來自麻省理工David H. Koch癌癥綜合研究所，哈佛大學(xué)醫(yī)學(xué)院麻省總醫(yī)院放射腫瘤科,，杜克大學(xué)放射致癌基因，制藥與癌癥生物學(xué)中心的科學(xué)家在最新一期的Science雜志上發(fā)表研究進展文章,，發(fā)現(xiàn)了p53調(diào)控的GI綜合癥的生物機制,。
放射損傷是由放射線照射引起的機體組織損害。一般來說,，放射線是由天然或人工能源產(chǎn)生的高能電磁波或高能粒子,。大劑量射線瞬間照射或低劑量射線長時間照射都可能引起組織損傷。某些射線的有害影響僅持續(xù)很短時間,，而有的可引起慢性疾病,。受大劑量射線照射后幾分鐘或幾天內(nèi)就出現(xiàn)明顯早期損害，而遠期的影響在幾周,、幾個月甚至幾年內(nèi)都不明顯,。
急性放射性損傷常常容易對胃腸道產(chǎn)生致命性的損害，這種放射線引起的胃腸道疾病被稱為GI syndrome（放射性胃腸綜合癥），胃腸綜合癥是在受到比30Gy小但仍然較高的（4Ｇｙ以上）輻射引起的,。癥狀有嚴重惡心,、嘔吐和腹瀉，導(dǎo)致嚴重失水,。最初,，癥狀是由胃腸道粘膜細胞壞死引起的。由于腸壁進行性損傷和細菌感染,，癥狀反復(fù)出現(xiàn),。最后，吸收營養(yǎng)的細胞完全破壞,，損傷部位大量滲血,。通常在輻射后4～6天新細胞再生。但即使這樣,，病人也很可能在2～3周后,，因骨髓衰竭死亡。
關(guān)于GI綜合癥的發(fā)病機制一直存在爭議,，有科學(xué)家認為,，GI綜合癥是因胃腸道上皮細胞受損所引起，而有的科學(xué)家認為,，GI綜合癥是由胃腸道內(nèi)皮細胞受損所引起,，此外，在受損細胞的死亡機制上也存在爭議,，有的科學(xué)家認為受損細胞通過細胞凋亡程序而死亡,，有的科學(xué)家則認為受損細胞通過其他的死亡程序而死。
現(xiàn)在,，來自MIT的Tyler Jacks研究團隊用小鼠模型找出了答案,，他們發(fā)現(xiàn)選擇性地沉默小鼠胃腸道上皮細胞或內(nèi)皮細胞中的前凋亡基因Bax和Bak1基因病不能保護小鼠在部分身體gamma射線照射后免于法陣為放射性胃腸綜合癥。然而與之相反,，選擇性地沉默小鼠胃腸道上皮細胞（而不是內(nèi)皮細胞）中的p53基因,，將導(dǎo)致小鼠對射線照射更為敏感，更易發(fā)展為GI綜合癥,。而在轉(zhuǎn)基因小鼠中高度表達p53基因?qū)⒂兄∈蟮挚股渚€的輻射,，避免發(fā)生GI綜合癥。
這些研究成果闡明了GI綜合癥的發(fā)病機制,，GI綜合癥因胃腸道上皮細胞受損而發(fā)病,，這些受損細胞的死亡受p53的調(diào)控，但是卻不是通過p53誘導(dǎo)的細胞凋亡路徑而死亡的,。（生物谷Bioon.com）
生物谷推薦原始出處：
Science December 17, 2009 DOI: 10.1126/science.1166202
p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis
David G. Kirsch,1,2,3, Philip M. Santiago,1 Emmanuelle di Tomasso,2 Julie M. Sullivan,3 Wu-Shiun Hou,1,Talya Dayton,1 Laura B. Jeffords,3 Pooja Sodha,1 Kim Mercer,1 Rhianna Cohen,1 Osamu Takeuchi,4 Stanley J. Korsmeyer,4,* Roderick Bronson,5 Carla F. Kim,1 Kevin M. Haigis,1,? Rakesh K. Jain,2 Tyler Jacks1,6,
Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells mediating the GI syndrome are derived from the epithelium or endothelium, and whether the target cells die by apoptosis or other mechanisms, are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after subtotal body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.
1 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2 Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
3 Departments of Radiation Oncology and Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27708, USA.
4 Dana Farber Cancer Institute, Boston, MA 02115, USA.
5 Tufts University School of Medicine and Veterinary Medicine, North Grafton, MA 05136, USA.
6 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
