Laboratory of Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, The Netherlands.
Respir Res. 2011 Aug 23;12(1):110. doi: 10.1186/1465-9921-12-110.
Cigarette smoke, the major risk factor for COPD, is known to activate matrix metalloproteinases in airway epithelium. We investigated whether metalloproteinases, particularly A Disintegrin and Metalloproteinase (ADAM)17, contribute to increased pro-inflammatory epithelial responses with respect to the release of IL-8 and TGF-α, cytokines implicated in COPD pathogenesis.
We studied the effects of cigarette smoke extract (CSE) and metalloproteinase inhibitors on TGF-α and IL-8 release in primary bronchial epithelial cells (PBECs) from COPD patients, healthy smokers and non-smokers.
We observed that TGF-α was mainly shed by ADAM17 in PBECs from all groups. Interestingly, IL-8 production occurred independently from ADAM17 and TGF-α shedding, but was significantly inhibited by broad-spectrum metalloproteinase inhibitor TAPI-2. CSE did not induce ADAM17-dependent TGF-α shedding, while it slightly augmented the production of IL-8. This was accompanied by reduced endogenous inhibitor of metalloproteinase (TIMP)-3 levels, suggesting that CSE does not directly but rather indirectly alter activity of ADAM17 through the regulation of its endogenous inhibitor. Furthermore, whereas baseline TGF-α shedding was lower in COPD PBECs, the early release of IL-8 (likely due to its shedding) was higher in PBECs from COPD than healthy smokers. Importantly, this was accompanied by lower TIMP-2 levels in COPD PBECs, while baseline TIMP-3 levels were similar between groups.
Our data indicate that IL-8 secretion is regulated independently from ADAM17 activity and TGF-α shedding and that particularly its early release is differentially regulated in PBECs from COPD and healthy smokers. Since TIMP-2-sensitive metalloproteinases could potentially contribute to IL-8 release, these may be interesting targets to further investigate novel therapeutic strategies in COPD.
香烟烟雾是 COPD 的主要危险因素，已知其可激活气道上皮中的基质金属蛋白酶。我们研究了金属蛋白酶，尤其是 A 型解整合素金属蛋白酶 17（ADAM17），是否会导致 COPD 发病机制中涉及的细胞因子白细胞介素-8（IL-8）和转化生长因子-α（TGF-α）的促炎上皮反应增加。
我们研究了香烟烟雾提取物（CSE）和金属蛋白酶抑制剂对 COPD 患者、健康吸烟者和非吸烟者的原代支气管上皮细胞（PBEC）中 TGF-α和 IL-8 释放的影响。
我们观察到 TGF-α主要由各组 PBEC 中的 ADAM17 脱落。有趣的是，IL-8 的产生与 ADAM17 和 TGF-α 的脱落无关，但被广谱金属蛋白酶抑制剂 TAPI-2 显著抑制。CSE 不会诱导 ADAM17 依赖性 TGF-α脱落，但会轻微增加 IL-8 的产生。这伴随着内源性金属蛋白酶抑制剂（TIMP）-3 水平的降低，表明 CSE 不是直接而是通过调节其内源性抑制剂间接改变 ADAM17 的活性。此外，尽管 COPD PBEC 的基线 TGF-α脱落较低，但 COPD PBEC 的早期 IL-8 释放（可能由于其脱落）高于健康吸烟者。重要的是，这伴随着 COPD PBEC 中 TIMP-2 水平的降低，而两组之间的基线 TIMP-3 水平相似。
我们的数据表明，IL-8 的分泌不受 ADAM17 活性和 TGF-α脱落的调节，并且特别是其早期释放在 COPD 和健康吸烟者的 PBEC 中受到不同的调节。由于 TIMP-2 敏感的金属蛋白酶可能有助于 IL-8 的释放，因此它们可能是进一步研究 COPD 新型治疗策略的有趣靶点。
