Qi Shufan, den Hartog Gertjan J M, Bast Aalt
Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
Toxicol Appl Pharmacol. 2009 May 15;237(1):111-8. doi: 10.1016/j.taap.2009.02.019. Epub 2009 Mar 4.
Reactive oxygen species (ROS) have been implicated in the pathogenesis of fibrosis. However, it remains unclear which ROS is the major cause. We hypothesize that superoxide elicits specific toxicity to human lung fibroblasts and plays an important role in the development of pulmonary fibrosis. In this study, superoxide generated from xanthine and xanthine oxidase activated lung fibroblasts by increasing the release of TGF-beta1 and collagen. This was associated with increased levels of intracellular superoxide. SOD and tempol, by scavenging respectively extracellular and intracellular superoxide, prevented the activation of fibroblasts induced by exposure to exogenous superoxide, whereas catalase did not. Moreover, hydrogen peroxide did not activate fibroblasts. Apparently, superoxide rather than hydrogen peroxide is involved in the regulation of TGF-beta1 and collagen release in lung fibroblasts. The chloride channel blocker, DIDS, inhibited the increase of intracellular superoxide levels induced by exogenous superoxide and consequently prevented the activation of fibroblasts. This suggests that the cellular influx of superoxide through chloride channels is essential for superoxide-induced activation of fibroblasts. ERK1/2 and p38 MAPKs are involved in the intracellular pathway leading to superoxide-induced fibroblasts activation. Superoxide possesses until now undiscovered specific pro-fibrotic properties in human lung fibroblasts. This takes place via the cellular influx of superoxide through chloride channels rather than via the formation of hydrogen peroxide.
活性氧（ROS）与纤维化的发病机制有关。然而，尚不清楚哪种ROS是主要原因。我们假设超氧化物对人肺成纤维细胞具有特定毒性，并在肺纤维化的发展中起重要作用。在本研究中，黄嘌呤和黄嘌呤氧化酶产生的超氧化物通过增加TGF-β1和胶原蛋白的释放来激活肺成纤维细胞。这与细胞内超氧化物水平的升高有关。超氧化物歧化酶（SOD）和tempol分别通过清除细胞外和细胞内的超氧化物，阻止了暴露于外源性超氧化物所诱导的成纤维细胞激活，而过氧化氢酶则没有。此外，过氧化氢不会激活成纤维细胞。显然，超氧化物而非过氧化氢参与了肺成纤维细胞中TGF-β1和胶原蛋白释放的调节。氯离子通道阻滞剂DIDS抑制了外源性超氧化物诱导的细胞内超氧化物水平的升高，从而阻止了成纤维细胞的激活。这表明超氧化物通过氯离子通道的细胞内流入对于超氧化物诱导的成纤维细胞激活至关重要。ERK1/2和p38丝裂原活化蛋白激酶（MAPKs）参与了导致超氧化物诱导的成纤维细胞激活的细胞内途径。迄今为止，超氧化物在人肺成纤维细胞中具有尚未被发现的特定促纤维化特性。这是通过超氧化物通过氯离子通道的细胞内流入而不是通过过氧化氢的形成来实现的。
