在过敏性哮喘动物模型中，层粘连蛋白b1竞争肽YIGSR能诱发气道平滑肌过度收缩和过度增殖
2011/03/24
摘要
背景：纤维增生性气道重构包括气道平滑肌(ASM)体积和收缩性的增加，是导致哮喘患者气道高反应性的原因。体外实验显示，ASM细胞成熟，形成具有收缩性表型的细胞，依赖于层粘连蛋白，后者可被层粘连蛋白竞争性肽YIGSR（酪氨酸-异亮氨酸-甘氨酸-丝氨酸-精氨酸）所抑制。然而，体内层粘连蛋白在慢性哮喘时ASM重构中的作用尚不清楚。
方法：通过建立豚鼠过敏性哮喘模型，研究采用YIGSR气道局部治疗对反复过敏原暴露诱发的气道重构特征的影响，这些特征包括：ASM过度增殖、过度收缩、炎症和纤维化。人ASM细胞培养，研究YIGSR对ASM体外增殖的直接影响。
结果：局部采用YIGSR治疗，能降低过敏原诱导的ASM过度增殖和肺部增殖细胞核抗原(PCNA，细胞增殖标志物)的表达。此外，在生理盐水和过敏原刺激的动物中，YIGSR治疗能增加sm-MHC表达和ASM的收缩性。这表明，层粘连蛋白竞争肽YIGSR治疗，模拟了体内层粘连蛋白的功能，而不是抑制其功能。同时，YIGSR治疗能增加过敏原接触诱发的纤维化和粘膜下嗜酸性粒细胞。固定化的YIGSR处理能减少离体情况下PDGF诱导的ASM增殖，该作用呈现YIGSR浓度依赖性，该作用与层粘连蛋白包被的培养板细胞培养结果类似。固定化的YIGSR与层粘连蛋白的作用能被可溶性YIGSR所拮抗。
结论：这些结果显示，层粘连蛋白竞争性肽YIGSR能促进体内ASM收缩和抑制ASM增殖，该作用可能与细胞暴露的微环境（YIGSR）相关。
（陈欣 审校）
Respir Res. 2010 Dec 3;11(1):170. [Epub ahead of print]
The laminin beta1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma.
Dekkers BG, Bos IS, Halayko AJ, Zaagsma J, Meurs H.
Abstract
BACKGROUND: Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established.
METHODS: Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro.
RESULTS: Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR. CONCLUSION: These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.
Respir Res. 2010 Dec 3;11(1):170. [Epub ahead of print]
背景：纤维增生性气道重构包括气道平滑肌(ASM)体积和收缩性的增加，是导致哮喘患者气道高反应性的原因。体外实验显示，ASM细胞成熟，形成具有收缩性表型的细胞，依赖于层粘连蛋白，后者可被层粘连蛋白竞争性肽YIGSR（酪氨酸-异亮氨酸-甘氨酸-丝氨酸-精氨酸）所抑制。然而，体内层粘连蛋白在慢性哮喘时ASM重构中的作用尚不清楚。
方法：通过建立豚鼠过敏性哮喘模型，研究采用YIGSR气道局部治疗对反复过敏原暴露诱发的气道重构特征的影响，这些特征包括：ASM过度增殖、过度收缩、炎症和纤维化。人ASM细胞培养，研究YIGSR对ASM体外增殖的直接影响。
结果：局部采用YIGSR治疗，能降低过敏原诱导的ASM过度增殖和肺部增殖细胞核抗原(PCNA，细胞增殖标志物)的表达。此外，在生理盐水和过敏原刺激的动物中，YIGSR治疗能增加sm-MHC表达和ASM的收缩性。这表明，层粘连蛋白竞争肽YIGSR治疗，模拟了体内层粘连蛋白的功能，而不是抑制其功能。同时，YIGSR治疗能增加过敏原接触诱发的纤维化和粘膜下嗜酸性粒细胞。固定化的YIGSR处理能减少离体情况下PDGF诱导的ASM增殖，该作用呈现YIGSR浓度依赖性，该作用与层粘连蛋白包被的培养板细胞培养结果类似。固定化的YIGSR与层粘连蛋白的作用能被可溶性YIGSR所拮抗。
结论：这些结果显示，层粘连蛋白竞争性肽YIGSR能促进体内ASM收缩和抑制ASM增殖，该作用可能与细胞暴露的微环境（YIGSR）相关。
（陈欣 审校）
Respir Res. 2010 Dec 3;11(1):170. [Epub ahead of print]
The laminin beta1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma.
Dekkers BG, Bos IS, Halayko AJ, Zaagsma J, Meurs H.
Abstract
BACKGROUND: Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established.
METHODS: Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro.
RESULTS: Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR. CONCLUSION: These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.
Respir Res. 2010 Dec 3;11(1):170. [Epub ahead of print]
