Tintinger G, Steel H C, Anderson R
Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, South Africa.
Clin Exp Immunol. 2005 Aug;141(2):191-200. doi: 10.1111/j.1365-2249.2005.02800.x.
Neutrophils are relatively insensitive to the anti-inflammatory actions of conventional chemotherapeutic agents, including corticosteroids, emphasizing the requirement for novel pharmacological strategies to control the potentially harmful proinflammatory activities of these cells. In the case of commonly-occurring inflammatory diseases of the airways, the neutrophil is the primary mediator of inflammation in conditions such as chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, bronchiectasis and non-eosinophilic bronchial asthma. Recent insights into the mechanisms utilized by neutrophils to restore Ca(2+) homeostasis following activation with Ca(2+)-mobilizing, proinflammatory stimuli have facilitated the identification of novel targets for anti-inflammatory chemotherapy in these cells. The most amenable of these from a chemotherapeutic perspective, is the cyclic AMP-dependent protein kinase-modulated endomembrane Ca(2+)-ATPase which promotes clearance of the cation from the cytosol of activated neutrophils. Second generation type 4 phosphodiesterase inhibitors and adenosine receptor agonists operative at the level of subtype A2A adenosine receptors, which are currently undergoing clinical and preclinical assessment respectively, hold promise as pharmacologic modulators during the restoration of Ca(2+) homeostasis. If this promise is realized, it may result in novel chemotherapeutic strategies for the control of hyperacute and chronic inflammatory conditions in which neutrophils are primary offenders. Alternative, potential future targets include the Na(+), Ca(2+)-exchanger and store-operated Ca(2+) channels, which cooperate in the refilling of intracellular Ca(2+) stores.
中性粒细胞对包括皮质类固醇在内的传统化疗药物的抗炎作用相对不敏感，这凸显了需要新的药理学策略来控制这些细胞潜在有害的促炎活性。在常见的气道炎症性疾病中，中性粒细胞是慢性阻塞性肺疾病、囊性纤维化、急性呼吸窘迫综合征、支气管扩张症和非嗜酸性支气管哮喘等病症中炎症的主要介质。最近对中性粒细胞在受到动员钙离子的促炎刺激激活后恢复钙离子稳态所利用机制的深入了解，有助于确定这些细胞中抗炎化疗的新靶点。从化疗角度来看，其中最适合的是环磷酸腺苷依赖性蛋白激酶调节的内膜钙离子ATP酶，它能促进激活的中性粒细胞胞质溶胶中阳离子的清除。第二代4型磷酸二酯酶抑制剂和作用于A2A亚型腺苷受体水平的腺苷受体激动剂，目前分别正在进行临床和临床前评估，有望成为恢复钙离子稳态过程中的药理学调节剂。如果这一前景得以实现，可能会产生控制中性粒细胞为主要致病因素的超急性和慢性炎症病症的新化疗策略。其他潜在的未来靶点包括钠钙交换体和储存性钙离子通道，它们在细胞内钙离子储存的再填充过程中协同作用。
