Department of Molecular Pharmacology, University of Groningen, The Netherlands.
Am J Respir Crit Care Med. 2010 Mar 15;181(6):556-65. doi: 10.1164/rccm.200907-1065OC. Epub 2009 Dec 17.
Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. The mechanisms driving these changes are, however, incompletely understood. Recently, an important role for extracellular matrix proteins in regulating ASM proliferation and contractility has been found, suggesting that matrix proteins and their integrins actively modulate airway remodeling.
To investigate the role of RGD (Arg-Gly-Asp)-binding integrins in airway remodeling in an animal model of allergic asthma.
Using a guinea pig model of allergic asthma, the effects of topical application of the integrin-blocking peptide RGDS (Arg-Gly-Asp-Ser) and its negative control GRADSP (Gly-Arg-Ala-Asp-Ser-Pro) were assessed on markers of ASM remodeling, fibrosis, and inflammation induced by repeated allergen challenge. In addition, effects of these peptides on human ASM proliferation and maturation were investigated in vitro.
RGDS attenuated allergen-induced ASM hyperplasia and hypercontractility as well as increased pulmonary expression of smooth muscle myosin heavy chain and the proliferative marker proliferating cell nuclear antigen (PCNA). No effects were observed for GRADSP. The RGDS effects were ASM selective, as allergen-induced eosinophil and neutrophil infiltration as well as fibrosis were unaffected. In cultured human ASM cells, we demonstrated that proliferation induced by collagen I, fibronectin, serum, and platelet-derived growth factor requires signaling via RGD-binding integrins, particularly of the alpha(5)beta(1) subtype. In addition, RGDS inhibited smooth muscle alpha-actin accumulation in serum-deprived ASM cells.
This is the first study indicating that integrins modulate ASM remodeling in an animal model of allergic asthma, which can be inhibited by a small peptide containing the RGD motif.
气道重塑，包括气道平滑肌（ASM）质量和收缩力的增加，导致哮喘的气道高反应性。然而，驱动这些变化的机制尚不完全清楚。最近，细胞外基质蛋白在调节 ASM 增殖和收缩性方面的重要作用已经被发现，这表明基质蛋白及其整合素积极调节气道重塑。
研究 RGD（精氨酸-甘氨酸-天冬氨酸）结合整合素在变应性哮喘动物模型中的气道重塑中的作用。
使用豚鼠变应性哮喘模型，评估整合素阻断肽 RGDS（精氨酸-甘氨酸-天冬氨酸-丝氨酸）及其阴性对照 GRADSP（甘氨酸-精氨酸-丙氨酸-天冬氨酸-丝氨酸-脯氨酸）对反复变应原刺激引起的 ASM 重塑、纤维化和炎症标志物的影响。此外，还研究了这些肽对体外人 ASM 增殖和成熟的影响。
RGDS 减弱了变应原诱导的 ASM 增生和高收缩性，以及增加的肺平滑肌肌球蛋白重链表达和增殖标志物增殖细胞核抗原（PCNA）。GRADSP 无作用。RGDS 效应是 ASM 选择性的，因为变应原诱导的嗜酸性粒细胞和中性粒细胞浸润以及纤维化不受影响。在培养的人 ASM 细胞中，我们证明了胶原 I、纤维连接蛋白、血清和血小板衍生生长因子诱导的增殖需要通过 RGD 结合整合素信号转导，特别是 alpha(5)beta(1)亚型。此外，RGDS 抑制了血清剥夺的 ASM 细胞中平滑肌 alpha-肌动蛋白的积累。
这是第一项表明整合素调节变应性哮喘动物模型中 ASM 重塑的研究，可被含有 RGD 基序的小肽抑制。
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