小中大 Apoptosis<br><br>I. Introduction- Apoptosis is a form of cell death resulted from the activation of intracellular self-destruction biochemical programs. Multicellular organisms including human use these self-destruction mechanisms to sculpt functional organs during development. In adult organism, apoptosis is used to maintain a relatively constant number of cells in a given tissue so that the proliferation of new cells from stem cells going through the cell cycle is countered by a selective removal of damaged, infected, or oncogenic cells. The process occurs so cleanly and fast that it was overlooked by biologists for years. Despite delayed recognition, apoptosis is now seen as an essential basic system for complex multicellular organisms and plays important roles in the progression and the prevention of human diseases.<br><br>II. Overview of apoptosis- (Greek term for leaves falling from the tops of trees)<br>A. Apoptosis vs. Necrosis<br>1. Necrosis is a destructive form of cell death due to physical injury, ischemic infarct or bacterial toxins. The release of cellular contents causes a local inflammatory reaction<br>2. Apoptosis is a programmed or intentional form of cell death. Distinct morphological changes allow the cell to be phagocytosed by other cells without leaking cytoplasmic contents or causing an inflammatory reaction.<br>B. Physiologic functions<br>1. Eliminating damaged cells-apoptosis is a natural response of cells that encounter un-repairable damage such as excessive DNA lesions.<br>2. Tissue homeostasis-parallels cell division to maintain even cell number.<br>3. Removal of unwanted immune cells- massive numbers of immune cells are produced against a challenge, but most of them have to undergo apoptosis once the antigen is gone. Failure to undergo apoptosis may result in auto-immune disease.<br>4. Neural development- a surplus of neurons competes for target sites and growth factors; cells that do not find an appropriate target die by apoptosis. Failure of neuronal cell death may cause spina bifida and cranioschesis.<br>5. Regression of embryonic structures- apoptosis removes cell structures that are no longer necessary- such as the primitive kidney, or the Mullerian duct in a male or to sculpt body structure such as by removing the cells between the fingers.<br><br>C. Morphological changes to apoptotic cells- the program causes a rapid set of events that insures the cell will rapidly cease functioning, destroy any potentially harmful genetic information, and to package the cell to be quietly cannibalized by its neighbors and macrophages.<br>1. Cell shrinkage<br>2. Membrane blebbing<br>3. Nuclear membrane breakdown<br>3. Chromatin condensation<br>4. DNA fragmentation- cut into a distinct ladder by cutting between nucleosomes<br>5. Flipping of phosphatidylserine (PS) from inside to outside of plasma membrane that serves a signal for phagocytosis.<br>6. Release of apoptotic bodies- bite size fragments in membrane bound vesicles for neighboring cells to phagocytose and dispose of. Cellular contents are never leaked into bloodstream.<br><br>III. Cell Death Machinery-There are two best-defined apoptotic pathways cells use to carry out their death wish. One started at the cell surface by the activation of cell death receptors including Fas/CD95 and tumor necrosis factor receptor, TNFR. These receptors receive death signal from outside. Protein factors such as Fas ligand and TNF bind to their receptors and initiate a pathway that leads to apoptosis. Another apoptotic pathway starts from mitochondria. Intracellular apoptotic signals such as excessive DNA damage, growth factor deprivation, metabolic imbalance, and ischemic condition, can trigger the activation of this pathway through mitochondria. <br><br>A. Caspase Proteases- the proteases that execute apoptosis. Cas
