日本外科代謝栄養学会

6. アポトーシス（apoptosis）

　アポトーシス（apoptosis）は計画細胞死（programmed cell death）とも呼ばれ、発生や分化における形態と機能の獲得、生体の恒常性維持や防御、老化と個体死に至るまでの各段階で重要な役割を果たす。複雑に制御された細胞死実行経路によって誘導されるものであり、物理的、化学的組織障害によって惹起される壊死とは根本的に異なる。DNAや核の断片化、核凝縮を特徴とする。アポトーシスを誘導する特異的受容体がFasである。FasとFasリガンドが結合した三量体は、FADDを介してcaspaseカスケードの初期反応であるcaspase－８の活性化を行う。そこから下流のシグナル伝達経路は現在二つあると考えられ、細胞の種類（Type1と2）によって使いわけられている １） 。Type1の細胞では、caspase－８が他のcaspase前駆体を切断して活性化することによりcaspaseカスケードが活性化され、染色体の断片化などの特徴的現象がおこる。Type2の細胞では、caspase－８はBcl－２ファミリーのメンバーであるBidを切断する。切断されたBidはミトコンドリアに移動し膜の透過性を亢進させる。その結果、ミトコンドリアからは、Apaf－１の活性化を介してcaspaseカスケードを活性化するチトクロムCやAIF、Smac／DIBLOが放出され、同様に染色体の断片化などの特徴的現象がおこる。Bcl－２はアポトーシスを抑制するが、反対に促進に働くBaxやBidとホモロジーを有する。これら三者は、互いに結合してミトコンドリアの膜の存在し、その透過性を調節している２）。アポトーシスによる細胞死は神経疾患、心筋症などの疾患関連の細胞脱落、放射線療法および化学療法時の腫瘍細胞死の一部にも関与する。また、心筋梗塞など虚血にともなう細胞死へのアポトーシスの関与も判明した ３） 。さらに、経腸栄養が腸管上皮細胞のアポトーシスを抑制するとの報告もみられ、栄養管理との関連も注目されている（参考文献抄録参照）。なお、アポトーシスの判定にはTUNEL法による染色や、DNAの泳動像からDNA断片化によるラダーパターンを証明する方法が簡便である。

文　献

• Scaffidi C,Fulda S,Srinivasan A et al:Two CD ９５（APO－１／Fas）signaling pathways.EMBO J １７:１６７５－８７,１９９８
• 清水重臣，辻本賀英：Bcl－２ファミリータンパク質とミトコンドリア．実験医学１９（増刊）：１６３７－４３，２００１
• Itoh G,Tamura J,Suzuki M,et al:DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis.Am J Pathol １４６:１３２５－３１,１９９５

参考文献抄録

Diet and apoptosis.

　A range of compounds in or derived from the diet modulates apoptosis in cell cultures in vitro.These observations have important implications concerning the mechanisms.Whereby dietary components affect health.Proapoptotic compounds couldprotect against cancer by enhancing elimination of initiated,precancerous cells,and antiapoptotic compounds could promote tumor formation by inhibiting apoptosis in genetically damaged cells.Proapoptotic compounds could also contribute to age‐related degenerative diseases by activating cell death in postmitotic cells or shifting the normal balance of mitosis and apoptosis in tissues with regenerative capacity.Many age‐related diseases,for example macular degenertion and Parkinson’s disease,appear to have oxidative stress as an underlying componentthat interacts with genetic,dietary,and environmental factors to determine relative risk in an individual.Oxidative stress activates apoptosis,and antioxidants protect against apoptosis in vitro;thus,a central role of dietary antioxidants may be to protect against apoptosis.However,little in vivo data are available to directly link diet with altered apoptosis as an underlying determinant of disease.

　Moreover,the possible antagonistic effects of different dietary components and the uncertainty about whether proapoptotic compounds that may protect against cancer could contribute to degenerative diseases and vice versa indicate that there is a great need for better in vivo assessment of apoptosis and that caution should be exercised when extrapolating in vitro data on apoptosis to in vivo dietary recommendations.

Watson WH,Cai J,Jones DP:Annu Rev Nutr 20:485－505,2000

Recommended dietary allowances（RDAs）for genomic stability.

　Diet as a key factor in determining genomic stability is more important than previously imagined because we now know it impacts on all relevant pathways,i.e. exposure to dietary carcinogens,activation／detoxification of carcinogens,DNA repair,DNA synthesis and apoptosis.Current recommended dietary allowances for vitamins and minerals are based largely on the prevention of diseases of deficiency such as a scurvy in the case of Vitamin C.Because diseases of development,degenerative discase and ageing itself are partly caused by damage to DNA,it seems logical that we should focus better our attention on defining optimal requirements of key minerals and vitamins for preventing damage to both nuclear and mitochondrial DNA.To date our knowledge on optimal micronutrient levels for genomicstability is scanty and disorganised.Appropriately designed placebo,controlled trials are required to define recommended dietary allowances for genomic stability.Recently,it has been shown that above RDA intakes of folic acid and Vitamin B12 are required to reduce the micronucleus index in humans by ２５％.In the future,clinical trials with a defined wider array of complementary DNA damage end‐points would be necessary.That there is a need for an international collaborative group to establish RDAs for genomic stability is self‐evident and this paperis a call for such a process to begin.

Fenech M.Mutat Res 480－1:51－4,2001

Enteral feeding decreases gut apoptosis,permeability,and lung inflammation during murine endotoxemia.

　We tested the hypothesis that endotoxemia and fasting are associated with increased gut apoptotic activity,gut permeability,and inflammation in a distant organ.Fed or fasted CD－１ mice were studied ６h after intraperitoneal injection of either saline （sham） or endotoxin （４mg／kg of ０１１１:B４ Escherichia coli lipopolysaccharide）.We found that endotoxin increased gut caspase－３ and －６ activity by ４．９＋／－０．６－ and ４．５＋／－０．５－ fold,respectively （P＜０．００１）,and increased terminal deoxynucleotidyltransferase‐mediated dUTP nick‐end labeling（TUNEL） staining of mucosal cells （P＜０．０５）.Feeding decreased caspase－３ activity by ４０％（P＜０．０５） and decreased endotoxin‐induced TUNEL staining （P＜０．０５）.Endotoxin increased gut poly （ADP‐ribose） polymerase activity by １５％ （P＜０．０５）.Endotoxin increased gut permeability by ４４％ （P＜０．０５）,an effect reduced ３６％ by feeding （P＜０．０５）.Similarly,endotoxin increased pulmonary neutrophil infiltration （６．０＋／－１．０－fold,P＜０．００１） and increased lung interleukin （IL）－６ （５．９＋／－０．１－fold,P＜０．００１） and macrophage inflammatory protein （MIP）－２ expression （２９０＋／－４０－fold,P＜０．００１）,whereas feeding decreased this effect by ４３％ for neutrophils,４０％ for IL－６ （P＜０．０５）,and ３５％ for MIP－２ （P＜０．０５）.Thus endotoxin increases gut apoptotic activity,gut permeability,and pulmonary inflammation.Enteral feeding may decreast the distant organ inflammation by reducing gut apoptosis,thereby maintaining gut mucosal function during endotoxemia.

Alscher KT,Phang PT,McDonald TE,Walley KR:Am J Physiol Gastrointest Liver Physiol 281(2):G569－76,2001

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