2009 Group 8 Project

From CellBiology

CELL DEATH: NECROSIS

Introduction

Necrosis, derived from the Greek word neckros for ‘corpse’, is a type of irreversible and pathological cell death. It is mainly caused by early plasma membrane rupture , mitochondrial dysfunction, cell injury, infarction, inflammation and lysosomal rupture . There are several patterns of necrosis classified based on morphological criteria, including coagulative necrosis, liquefactive necrosis, caseous necrosis, fibrinoid necrosis and fat necrosis. Unlike apoptosis, necrosis is considered as uncontrolled, however current research suggests that this perhaps may not be the not the case.

History

[1]

  • 1858 – cell death was first discussed in a lecture given by Rudolf Virchow, a German pathologist and biologist. He termed it “necrobiosis” which is described as “degeneration, softening, necrosis, and mortification” [2]
  • 1877 – Carl Weigert and Julius Cohnheim identified coagulation necrosis - a white infract produced in cell death.
  • Up until 1971, the term “necrosis” was used for all types of cell death.
  • 1971 – the definition of cell death is modified to include a distinction between pathological and non-pathological forms.
  • In 1971 Kerr et al. first observed a form of non-pathologic cell death in certain tissues,terming it ‘shrinkage necrosis’.[3]Necrosis’ now refers to pathological forms of cell death.
  • 1972 - ‘Shrinkage necrosis’ is renamed ‘apoptosis’ as it became implicated in the control of organ homeostasis (Kerr et al. 1972). [4]The two basic types of cell death were now termed apoptosis, defined as a non-pathological, ‘programmed’ form of cell death, and necrosis, defined as a pathological, non-programmed form of cell death.
  • Nomenclature Committee on Cell Death 2009: necrosis is defined as being ‘morphologically characterized by a gain in cell volume (oncosis), swelling of organelles, plasma membrane rupture and subsequent loss of intracellular contents’[5]
  • Today there is increasing evidence to suggest that necrosis may not be just an accidental uncontrolled form of cell death. It is thought that necrosis may in fact controlled by various signal transduction pathways and catabolic mechanisms eg Toll-like receptors and death domain receptors


Apoptosis vs Necrosis

Apoptosis is under genetic control, requires ATP and is regulated by a variety of cellular signaling pathways. In apoptosis, the cell shrinks and becomes denser. Karyohexis, or breakdown of the nucleus, takes place. The DNA degenerates and chromosomal DNA is cleaved into internucleosomal fragments. The apoptotic cell divides into many parts by "budding", forming what are known as 'apoptotic bodies' surrounded by an intact plasma membrane, containing cell organelles and nuclear materials. These bodies are phagocytosed by neighbouring cells.


Necrosis is not a programmed cell death and is considered to be uncontrolled. It can be initiated accidentally by ischaemia, trauma or ATP depletion. No apoptotic bodies are formed. The plasma membrane integrity is not maintained in necrosis; the necrotic cell explodes and releases its cellular contents, including lysosomal enzymes, into the extracellular space. This cellular leakage triggers an inflammatory response. Necrosis is also known as caspase-independent cell death - caspases are not involved in this type of cell death and also no ATP is required.

The differences in apoptotic and necrotic death illustrated in the table below can be viewed in this animated video

Hand-drawn diagram


Apoptosis vs Necrosis
Apoptosis Necrosis
Regulation genetic programmed ischemia,trauma or ATP depletion
Control controlled uncontrolled
Cell sharp skrinkage, condensed swelling
Plasma membrane integrity maintained collasped
Cellular process budding blebbing
Cellular content packaged in apoptoic bodies leakage to extracellular fluid
DNA fragmentation, chromatin condensation no fragmentation
Energy ATP required not required
Inflammatory response absent present
Mediator caspase caspase-independent


[6] [7]


Cellular Processes

The term ‘necrosis’ is used for the presence of dead tissues or cells and is the total of the transformations which have occurred in cells after they have died. It is currently thought to be a type of cell death that is accidental as opposed to programmed. Necrosis this therefore thought of as a passive form of cell death because it does not require the complex regulatory mechanisms such as protein synthesis that are characteristic of programmed cell death. In addition to this, the process of necrosis has minimal energy requirements, whereas cell death by apoptosis requires energy in the form of ATP.

Figure 1. Condensed chromatin and dilated organelles of necrotic cells


Ultrastructural level

The full process of necrosis is complete only after 12-24 hours. Therefore, cells are dead long before any necrotic changes can be seen through a light microscope. Necrosis, therefore, refers to morphological features noticed after a cell has already died and attained equilibrium with its surroundings. In general, the death of a cell is accompanied by severe swelling, distension of organelles, condensed nuclear chromatin, “plasma membrane endocytosis and autophagy” [8]. However, the morphology of cells that are dying is fairly diverse. Necrosis is typified by rapid cell swelling and eventually full lysis of the cell. The cell membrane becomes permeable fairly early in the course of necrosis with loss of cell membrane integrity and the subsequent leakage of cytoplasmic contents and generation of an inflammatory response. This specific form of cell death is also characterised morphologically by intracellular swelling with the dilated organelles (Figure 1.) and the ribosomes dissociating from the endoplasmic reticulum (Ziegler & Groscurth, 2004). Clarke (1990) defined two different types of necrosis based on morphology and involvement of lysosomes, one being autophagic and the other being nonlysosomal disintegration [9] . Autophagic cell death is characterised by “numerous vacuoles in the cytoplasm filled with cellular remnants". The nonlysosomal cell death displays characteristic dilation of organelles and formation of unfilled spaces with degeneration proceeding without any measureable participation of lysosomes.

Figure 2: Morphology of necrosis

Detection of necrotic cells employs the distinguishing characteristic of a loss of cell membrane integrity. This subsequently allows the passage of small charged molecules that would not normally traverse the membrane and enter the cell.


Changes in the nucleus

The nucleus is one major cell feature that disintegrates late in the process of necrosis. The morphological changes that occur within the nucleus however, can be observed over time. The nuclear changes appear in three patterns (as indicated above) and all due to nonspecific breakdown of DNA.


The first pattern is identified as karyolysis. This is essentially the fading of basophilia of the chromatin which results in the dissolution of the nucleus by action of deoxyribonucleases. The second pattern is pyknosis, characterised by nuclear shrinkage and condensation of the nucleus which is mainly due to increased basophilia. In the third pattern, karyorrhexis, the nucleus which has already undergone pyknosis then undergoes fragmentation. Over time, the nucleus eventually disappears. However, pyknotic and fragemented nuclei although observable, are not a common feature in necrotic cell death [10].


Causes

A cell may undergo two different processes (below) leading to necrosis.

  • Primary necrosis: characterized by external chemical and physical damage to the cell.
  • Secondary necrosis: occurs in late apoptotic cells which fail to be engulfed by macrophages. Cells are not phagocytosed and thus lose membrane integrity, cease to be metabolically active and release their cytoplasmic content out into the extracellular matrix, or if in vitro, into the culture medium.

Primary necrosis is triggered through unregulated processes of membrane and cytosolic destruction under extreme conditions. These extreme conditions/stresses arise from various bacterial toxins and viruses, inadequate secretions of cytokines, nitric oxide and reactive oxygen species and calcium cytotoxicity. These will be discussed below

1. Mitochondrial Dysfunction and Reactive Oxygen Species (ROS)

  • Mitochondrial dysfunction is one of the major causes of necrosis due to ATP depletion. The mitochondria is a site of cellular oxygen consumption and responsible for generating ATP by oxidative phosphorylation. Insufficient oxygen supply to the cell causes the uncoupling of oxidative phosphorylation and the mitochondria cannot generate ATP.
  • As a consequence of energy depletion, the maintenance of the cell membrane potential is neglected. Early depolarization leads to excitotoxicity through excessive upregulation of glutamate and an increase in intracellular calcium concentration. At the early stage of oxygen deprivation, there is a formation of protrusions on the plasma membrane called blebs causing the cell to swell. Once the plasma membrane with blebs disrupts, the cell necrosis is irreversible. Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death
  • In the case of ischaemia, the lack of oxygen causes an increase Ca2+. In prolonged ischaemia, the Ca2+ overloaded mitochondria produce oxygen free radicals (OFR) such as superoxide, singlet oxygen and hydroxyl radicals. These OFR react with proteins and lipids inside the cell and form oxidized protein and peroxidised lipids which then disrupt the membrane structure. Recovery from ischaemia by reintroduction of oxygen will not prevent the formation of OFR but will cause an excess production of OFR leading to a worse condition. A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress

[11] [12]

2. Control of intracellular calcium

The endoplasmic reticulum is the major Ca2+ store for the cell and its regulated release of calcium is important for cellular signalling. Ca2+ is a stimulator of oxidative phosphorylation in the mitochondria. Mitochondrial calcium overload will cause an elevated flow of electrons to the electron transport chain resulting in increased levels of ROS. If the electron transport chain is not functioning well, there will be a decrease in the energy levels of the cell.

This depletion is further enhanced during oxygen deprivation in ischaemia.

  • The cell begins to use its glycogen stores anaerobically when energy levels are too low.
  • This causes acidosis and a further increase in Ca2+ influx into the cell.
  • Elevated increase in calcium will overstimulate oxidative phosphorylation and increase ROS.
  • ROS will disrupt the mitochondrial inner membrane and result in further loss of energy.
  • Transmembrane ion transport will slow down and cause an increase cell membrane permeability and thus a loss in the homeostasis of K+, Na+ and Ca2+ ions.
  • Now that the cell is severely deprived of ATP, the mitochondria and other organelles will swell and burst causing cell lysis; a characteristic feature of necrosis.

3. Proteases and necrosis

Proteases are considered the “executioners” of cell death because once a proteolytic cascade is set in motion, death is the only outcome. There are a variety of proteases that are involved in necrosis.

  • a) Cytosolic cysteine proteases (Caspases and Calpains)
  • b) Lysosomal proteases (Cathepsins)


a) Cytosolic Cysteine Proteases

Diagram: causes
  • Caspases

Caspases are cysteine proteases that are produced as inactive proteases called "zymogens" and are activated both during necrotic and apoptotic cell death. Mitochondrial damage due to excessive intracellular calcium and the release of cytochrome c and OFR can lead to the activation of caspases. Once activated, they proteolytically cleave a large range of cellular targets leading to cell death. In necrosis, caspases mediate the degradation of calpastatin and thus activate calpain proteases.

  • Calpains

Calpains are calcium dependent cysteine proteases that perform only a limited amount of proteolytic cleavage of cellular substrates. There are two main isoforms of calpains, Calpain 1 and Calpain 2, that have different sensitivity to calcium concentrations. An acute increase in the intracellular calcium concentration will trigger calpain activation leading to cleavage of cytoskeletal proteins.

During an event of extreme intracellular calcium, Calpains localise to the lysosomal membrane and cathepsins spill out into the cytoplasm catastrophically cleaving regulatory and structural proteins. Calpains then cleave the Na+/Ca2+ exchanger which functions to extrude Ca2+ from the cell further inceasing calcium levels and thus overactivating calpains. Calpain activation is prominently seen in neuronal cell necrosis.

More information on Calpains and their role in necrosis can be found on this student page: Calpains


b) Lysosomal proteases

  • Cathepsins

Cathepsins are lysosomal proteolytic enzymes that are also synthesized as inactive zymogens called "procathepsins". Cathepsins are localized in the lysosomal compartments of the cell traveling from the Golgi apparatus. With the right signaling, cathepsins are activated and released from these lysosomal compartments to begin their role of degrading extracellular matrix proteins such as collagen, laminin and elastin. Cathepsins can be divided into

  • Aspartic Cathepsins (Cathepsin D and E)
  • Cysteine Cathepsins (Cathepsin B, C, H, L, and S)
  • Serine Cathepsins (Cathepsin A and G)

Cathepsin activation and release is also highly dependent on intracellular Ca2+ concentrations. Elevated Ca2+ levels cause an overactivation of calpains which in turn cause lysosomal disruption. Lysosomal disruption will cause the release of cathepsins, particularly Cahtepsin B and Cathepsin L which degrade structural proteins in the cell.

[2] [13] [14] [15] [16] [17]

Patterns of Necrosis

[18] [19]

As a result of necrotic cell death, the affected tissues or organs display morphological changes. Based on this morphology, necrosis can be categorized into several distinct types or patterns. Such types, when observed at both the gross and microscopic level, can provide pathologists and clinicians with clues about its underlying cause.

Coagulative necrosis

Figure 3: Coagulative necrosis in the liver

Coagulative necrosis is the most common pattern of necrosis occurring in tissues or organs. Its morphological pattern is primarily a consequence of protein degradation frequently caused by ischemia where lack of oxygen causes cell death in a localized area. Coagulative necrosis can occur in all tissues, except the brain (liquefactive necrosis is the pattern observed here) and is characteristic of infarcts in solid organs, for example a myocardial infarction in the heart or a renal infarct in the kidney.


The gross morphology of an area of coagulative necrosis is observed as being a pale yellow-whitish colour with diminished transparency compared to the surrounding non-affected areas which have a good vascular supply. Initially foci may be swollen due to an inflammatory response elicited by the necrotic cells which release inflammatory factors such as cytokines and interleukin-2. Later the tissue becomes very firm.


When observed under a light microscope, the microscopic morphology of coagulative necrosis shows that despite the cells are dead and anucleate their basic cell shape, or ‘ghost’ outline (a term commonly used to describe their appearance), remains preserved for several days. An acute inflammatory response develops and this too is observable under the microscope with an influx of phagocytic leukocytes such as macrophages which remove the necrotic cells.


Provided there is an adequate amount of labile cells around the affected tissue, regeneration of this tissue can occur. Labile cells which are constantly dividing can replicate and replace the cells that were killed to restore the tissue back to normal. This is in contrast to stable or permanent cells (eg cardiac myocytes) which are not constantly replicating and so will not replace the affected tissue. Healing by fibrosis therefore follows, first with granulation tissue which is eventually replaced by fibrosis after a few months. During this time, fibroblasts can be microscopically observed in the affected tissue and the fibrosis is attributable to the firm gross appearance observed on the organ.

Thus the end result of this necrosis is a whitish-yellow area of firm tissue and a histological structure barely recognizable to the original.


Liquefactive necrosis

Figure 4: Liquefactive necrosis in the brain

Liquefactive necrosis is a pattern of necrosis which occurs as a consequence of enzymatic degradation. This is in contrast to coagulative necrosis which occurs as a result of protein degradation.


Liquefactive necrosis typically occurs in tissues which have a high lipid content, particularly the brain. Mentioned previously, whilst hypoxic cell death in most tissues normally results in coagulative necrosis, this pattern of necrosis is not usually typical to tissue in the central nervous system. Because these tissues have little structural framework, hypoxic cell death as in a cerebral infarct for example, results in disintegration of the necrotic cells and ultimately, transformation of the affected tissue into a liquid viscous mass. By taking a section through the brain, the macroscopic appearance of the liquefactive necrosis typically reveals the affected tissue to be gelatinous-looking. Microscopically, the tissue is edematous, with the neurons undergoing chromatolysis, with loss of cytological detail. An infiltrate of neutrophils, shortly replaced by macrophages, can also be observed, as well as microglia, phagocytes of the central nervous system. Removal of the necrotic cells is usually seen after two weeks concurrent with the repair process which is termed gliosis. A gross examination of the brain will now show destruction where the necrosis was and surrounding gliosis.


Liquefactive necrosis is also observed within abscesses caused by focal bacterial, and sometimes fungal, infections. Such bacterial or fungal infections result in the migration of polymorphonuclear leukocytes, specifically neutrophils and macrophages, to the site of insult. The leukocytes release enzymes to eliminate the offending microbes; however this comes to the detriment of the surrounding tissue which is also enzymatically digested, and the tissue is transformed into a viscous liquid material. Whenever liquefactive necrosis is caused by acute inflammation, the ‘liquefied’ tissue characteristically has a creamy-yellow colour and is called pus.


Caseous necrosis

Figure 5: Caseous necrosis in the kidney

Caseous necrosis is a form of necrosis characteristic of mycobaterial infections and is most commonly observed in tuberculosis lesions. The term ‘caseous’ (meaning cheese-like) arises from the gross morphology of the necrotic tissue, described to resemble crumbly yellow-white cottage cheese.


A microscopic examination of the necrotic area shows the architecture of the affected tissue to be completely destroyed: the cells are fragmented or lysed and have an amorphous and granular appearance. This is in contrast to the microscopic morphology of coagulative necrosis, where despite the cells being dead, the tissue architecture is preserved. Often the lesion is observed microscopically as a granuloma whereby there a focal area of necrosis is surrounded by a distinct inflammatory border. The granuloma comprises four recognisable layers; it has a centre of caseous necrosis which is surrounded by a layer of giant and epithelioid cells (activated macrophages). The third layer consists of leucocytes and the outer layer is a layer of fibrosis.


Fibrinoid necrosis

Figure 6: Fibrinoid necrosis of polyarteritis nodosa in arteries of the kidney
Fibrinoid necrosis is a type of necrosis that occurs specifically in blood vessels. It is associated with injury often caused by immunologically mediated reactions to blood vessels by the formation of immune complexes in the circulation. Immune complexes, which are essentially complexes of an antigen and an antibody, are deposited on the walls of blood vessels, along with fibrin, which leaks out from the blood vessels. These depositions result in its characteristic fibrinoid (or ‘fibrin-like’) appearance when viewed under the light microscope. Fibrin is easily identified by the fact it stains brightly with eosin. Following deposition of the immune complexes, an inflammatory response ensues with attempted phagocytosis of the immune complexes. The immune complexes can in addition cause platelet aggregation which enhances the inflammatory response and also initiates the formation of microthrombi contributing to local ischemia. This process can consequently culminate in the characteristic fibrinoid necrosis.

Polyarteritis nodosa, manifested by systemic vasculitis, is an example of a disease in which fibrinoid necrosis is observed.


Fat necrosis

Figure 7: Fat necrosis of the mesentery

Fat necrosis is another type of necrosis, which like fibrinoid necrosis, occurs in specific tissues. As the name suggests, fat necrosis occurs in tissues with a high lipid content and is primarily characterised by focal areas of fat destruction. It is usually caused by acute pancreatitis (inflammation of the pancreas) or by direct physical trauma to fat (for example as a result of surgery or by a physical blow).


The necrosis is ultimately due to the release of pancreatic lipases (enzymes that digest fat) out of the acinar cells and ducts of the pancreas and into the peritoneum. Here the lipases act on adipose tissue, particularly fat cell membranes, splitting triglyceride esters and causing free fatty acids to be released. The fatty acids may then combine with calcium to produce white-chalky deposits. This is called fat saponification and is visible at a gross level. A microscopic view of fat necrosis shows the shadowy outline of the adipocytes (fat cells) with a surrounding inflammatory reaction that is similar to coagulative necrosis but has the extra addition of calcium deposits.

Detection of tissue-specific necrosis

Leakage of intracellular proteins out of the necrotic cell provides a means in which tissue-specific necrosis can be detected for clinical purposes via blood or serum samples. Such is reflected by increased levels of these proteins in the blood/serum. For example, cardiac muscle contains a unique isoform of troponin, a contractile protein. Detection of it in the blood is widely used in the diagnosis of myocardial infarction (otherwise known as a heart attack).


Necrosis: Programmed Cell Death?

Until recently necrosis has largely been regarded as ‘unprogrammed’ cell death due to the fact that the death of the cell is due to extrinsic events occurring beyond its control, such as ischaemia or chemical injury . However, rather than occurring by accident, increasing evidence suggests that necrosis may perhaps involve a regulated program like apopotosis whereby cellular signaling pathways initiate it in response to specific cues.


For example, a study by Luke et al. in 2007 An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injuryfound that SRP-6 in Caenorhabditis elegans (a nematode worm which is used as a model eukaryotic organism) protected against necrosis caused by lysosomal injury. In addition, it also blocked necrosis triggered by heat shock, oxidative stress, hypoxia, and cation channel hyperactivity. The authors of the study concluded that 'multiple noxious stimuli converge upon a peptidase-driven, core stress response pathway that, in the absence of serpin regulation, triggers a lysosomal-dependent necrotic cell death routine'. [20]


Links to student pages

The links to the student pages are incorporated into the group assignment. Here are the links for easy access


Glossary

Abscess - a localised collection of pus

Eosinophilia - increased numbers of eosinophils circulating in the blood

Fibrosis - the extensive deposition of connective tissue, particularly collagen, in an organ or tissue, that occurs as a part of the reparative process after substantial tissue destruction

Gliosis - the process of repair and scar formation in the brain

Granuloma - a focal collection of chronic inflammatory immune cells which forms when the immune system tries to wall of foriegn material but cannot eliminate. Necrosis is often found within the centre of a granuloma

Hypoxic - an oxygen deficiency to the tissues or organs of the body

Infarct - a circumscribed area of necrosis in a tissue or organ resulting from obstruction to blood flow

Inflammation - a local response to cellular injury that serves as a mechanism to eliminate noxious agents and of damaged tissue and protect from further injury; may be acute or chronic - however when unqualified the term usually tends to refer to acute inflammation which is characterised by vascular dilatation, leukocyte infiltration, redness, heat, pain, swelling, and often loss of function

Ischaemia - a state occurring when there is an insufficient supply of blood to a tissue or organ

Karyolysis – dissolution of the nucleus by action of deoxyribonecleases

Kayorrhexis – fragmentation of the nucleus

Leukocyte - a white blood cell

Macrophages - phagocytic white blood cells that function in the destruction of foreign antigens, including microbes, as well as the removal of necrotic debris. They also function as antigen-presenting cells

Microthrombi - small thrombi. A thrombus is a solid or semi-solid mass derived from the constituents of blood within a blood vessel and remains attached to the place in which it was formed

Morphology - the structure of a tissue or organ; can be described at macroscopic(gross) and microscopic levels

Necrosis - a type of cell death 'morphologically characterized by a gain in cell volume (oncosis), swelling of organelles, plasma membrane rupture and subsequent loss of intracellular contents'

Neutrophils - are described as polymorphonuclear granulocytic white blood cells, in that they have a multi-lobed nucleus and a granulocytic cytoplasm. These cells function as phagocytes, capable of ingesting microbes and particulate matter. They are also one of the first cell types to be seen at a site of acute inflammation

Phagocytosis - the engulfment, ingestion and usually destruction of particulate or foreign matter by phagocytic cells

Proteases - Enzymes that hydrolyse peptide bonds and are highly involved in the degradation of the cell

Pus - a thick yellowish white semi-fluid matter consisting of both necrotic and living neutrophils, exudate, microbes and tissue debris

Pyknosis – condensation and skrinkage of the nucleus

Zymogens - Inactive enzyme precursor that requires a biochemical change to be activated. They are synthesised to protect the cell from unwanted enzymatic activity. They are activated only when required



References

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  3. Kerr, J.F. 1971. Shrinkage necrosis: A distinct mode of cellular death. J. Pathol. 105: 13–20. PMID: 4108566
  4. Kerr, J.F., Wyllie, A.H., and Currie, A.R. 1972. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26: 239–257.PMID: 4561027
  5. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G; Nomenclature Committee on Cell Death 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009 Jan;16(1):3-11. Epub 2008 Oct 10. PMID: 18846107
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  8. Syntichaki P, Tavernarakis N. (2002) Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos? EMBO Rep. Jul;3(7):604-9. [1] PMID: 12101090]
  9. Clarke PG. (1990) Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl).;181(3):195-213. Review. [2] PMID: 2186664
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  11. Lemasters JJ, Qian T, Bradham CA, Brenner DA, Cascio WE, Trost LC, Nishimura Y, Nieminen AL, Herman B. Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death.J Bioenerg Biomembr. 1999 Aug;31(4):305-19. Review. PMID: 10665521
  12. Huang Q, Wu YT, Tan HL, Ong CN, Shen HM. A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress. Cell Death Differ. 2009 Feb;16(2):264-77. Epub 2008 Oct 31. PMID: 18974775
  13. Chwieralski CE, Welte T, Bühling F. Cathepsin-regulated apoptosis. Apoptosis. 2006 Feb;11(2):143-9. Review.
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  19. http://www.uvm.edu/~jkessler/PATH301/301celli.htm#anchor14092699
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  • Power. C., Fanning Noel and Redmond. P. (2002), CELLULAR APOPTOSIS AND ORGAN INJURY IN SEPSIS: A REVIEW, Shock, 18(3),197-211


2009 Group Projects

Group 1 Meiosis | Group 2 Cell Death - Apoptosis | Group 3 Cell Division | Group 4 Trk Receptors | Group 5 The Cell Cycle | Group 6 Golgi Apparatus | Group 7 Mitochondria | Group 8 Cell Death - Necrosis | Group 9 Nucleus | Group 10 Cell Shape