1) and its counterreceptor ligand lymphocyte function-associated antigen-1 (LFA-1; i.e., CD11a/CD18) were examined in isolated rabbit airway smooth muscle (ASM) tissues and cultured human ASM cells passively sensitized with sera from atopic asthmatic patients or nonatopic nonasthmatic (control) subjects. Relative to control tissues, the atopic asthmatic sensitized ASM exhibited significantly enhanced maximal contractility to acetylcholine and attenuated relaxation responses to isoproterenol. These proasthmatic changes in agonist responsiveness were ablated by pretreating the atopic sensitized tissues with a monoclonal blocking antibody (MAb) to either ICAM-1 or CD11a, whereas a MAb directed against the related beta(2)-integrin Mac-1 had no effect. Moreover, relative to control tissues, atopic asthmatic sensitized ASM cells displayed an autologously upregulated mRNA and cell surface expression of ICAM-1, whereas constitutive expression of CD11a was unaltered. Extended studies further demonstrated that 1) the enhanced expression and release of soluble ICAM-1 by atopic sensitized ASM cells was prevented when cells were pretreated with an interleukin (IL)-5-receptor-alpha blocking antibody and 2) administration of exogenous IL-5 to naive (nonsensitized) ASM cells induced a pronounced soluble ICAM-1 release from the cells. Collectively, these observations provide new evidence demonstrating that activation of the CAM counterreceptor ligands ICAM-1 and LFA-1, both of which are endogenously expressed in ASM cells, elicits autologously upregulated IL-5 release and associated changes in ICAM-1 expression and agonist responsiveness in atopic asthmatic sensitized ASM.
细胞黏附分子（CAMs）在过敏性哮喘气道反应的病理生物学中具有重要作用，包括炎症细胞向肺部募集以及支气管反应性改变。为了阐明CAM相关介导特应性哮喘状态下气道反应性改变的机制，我们在分离的兔气道平滑肌（ASM）组织以及用特应性哮喘患者或非特应性非哮喘（对照）受试者血清被动致敏的培养人ASM细胞中，检测了细胞间黏附分子-1（ICAM-1）及其反受体配体淋巴细胞功能相关抗原-1（LFA-1；即CD11a/CD18）的表达和作用。相对于对照组织，特应性哮喘致敏的ASM对乙酰胆碱的最大收缩力显著增强，对异丙肾上腺素的舒张反应减弱。用针对ICAM-1或CD11a的单克隆阻断抗体（MAb）预处理特应性致敏组织，可消除这些激动剂反应性的促哮喘变化，而针对相关β(2)-整合素Mac-1的MAb则无作用。此外，相对于对照组织，特应性哮喘致敏的ASM细胞显示ICAM-1的mRNA和细胞表面表达自动上调，而CD11a的组成性表达未改变。进一步的研究表明：1）当用白细胞介素（IL）-5受体α阻断抗体预处理细胞时，特应性致敏的ASM细胞可溶性ICAM-1的表达和释放增强被阻止；2）向未致敏（未致敏）的ASM细胞施用外源性IL-5可诱导细胞显著释放可溶性ICAM-1。总体而言，这些观察结果提供了新的证据，表明CAM反受体配体ICAM-1和LFA-1的激活，二者均在ASM细胞中内源性表达，在特应性哮喘致敏的ASM中引发IL-5释放自动上调以及ICAM-1表达和激动剂反应性的相关变化。
