Presentation on theme: "Leicester Warwick Medical School"— Presentation transcript:
1Leicester Warwick Medical School CELL INJURYDr Gerald SaldanhaDept of Pathology
2Introduction This presentation will…… be a guide to cell injury and cell deathoutline causes and pathogenesis of cell injury/deathdescribe the morphological changes of cell injury/deathDescribe the process of apoptosis
3Introduction General considerations…… Adapt or die! Reaction patterns in a given cell/tissue is often limitedDegree of injury is a function of type, duration and severity of insult
4Types of insult - hypoxia IschaemiaLocal e.g. embolusSystemic e.g. cardiac failureHypoxaemiaOxygen problems e.g. altitudeHaemoglobin problems e.g. anaemiaOxidative phosphorylationE.g. cyanide poisoning
5Types of insult - chemical Many of the common poisons (arsenic, cyanide, mercury) interfere with cellular metabolism. If ATP levels drop below critical levels, affected cells will die.The list of pharmaceuticals that may have toxic effects on cells is enormous. Some act directly, but most have their effect through breakdown metabolites. Metabolism of alcohol (a type of drug) to acetaldehyde is one example.
6Types of insult - infections Fungi, Rickettsiae, Bacteria and VirusesE.g. viruses can take over protein translation machinery and subvert it entirely to the production of new virions.
7Types of insult - Physical Direct Physical EffectsExposure of tissue to extreme heat or cold results in direct injury that is often irreversible, resulting in a pattern of coagulative necrosis (see later).Sudden changes in pressure can cause cellular disruption (e.g. a hammer blow to the thumb).Electrical currents can cause direct breakdown of cellular membranes that may be irreversible.
8Types of insult –immune Inflammatory mediators such as interferons and interleukinscan alter both gene expression and cellular metabolism. The effects are designed to help cells combat an infectious process, but the resulting stress to the cells can be highly injurious and sometimes deadly.Activation of complementcan result in direct attack on a cell's surface membrane.Cytotoxic T-cells and NK cellscan mediate a direct attack on a target cell's and initiate the self-destruct cascade within a target cell.
9Types of insult - nutrition Dietary insufficiencyof protein, vitamins and/or minerals can lead to injury at the cellular level due to interference in normal metabolic pathways.Dietary excesscan likewise lead to cellular and tissue alterations that are detrimental e.g. fat is the biggest offender, or excess ingestion of "health supplements"
10Causes of cell injury - summary HypoxiaChemicalPhysicalInfectionImmuneNutritional deficiency (or excess!)
16Free radicals Free radical generation occurs by…. Absorption of irradiationE.g. OH•, and H•Endogenous normal metabolic reactionsE.g. O2-•, and H2O2Transition metalsE.g. Fe+++nitrous oxidean important paracrine-type mediator that helps regulate vascular pressureToxinse.g. carbon tetrachloride
17Free radicals Free radicals are removed by…. Spontaneous decay Anti-oxidantsE.g. Vitamin E, vitamin A, ascorbic acid, glutathioneStorage proteinsE.g. transferrin, ferritin, ceruloplasminEnzymesCatalase, SOD, glutathione peroxidase
18Free radicals Injure cells by….. Membrane lipid peroxidation Autocatalytic chain reactionInteraction with proteinsProtein fragmentation and protein-protein cross-linkageDNA damageSingle strand breaks (genomic and mitochondrial)
19General protective mechanisms Heat shock response genescomprise a large group of genesexpression is up-regulated in the face of cell stressors andserve to protect proteins from stress-related damage"clean up" damaged proteins from the cell.Many tissues and organs can survive significant injury if they are "pre-stressed"Ways to exploit this phenomenon to improve organ transplantation and tissue repairs are being tested in clinical trials.
23Necrosis Definition Patterns Death of groups of contiguous cells in tissue or organPatternsCoagulativeLiquefactiveCaseousFat necrosis(gangrene)(Infarct)Red/haemorrhagicWhite
24Coagulative necrosisCells have died but the basic shape and architecture of the tissue enduresMost common manifestation of ischaemic necrosis in tissues.Affected tissue maintains solid consistency.In most cases the necrotic cells are ultimately removed by inflammatory cells.The dead cells may be replaced by regeneration from neighboring cells, or by scar (fibrosis).
27Liquefactive necrosis Complete dissolution of necrotic tissue.Most commonly due to massive infiltration by neutrophils (abscess formation).Release of reactive oxygen species and proteasesLiquefaction is also characteristic of ischaemic necrosis in the brain.
29Caseous necrosisAccumulation of amorphous (no structure) debris within an area of necrosis.Tissue architecture is abolished and viable cells are no longer recognizable.Characteristically associated with the granulomatous inflammation of tuberculosis. Also seen in some fungal infections.
32Fat necrosisResults from the action of lipases released into adipose tissue.pancreatitis, trauma.Free fatty acids accumulate and precipitate as calcium soaps (saponification).These precipitates are grossly visible as pale yellow/white nodulesMicroscopically, the digested fat loses its cellular outlines. There is often local inflammation
34Gangrene ("gangrenous necrosis") Not a separate kind of necrosis at all, but a term for necrosis that is advanced and visible grossly.If there's mostly coagulation necrosis, (i.e., the typical blackening, desiccating foot which dried up before the bacteria could overgrow), we call it dry gangrene.If there's mostly liquefactive necrosis (i.e., the typical foul-smelling, oozing foot infected with several different kinds of bacteria), or if it's in a wet body cavity, we call it wet gangrene.
39Apoptosis - basicsis a distinct reaction pattern which represents programmed single-cell suicide.Cells actually expend energy in order to die.Derived from Greek "falling off" (as for autumn leaves)Apoptosis is "the physiological way for a cell to die", seen in a variety of normal situations.
40Apoptosis - morphology Necrosis:pathological response to cellular injury.Chromatin clumps, mitochondria swell and rupture, membrane lyses, cell contents spill, inflammatory response triggeredApoptosisDNA cleaved at specific sites bp fragments.Cytoplasm shrinks without membrane ruptureBlebbing of plasma and nuclear membranesCell contents in membrane bounded bodies, no inflammation
41Apoptosis - normalA stain for apoptotic cells in the developing paw of a foetal mouse.
42Apoptosis -pathological Graft-versus-host disease in colonic mucosa
43Apoptosis - triggers Withdrawal of growth stimuli Death signals E.g. growth factorsDeath signalsE.g. TNF and FasDNA damagep53 plays an important roleAll cells are equipped with the tools of their own destruction. The final common pathway in most instances of cell death involves the activation of cascades of cysteine-type proteases called caspaces. These cascades, which can be turned on through a variety of mechanisms, lead to the fatal destruction of proteins, lipids and nucleic acids, resulting in the irreversible signs of cell injury noted in the previous page.
44Apoptosis - mechanisms Extrinsic factorsE.g. by members of the TNF familyIntrinsic mechanismsE.g. hormone withdrawalThe two major pathways for caspase activation in mammalian cells are outlined. The extrinsic pathway (left) can be induced by members of the TNF family of cytokine receptors that are present at the surface of many cells. Upon activation, these receptors recruit adapter proteins to their cytosolic "death domains" (DD), including Fadd, which then bind and cleave pro-caspases, particularly pro-caspase-8. The intrinsic pathway (right) can be induced by various stimuli (discussed below), resulting in the release of cytochrome c from mitochondria. In the cytosol, cytochrome c binds and activates Apaf-1, allowing it to bind and activate pro-caspase-9. Active caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) have each been shown to directly cleave and activate the effector protease, caspase-3. Other caspases can also become involved in these pathways. The two pathways are not mutually exclusive; both may become activated in response to an insult. Thus, this schematic represents an oversimplification of the events that occur in vivo.
45Summary This talk has covered…. Causes of cell injury Cellular targets PathogenesisMorphology of cell injuryPatterns of necrosisApoptosis
46Final thought… Our lives are filled with joys and strife, And what is death but part of life?Will come the day that we must die,And leave behind those learning why.