气道平滑肌重构在重度长期持续的哮喘患者中是一个动态过程
2010/08/11
背景：气道平滑肌过度增生的起源以及在哮喘发病过程中何时出现平滑肌增生尚不清楚。
目的：体内、体外试验检测气道平滑肌细胞中2个增殖标记物【增殖细胞核抗原（PCNA）和Ki67】的相对敏感性。此外，通过定量检测增殖率和增殖面积，研究哮喘患者的平滑肌重构是否为一动态过程。最后，我们对重构的一个生物标记物-肝素结合表皮生长因子进行了检测。
方法：对中度或重度哮喘患者及健康对照者的支气管活检标本进行检测（每组9名）。体外培养来自移植供体气管的气道平滑肌细胞。通过在体检测PCNA和Ki67以及与平滑肌特异性α-肌动蛋白细胞共表达，定量检测增值率。对平滑肌面积进行形态学评价。通过原位杂交和免疫组化，检测肝素结合表皮生长因子的组织表达，通过RT-PCR检测培养细胞肝素结合表皮生长因子的表达。
结果：增殖细胞核抗原和Ki67与体内、体外细胞增殖相关，但PCNA为更为敏感的增殖标志。与健康对照相比，重度哮喘患者平滑肌细胞面积增加3.4倍，PCNA阳性细胞核比率增加5倍。培养的增殖平滑肌细胞和重度哮喘患者气道平滑肌细胞其肝素结合表皮生长因子表达上调。
结论：增殖细胞核抗原是细胞增殖的高度敏感指标，肝素结合表皮生长因子是重度哮喘患者气道平滑肌重构的潜在生物标志物。
（林江涛 审校）
J Allergy Clin Immunol. 2010 May;125(5):1037-1045.e3.
Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma.
Hassan M, Jo T, Risse PA, Tolloczko B, Lemière C, Olivenstein R, Hamid Q, Martin JG.
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
Abstract
BACKGROUND: The origin of the excess airway smooth muscle in asthma and when in the course of the disease it is acquired are uncertain.
OBJECTIVES: We examined the relative sensitivities of 2 markers of proliferation, proliferating cell nuclear antigen (PCNA) and Ki 67, in airway smooth muscle in vivo and in vitro. We then studied whether muscle remodeling is a dynamic process in asthma by quantifying proliferation rate and area. Finally we examined heparin-binding epidermal growth factor as a biomarker of remodeling.
METHODS: We obtained bronchoscopic biopsies from subjects with moderate or severe asthma and healthy controls (n = 9/group). For in vitro studies, airway smooth muscle cells were cultured from tracheas of transplant donors. The proliferation rate was quantified from PCNA and Ki 67, co-localized to smooth muscle-specific alpha-actin cells in vivo. Muscle area was assessed morphometrically. We examined the expression of heparin-binding epidermal growth factor on tissues by in situ hybridization and by immunohistochemistry and in cells in culture by RT-PCR.
RESULTS: Proliferating cell nuclear antigen and Ki 67 were highly correlated, but PCNA was a significantly more sensitive marker both in vivo and in vitro. Muscle area was 3.4-fold greater and the fraction of PCNA(+) nuclei in muscle was 5-fold greater in severe asthma than in healthy subjects. Heparin-binding epidermal growth factor was upregulated in proliferating muscle cells in culture and in airway smooth muscle in severe asthmatic tissues.
CONCLUSION: Proliferating cell nuclear antigen is a highly sensitive marker of proliferation and heparin-binding epidermal growth factor is a potential biomarker during active remodeling of ASM in severe asthma.
J Allergy Clin Immunol. 2010 May;125(5):1037-1045.e3.
目的：体内、体外试验检测气道平滑肌细胞中2个增殖标记物【增殖细胞核抗原（PCNA）和Ki67】的相对敏感性。此外，通过定量检测增殖率和增殖面积，研究哮喘患者的平滑肌重构是否为一动态过程。最后，我们对重构的一个生物标记物-肝素结合表皮生长因子进行了检测。
方法：对中度或重度哮喘患者及健康对照者的支气管活检标本进行检测（每组9名）。体外培养来自移植供体气管的气道平滑肌细胞。通过在体检测PCNA和Ki67以及与平滑肌特异性α-肌动蛋白细胞共表达，定量检测增值率。对平滑肌面积进行形态学评价。通过原位杂交和免疫组化，检测肝素结合表皮生长因子的组织表达，通过RT-PCR检测培养细胞肝素结合表皮生长因子的表达。
结果：增殖细胞核抗原和Ki67与体内、体外细胞增殖相关，但PCNA为更为敏感的增殖标志。与健康对照相比，重度哮喘患者平滑肌细胞面积增加3.4倍，PCNA阳性细胞核比率增加5倍。培养的增殖平滑肌细胞和重度哮喘患者气道平滑肌细胞其肝素结合表皮生长因子表达上调。
结论：增殖细胞核抗原是细胞增殖的高度敏感指标，肝素结合表皮生长因子是重度哮喘患者气道平滑肌重构的潜在生物标志物。
（林江涛 审校）
J Allergy Clin Immunol. 2010 May;125(5):1037-1045.e3.
Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma.
Hassan M, Jo T, Risse PA, Tolloczko B, Lemière C, Olivenstein R, Hamid Q, Martin JG.
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
Abstract
BACKGROUND: The origin of the excess airway smooth muscle in asthma and when in the course of the disease it is acquired are uncertain.
OBJECTIVES: We examined the relative sensitivities of 2 markers of proliferation, proliferating cell nuclear antigen (PCNA) and Ki 67, in airway smooth muscle in vivo and in vitro. We then studied whether muscle remodeling is a dynamic process in asthma by quantifying proliferation rate and area. Finally we examined heparin-binding epidermal growth factor as a biomarker of remodeling.
METHODS: We obtained bronchoscopic biopsies from subjects with moderate or severe asthma and healthy controls (n = 9/group). For in vitro studies, airway smooth muscle cells were cultured from tracheas of transplant donors. The proliferation rate was quantified from PCNA and Ki 67, co-localized to smooth muscle-specific alpha-actin cells in vivo. Muscle area was assessed morphometrically. We examined the expression of heparin-binding epidermal growth factor on tissues by in situ hybridization and by immunohistochemistry and in cells in culture by RT-PCR.
RESULTS: Proliferating cell nuclear antigen and Ki 67 were highly correlated, but PCNA was a significantly more sensitive marker both in vivo and in vitro. Muscle area was 3.4-fold greater and the fraction of PCNA(+) nuclei in muscle was 5-fold greater in severe asthma than in healthy subjects. Heparin-binding epidermal growth factor was upregulated in proliferating muscle cells in culture and in airway smooth muscle in severe asthmatic tissues.
CONCLUSION: Proliferating cell nuclear antigen is a highly sensitive marker of proliferation and heparin-binding epidermal growth factor is a potential biomarker during active remodeling of ASM in severe asthma.
J Allergy Clin Immunol. 2010 May;125(5):1037-1045.e3.
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独特蛋白酶表型的上皮内肥大细胞积聚在高Th2细胞型哮喘中的作用
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中重度哮喘患者气道内凝血因子的测定及吸入皮质激素对其的影响
