Yonezawa Daiki, Sekiguchi Fumiko, Miyamoto Misato, Taniguchi Eiichi, Honjo Masami, Masuko Takashi, Nishikawa Hiroyuki, Kawabata Atsufumi
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-osaka 577-8502, Japan.
Toxicology. 2007 Nov 20;241(1-2):11-8. doi: 10.1016/j.tox.2007.07.020. Epub 2007 Aug 6.
We investigated effect of hydrogen sulfide (H(2)S) on oxidative stress-caused cell death in gastric mucosal epithelial cells. In rat normal gastric epithelial RGM1 cells, NaHS, a H(2)S donor, at 1.5mM strongly suppressed hydrogen peroxide (H(2)O(2))-caused cell death, while it slightly augmented the H(2)O(2) toxicity at 0.5-1mM. The protective effect of NaHS was abolished by inhibitors of MEK or JNK, but not of p38 MAP kinase. NaHS at 1.5mM actually phosphorylated ERK and JNK in RGM1 cells. Glibenclamide, an ATP-sensitive K(+) (K(ATP)(+)) channel inhibitor, did not affect the protective effect of NaHS, although mRNAs for K(ATP)(+) channel subunits, Kir6.1 and SUR1, were detected in RGM1 cells. In anesthetized rats, oral administration of NaHS protected against gastric mucosal lesion caused by ischemia-reperfusion. These results suggest that NaHS/H(2)S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of MAP kinase pathways, a therapeutic dose range being very narrow.
我们研究了硫化氢（H₂S）对胃黏膜上皮细胞氧化应激所致细胞死亡的影响。在大鼠正常胃上皮RGM1细胞中，硫化氢供体硫氢化钠（NaHS）在1.5 mM时能强烈抑制过氧化氢（H₂O₂）所致的细胞死亡，而在0.5 - 1 mM时则会轻微增强H₂O₂的毒性。MEK或JNK的抑制剂可消除NaHS的保护作用，但p38丝裂原活化蛋白激酶（MAP）的抑制剂则无此作用。1.5 mM的NaHS实际上使RGM1细胞中的细胞外信号调节激酶（ERK）和JNK磷酸化。格列本脲，一种ATP敏感性钾（KATP⁺）通道抑制剂，虽在RGM1细胞中检测到KATP⁺通道亚基Kir6.1和SUR1的mRNA，但不影响NaHS的保护作用。在麻醉大鼠中，口服NaHS可预防缺血再灌注所致的胃黏膜损伤。这些结果表明，NaHS/H₂S可能通过刺激MAP激酶途径来保护胃黏膜上皮细胞免受氧化应激，其治疗剂量范围非常狭窄。
