Lecture 1.1a - Cell injury and cell death 1.pdf

Cell injury: ◦All cells have effective mechanisms to deal with mild changes in environmental conditions - this is homeostasis. ◦More severe changes in environment lead to cell adaptation, injury or cell death. ◦Depending on the nature and intensity of the injury, cells may respond w...

Cell injury: ◦All cells have effective mechanisms to deal with mild changes in environmental conditions - this is homeostasis. ◦More severe changes in environment lead to cell adaptation, injury or cell death. ◦Depending on the nature and intensity of the injury, cells may respond with an increased or decreased level of activity (e.g. hyperplasia and atrophy). ◦When cells reach the limits of their adaptive response they may show evidence of reversible injury or become irreversibly injured and die. ◦Degree of injury depends on: ‣ Type of injury ‣ Severity of injury ‣ Type of tissue ◦Cells can be hurt by many agents, but despite the many and varied things that can injure cells, they only have a limited number of ways to react. Reversible: ◦Swelling - both the cell and organelles due to Na+/K+ pump failure ◦Cytoplasmic blebs, which are symptomatic of cell swelling ◦Clumped chromatin due to reduced pH ◦Ribosome separation from the endoplasmic reticulum due to failure of energy-dependent process of maintaining ribosomes in the correct location. Irreversible: ◦Increased cell swelling ◦Nuclear changes - pyknosis, karyolysis or karyorrhexis ◦Swelling and rupture of lysosomes - reflects membrane damage ◦Membrane defects ◦The appearance of myelin figures (which are damaged membranes) ◦Lysis of the endoplasmic reticulum due to membrane defects ◦Amorphous densities in swollen mitochondria The cell injury response is part of a continuum: Cell injury: ◦Cell injury results when cells are stressed and can no longer adapt  Duration of injury: Which cell components are most susceptible to injury?: What kind of stimuli can cause injury?: ◦Hypoxia ◦Toxins ◦Physical agents: ‣ Direct trauma ‣ Extremes of temperature ‣ Changes in pressure ‣ Electric currents ◦Radiation ◦Micro-organisms ◦Immune mechanisms ◦Dietary insufficiency and deficiencies, dietary excess Hypoxia: ◦Hypoxia is a deficiency of oxygen that can result in a reduction in aerobic oxidative respiration. Extremely important common cause of cell injury/cell death. ◦Hypoxia vs ischaemia ◦Causes of hypoxia: ‣ Hypoxaemic hypoxia - arterial content of oxygen is low Reduced inspired pO2 at altitude Reduced absorption secondary to lung disease ‣ Anaemia hypoxia - decreased ability of haemoglobin to carry oxygen Anaemia  Carbon monoxide poisoning ‣ Histiocytic hypoxia - inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes Cyanide poisoning ‣ Ischaemic hypoxia - interruption to blood supply Blockage of a vessel Heart failure Hypoxic cell injury summary: ◦Cell is deprived of oxygen ◦Mitochondrial ATP production stops ◦The ATP-driven membrane ionic pumps run down ◦Sodium and water seep into the cell ◦The cell swells, and the plasma membrane is stretched ◦Glycolysis enables the cell to limp on for a while ◦The cell initiates a heart-shock (stress) response, which will probably not be able to cope if the hypoxia persists. ◦The pH drops as cells produce energy by glycolysis and lactic acid accumulates. ◦Calcium enters the cell ◦Calcium activates: ‣ Phospholipases, causing cell membranes to lose phospholipids ‣ Proteases, damaging cytoskeletal structures and attacking ‣ Membrane proteins ‣ ATPase, causing more loss of ATP ‣ Endonucleases, causing the nuclear chromatin to clump ◦The ER and other organelles swell ◦Enzymes leak out of lysosomes and these enzymes attack cytoplasmic components. ◦All cell membranes are damaged and start to show blebbing ◦At some point the cell dies, possibly killed by the burst of a bleb. Toxins: ◦Glucose and salt in hypertonic solutions ◦High concentration of oxygen ◦Poisons ◦Pollutants ◦Insecticides ◦Herbicides ◦Asbestos ◦Alcohol ◦Narcotic drugs ◦Medicines How does the immune system damage the body’s cells?: ◦Hypersensitivity reactions - host tissue is injured secondary to an overly vigorous immune reaction ‣ E.g. urticaria (= hives) ◦Autoimmune reactions - immune system fails to distinguish self from non-self  ‣ E.g. Grave’s disease of thyroid Other methods of cell injury: ◦Sequence of events for other injuries may be different but as the cell has a limited response to injury , outcome is often similar. ‣ Other forms of injury might attack different key structures, e.g. extreme cold (frostbite) damages membranes initially ‣ Free radicals also damage membranes Ischaemia-reperfusion injury: ◦If blood flow is returned to a tissue which has been subject to ischaemia but isn't yet necrotic, sometimes the injury that is then sustained is worse than if blood flow was not restored. This is called ischaemia-reperfusion injury. It may be due to: ‣ Increased production of oxygen free radicals with reoxygenation as a result of a burst of mitochondrial activity. ‣ Increased number of neutrophils following reinstatement of blood supply resulting in more inflammation and increased tissue injury. ‣ Delivery of complement proteins and activation of the complement pathway. What are free radicals?: ◦Reactive oxygen species ◦Single unpaired electron in an outer orbit - an unstable configuration hence react with other molecules, often producing further free radicals: ‣ OH* (hydroxyl radical) ‣ O2*- (superoxide) ◦Free radicals are particularly produced in chemical and radiation injury, ishaemia-reperfusion injury, cellular ageing and at high oxygen concentrations. They: ‣ Attack lipids in cell membranes and cause lipid peroxidation ‣ Damage proteins, carbohydrates and nucleic acids ‣ Are mutagenic When are free radicals produced?: ◦Normal metabolic reactions e.g. oxidative phosphorylation ◦Inflammation - oxidative burst of neutrophils ◦Radiation: H20 -> OH* ◦Contact with unbound metals within the body - iron (by Fenton reaction) and copper ‣ Free radical damage occurs in haemachromatosis and Wilson’s disease ◦Drugs and chemicals - e.g. In the liver during metabolism of paracetamol or carbon tetrachloride by P450 system How does the body control free radicals?: ◦Anti-oxidant scavengers - donate electrons to the free radical (vitamins A,C and E) ◦Metal carrier and storage proteins (transferrin, ceruloplasmin) - sequester iron and copper ◦Enzymes that neutralise free radicals: ‣ Superoxide dismutase (SOD) ‣ Catalase ‣ Glutathione peroxidase How do free radicals injure cells?: ◦If the number of free radicals overwhelms the anti-oxidant system = oxidative imbalance ◦Most important target are lipids in cell membranes  ‣ Cause lipid peroxidation ‣ This leads to generation of further free radicals -> autocatalytic chain reaction ◦Also oxidises proteins, carbohydrates and DNA ‣ These molecules become bent out of shape, broken or cross-linked ‣ Mutagenic and therefore carcinogenic How else can the cell protect itself against injury?: What do injured and dying cells look like under a microscope?: How can we diagnose cell death?: ◦Dye exclusion assays ◦The diagnosis of cell death in short time is best measure on their functional capability rather than morphological criteria e.g. increased permeability of the cell membrane