Pulmonary and Critical Care Department, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China ; Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
J Inflamm Res. 2013;6:25-33. doi: 10.2147/JIR.S35136. Epub 2013 Feb 27.
The balance between production and degradation of extracellular matrix is crucial in maintaining normal tissue structure. This study was designed to investigate the effect of budesonide on fibroblast-mediated tissue repair and remodeling.
Using human fetal lung fibroblasts in a three-dimensional collagen gel culture system, we investigated the effect of budesonide (1-1000 nM) on collagen gel contraction and degradation in the presence or absence of Inflammatory cytokines (interleukin-1β and tumor necrosis factor α; 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 μg/mL. The effects of budesonide on metalloproteinase production and activation were also investigated.
Inflammatory cytokines significantly inhibited collagen gel contraction mediated by lung fibroblasts. Budesonide counteracted the effect of cytokines in a concentration-dependent manner (to 50%, P < 0.01). Budesonide 100 nM almost completely inhibited the release and mRNA expression of metalloproteinase-1, metalloproteinase-3, and metalloproteinase-9 induced by the cytokines (P< 0.05). Exposure to the cytokines plus trypsin increased collagen degradation and conversion of the metalloproteinases to lower molecular weight forms corresponding to their active forms. Budesonide blocked both enhanced collagen degradation (P< 0.01) and suppressed trypsin-mediated conversion of cytokine-induced metalloproteinase-9 and metalloproteinase-3 to lower molecular weight forms. Similar effects were observed with dexamethasone 1 μM, suggesting a class effect.
These findings demonstrate that budesonide directly modulates contraction of collagen gels and can decrease collagen degradation under Inflammatory conditions. The mechanism of this effect is through suppressing gene expression, release, and activation of metalloproteinases. By modulating the release and activity of metalloproteinases, inhaled budesonide may be able to modify airway tissue repair and remodeling.
细胞外基质的产生和降解之间的平衡对于维持正常组织结构至关重要。本研究旨在研究布地奈德对成纤维细胞介导的组织修复和重塑的影响。
我们使用三维胶原凝胶培养系统中的人胎肺成纤维细胞，研究布地奈德（1-1000 nM）在存在或不存在炎性细胞因子（白细胞介素-1β和肿瘤坏死因子-α；每种 5ng/mL）以及为了激活潜在的蛋白酶，丝氨酸蛋白酶胰蛋白酶 0.25μg/mL 的情况下对胶原凝胶收缩和降解的影响。还研究了布地奈德对金属蛋白酶产生和激活的影响。
炎性细胞因子显著抑制肺成纤维细胞介导的胶原凝胶收缩。布地奈德以浓度依赖性方式拮抗细胞因子的作用（至 50%，P<0.01）。布地奈德 100 nM 几乎完全抑制细胞因子诱导的金属蛋白酶-1、金属蛋白酶-3 和金属蛋白酶-9 的释放和 mRNA 表达（P<0.05）。暴露于细胞因子加胰蛋白酶增加胶原降解和细胞因子诱导的金属蛋白酶-9 和金属蛋白酶-3 向与其活性形式相对应的较低分子量形式的转化。布地奈德阻断了这两种增强的胶原降解（P<0.01）和抑制胰蛋白酶介导的细胞因子诱导的金属蛋白酶-9 和金属蛋白酶-3 向较低分子量形式的转化。1μM 地塞米松也观察到类似的效果，表明存在类效应。
这些发现表明布地奈德直接调节胶原凝胶的收缩，并可在炎症条件下减少胶原降解。这种作用的机制是通过抑制基因表达、释放和金属蛋白酶的激活。通过调节金属蛋白酶的释放和活性，吸入布地奈德可能能够改变气道组织修复和重塑。
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