{"id":6265,"date":"2026-05-27T21:20:25","date_gmt":"2026-05-28T01:20:25","guid":{"rendered":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/?post_type=chapter&#038;p=6265"},"modified":"2026-06-04T22:08:43","modified_gmt":"2026-06-05T02:08:43","slug":"cell-death-planned-and-unplanned","status":"web-only","type":"chapter","link":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/chapter\/cell-death-planned-and-unplanned\/","title":{"raw":"Section 7 Cell Death - Planned and Unplanned","rendered":"Section 7 Cell Death &#8211; Planned and Unplanned"},"content":{"raw":"<span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\">Cell death is a normal and essential part of life.\u00a0 However, not all cell death is the same.\u00a0 There are two fundamentally different types:\u00a0 <strong>planned cell death<\/strong> (apoptosis) and <strong>unplanned cell death<\/strong> (necrosis).\u00a0 Understanding the difference between them - and the conditions that trigger each - is central to understanding how disease affects the body.\u00a0 \u00a0\u00a0<\/span>\r\n<h3><span style=\"color: #1f5c99\"><strong>Apoptosis:\u00a0 Planned Cell Death<\/strong><\/span><\/h3>\r\n<span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Apoptosis<\/strong> (sometimes called programmed cell death) is a tightly regulated, orderly process in which aging or damaged cells are eliminated to make room for new, more functional ones.\u00a0 It is driven by an <strong>internal enzymatic cascade<\/strong> involving proteins called <strong>caspases,<\/strong> and it results in a clean, contained death that does not trigger inflammation.<\/span>\r\n\r\n<strong><span style=\"color: #2e75b6\">Apoptosis in Normal Life<\/span><\/strong>\r\n\r\nApoptosis is not a sign of disease - it is a routine, continuous process that keeps tissues healthy.\u00a0 Consider the following examples:\r\n<ul>\r\n \t<li><strong>Red blood cell (RBC) turnover:<\/strong>\u00a0 RBCs live approximately 120 days.\u00a0 Millions undergo apoptosis every day and are simultaneously replaced by new cells produced in the bone marrow.\u00a0 This balance keeps the RBC population stable.<\/li>\r\n \t<li><strong>Skin cell turnover: <\/strong> Skin cells replace themselves approximately every 30 days through a cycle of apoptosis and mitosis.\u00a0 Similarly, the epithelial cells lining the <strong>mucosa membranes<\/strong> of the <strong>respiratory<\/strong> and <strong>digestive tracts<\/strong> experience frequent turnover (every 30-50 days and every 3-5 days respectively).<\/li>\r\n \t<li><strong>Embryonic development: <\/strong> Apoptosis plays a critical role in shaping the body before birth.\u00a0 For example, the webbing between <strong>fingers<\/strong> and <strong>toes<\/strong> during fetal development is removed through apoptosis, sculpting the final form of the hands and feet.\u00a0 <strong>Heart<\/strong> development and the remodeling of other organs during fetal stages also rely on apoptosis.<\/li>\r\n \t<li><strong>Breast tissue remodeling: <\/strong> During pregnancy, breast tissue grows to support lactation.\u00a0 After breastfeeding ends, apoptosis returns breast tissue to its pre-pregnancy size.<\/li>\r\n<\/ul>\r\nNote that some cell types - particularly neurons - do not undergo ongoing turnover.\u00a0 After birth, the number of neurons a person has is largely fixed for life, which is one reason that neurological damage can be so significant.\r\n\r\n<strong><span style=\"color: #2e75b6\">Triggers of Apoptosis<\/span><\/strong>\r\n\r\nWhile apoptosis is normal, it can also be triggered by a variety of stressors.\u00a0 Triggers are classified as either <strong>extrinsic<\/strong> (coming from outside the cells) or <strong>intrinsic<\/strong> (arising from within the cell):\r\n<table class=\"grid landscape\" style=\"border-collapse: collapse;width: 100%;height: 30px\" border=\"0\">\r\n<tbody>\r\n<tr style=\"height: 15px\">\r\n<td class=\"border\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Extrinsic triggers<\/strong><\/span><\/td>\r\n<td style=\"width: 82.0463%;height: 15px\"><strong>Bacterial LPS<\/strong> (lipopolysaccharide):\u00a0 A component of the bacterial cell membrane that activates a 'death receptor' on the surface of human cells initiating the caspase cascade.\r\n\r\nSome <strong>pro-inflammatory cytokines<\/strong> released by White Blood Cells can also activate the 'death receptor' stimulating the apoptotic enzyme cascade, providing an important defence mechanism against pathogens that have infected cells.<\/td>\r\n<\/tr>\r\n<tr style=\"height: 15px\">\r\n<td class=\"shaded\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Intrinsic triggers<\/strong><\/span><\/td>\r\n<td class=\"shaded\" style=\"width: 82.0463%;height: 15px\"><strong>Reactive Oxygen Species (ROS)<\/strong> increased levels\r\n\r\n<strong>DNA damage<\/strong>\r\n\r\n<strong>Hypoxia<\/strong> (low oxygen \/ low ATP)\r\n\r\n<strong>Senescence<\/strong> (cellular aging)\r\n\r\nAll of these activate the intrinsic pathway of the caspase cascade within the cell.<\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\n<div class=\"textbox textbox--key-takeaways\"><header class=\"textbox__header\">\r\n<p class=\"textbox__title\"><strong>Why Does DNA Damage Trigger Apoptosis?<\/strong><\/p>\r\n\r\n<\/header>\r\n<div class=\"textbox__content\">\r\n\r\nWhen a cell detects that its DNA has been mutated, apoptosis serves as a critical <strong>safety net<\/strong>.\u00a0 A cell with a mutated genome is at risk of dividing and passing on those mutations potentially leading to either <strong>cancer<\/strong> or <strong>loss of normal organ function.<\/strong>\u00a0 By eliminating itself, the cell prevents this from happening.\u00a0 Similarly a cell experiencing chronically low ATP due to <strong>hypoxia<\/strong> becomes less functional and potentially more prone to mutation - making apoptosis a logical and protective response.\r\n\r\n<\/div>\r\n<\/div>\r\n<div class=\"textbox textbox--exercises\"><header class=\"textbox__header\">\r\n<p class=\"textbox__title\"><strong>Telomere Shortening and Cellular Aging<\/strong><\/p>\r\n\r\n<\/header>\r\n<div class=\"textbox__content\">\r\n\r\nEach time a cell divides, the <strong>telomeres<\/strong> - protective caps at the ends of chromosomes - shorten slightly.\u00a0 After approximately 50 rounds of cell division telomeres reach a critical minimal length.\u00a0 At this point, the cell recognized that it is 'old' and becomes susceptible to DNA damage and cancer.\u00a0 Telomere shortening therefore acts as a built-in trigger for <strong>apoptosis,<\/strong> ensuring that aged cells make way for newer, healthier replacements.\r\n\r\nThe <strong>Hayflick limit<\/strong> refers to the number of times a human cell can divide before it stops and enters a state of <strong>cellular senescence<\/strong>.\u00a0 The Hayflick limit varies depending on the specific cell type.\u00a0 Senescence is a state of cell cycle arrest, that differs from maturation and differentiation.\u00a0 Senescent cells remain metabolically active and while cleared by young healthy immune systems, they can remain as \"<strong>zombie cells<\/strong>\" that accumulate, secrete harmful chemicals, and contribute to tissue deterioration in chronic disease and aging.\r\n\r\n<\/div>\r\n<\/div>\r\n&nbsp;\r\n\r\n<strong><span style=\"color: #2e75b6\">The Apoptotic Process:\u00a0 What it Looks Like<\/span><\/strong>\r\n\r\nUnder a microscope, apoptosis follows a recognizable sequence of steps:\r\n<ul>\r\n \t<li><strong>Step 1 - Cell shrinkage:<\/strong>\u00a0 The cell shrinks and rounds up.<\/li>\r\n \t<li><strong>Step 2 - Chromatin condensation: <\/strong> The DNA condenses and forms compact patches against the inner surface of the nuclear envelope.<\/li>\r\n \t<li><strong>Step 3 - Nuclear disintegration: <\/strong> The nuclear envelope breaks down and the DNA fragments.<\/li>\r\n \t<li><strong>Step 4 - Membrane blebbing and apoptotic body formation: <\/strong> The cell membrane bubbles outward forming small, membrane bound vesicles called <strong>apoptotic bodies<\/strong>.\u00a0 Each apoptotic body carries transmembrane 'flag' proteins that signal <strong>macrophages<\/strong> to engulf and recycle it.<\/li>\r\n<\/ul>\r\nThe process is clean and efficient.\u00a0 Macrophages rapidly phagocytose the apoptotic bodies, recycling their components without triggering an inflammatory response - a key distinction from unplanned cell death.\r\n\r\n[caption id=\"attachment_2276\" align=\"alignnone\" width=\"300\"]<a href=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis.png\" target=\"_blank\" rel=\"noopener\"><img class=\"wp-image-2276 size-medium\" src=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-300x286.png\" alt=\"Structural changes of cells undergoing necrosis or apoptosis\" width=\"300\" height=\"286\" \/><\/a> Apoptosis consists of regulated cell death that does not result in inflammation, while necrosis is unregulated cell death that results in an uncontrolled release of inflammatory agents, causing inflammation.[\/caption]\r\n<h3><span style=\"color: #1f5c99\"><strong>Unplanned Cell Death:\u00a0 Necrosis<\/strong><\/span><\/h3>\r\n<span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Necrosis<\/strong> occurs when cells are damaged so severely that they burst and die in an uncontrolled manner.\u00a0 Unlike apoptosis, necrotic cell death is messy - cells <strong>lyse<\/strong> (rupture), spilling their contents into the surrounding tissue.\u00a0 This triggers <strong>inflammation:<\/strong> white blood cells, such as <strong>neutrophils<\/strong> are recruited to the area and, while they help clean up the debris, they can also cause collateral damage to neighbouring cells through the release of <strong>Reactive Oxygen Species (ROS)<\/strong>.<\/span>\r\n<h3><span style=\"color: #1f5c99\"><strong>The Number One Cause of Unplanned Cell Death:\u00a0 Ischemia<\/strong><\/span><\/h3>\r\n<span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Ischemia<\/strong> - the interruption of blood flow to a tissue - is the leading cause of unplanned cell death in humans.\u00a0 When blood flow is blocked or reduced (e.g., by a blocked or compressed blood vessel), three harmful conditions arise simultaneously:<\/span>\r\n<ul>\r\n \t<li><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Oxygen deprivation (hypoxia): <\/strong> Hypoxia (hypo- = below, -oxia = oxygen) means reduced oxygen in tissues.\u00a0 Without oxygen, cells cannot perform aerobic cellular respiration and ATP production falls dramatically.<\/span><\/li>\r\n \t<li><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Nutrient deprivation: <\/strong> Glucose, vitamins, and other building blocks essential for cellular function are no longer delivered.\u00a0\u00a0<\/span><\/li>\r\n \t<li><strong>Waste accumulation:<\/strong>\u00a0 Metabolic waste products build up and become toxic to cells.<\/li>\r\n<\/ul>\r\nTogether, these three factors cause far more cell injury than oxygen deprivation alone.\r\n<div class=\"textbox textbox--key-takeaways\"><header class=\"textbox__header\">\r\n<p class=\"textbox__title\"><strong>Which Organs are Most Sensitive to Hypoxia?<\/strong><\/p>\r\n\r\n<\/header>\r\n<div class=\"textbox__content\">\r\n\r\nThe organs most vulnerable to hypoxia are those with the highest energy demands - the <strong>brain, heart,<\/strong> and <strong>kidneys.<\/strong> None of these organs can store oxygen; they depend on a continuous blood supply.\u00a0 Brain cells (neurons) can survive only approximately <strong>3-5 minutes<\/strong> without oxygen before they begin to die.\u00a0 This is why strokes and cardiac arrest must be treated immediately to minimize permanent damage.\r\n\r\n<\/div>\r\n<\/div>\r\n<strong><span style=\"color: #2e75b6\">How Ischemia Damages Cells:\u00a0 A Step-by-Step Breakdown<\/span><\/strong>\r\n\r\nThe cellular consequences of <strong>ischemia<\/strong> follow a predictable, escalating cascade:\r\n<ul>\r\n \t<li><strong>Low ATP \u2192 pump failure: <\/strong> Cells maintain their internal environment using two critical ion pumps that both require ATP:\u00a0 the sodium-potassium pump (which moves 3 Na<sup>+<\/sup> out and 2 K<sup>+<\/sup> in) and a calcium-sodium exchanger (which expels Ca<sup>2+<\/sup>).\u00a0 Without sufficient ATP, both pumps fail.<\/li>\r\n \t<li><strong>Calcium accumulation: <\/strong> Ca<sup>2+<\/sup> floods into the cell and inappropriately activates two destructive enzymes:\r\n<ul>\r\n \t<li><strong>Phospholipase: <\/strong> degrades the phospholipids of the cell membrane, cause the cell to lose <strong>membrane integrity<\/strong> and become leaky.<\/li>\r\n \t<li><strong>Protease:<\/strong>\u00a0 degrades cytoskeletal proteins (the cell's internal scaffolding), causing the cell to lose its supportive structure and shape.<\/li>\r\n<\/ul>\r\n<\/li>\r\n \t<li><strong>Membrane phospholipid depletion:<\/strong>\u00a0 A third enzyme - <strong>phospholipid reacylation synthase<\/strong> - normally replaces phospholipids in the membrane during natural turnover.\u00a0 This enzyme requires ATP and therefore also fails during ischemia, meaning damaged phospholipids cannot be replenished.<\/li>\r\n \t<li><strong>Sodium and water influx: <\/strong> As the membrane becomes leaky, sodium and water rush into the cell.\u00a0 The cell swells and may ultimately burst.<\/li>\r\n \t<li><strong>Anerobic metabolism and intracellular acidosis:<\/strong>\u00a0 in an attempt to survive, the cell has switched to anaerobic cellular respiration (glycolysis alone).\u00a0 The generates some ATP but also produces large amounts of lactic acid, lowering intracellular pH.\u00a0 Enzyme function declines as the cell becomes increasingly acidic.<\/li>\r\n<\/ul>\r\n<div class=\"textbox textbox--key-takeaways\"><header class=\"textbox__header\">\r\n<p class=\"textbox__title\"><strong>Ischemia, Reperfusion, and Calcium Flooding<\/strong><\/p>\r\n\r\n<\/header>\r\n<div class=\"textbox__content\">\r\n\r\nRestoring blood flow <strong>(reperfusion)<\/strong> to ischemic tissue is necessary for recovery but carries its own risks.\u00a0 When blood rushes back into a leaky, calcium-starved cell, the high <strong>calcium<\/strong> concentration of blood floods in through the damaged membrane.\u00a0 This triggers a surge of <strong>phospholipase<\/strong> and <strong>protease<\/strong> activity, accelerating membrane destruction and cell death.\r\n\r\nAdditionally, reperfusion brings a wave of <strong>white blood cells<\/strong> (WBCs) to the area.\u00a0 While WBCs such as <strong>neutrophils<\/strong> and <strong>macrophages<\/strong> are essential for clearing debris, they also release <strong>Reactive Oxygen Species<\/strong> (ROS, e.g., peroxide, superoxide, hydroxide ions) - highly reactive molecules with unpaired electrons that can damage cell membranes, proteins, and DNA.\u00a0 This collateral damage to neighbouring cells is known as <strong>reperfusion injury<\/strong>.\u00a0 For this reason, reperfusion is carried out at a controlled pace in clinical settings.\r\n\r\n<\/div>\r\n<\/div>\r\n<h3><span style=\"color: #1f5c99\"><strong>Reactive Oxygen Species (ROS) and Oxidative Stress<\/strong><\/span><\/h3>\r\n<span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Reactive Oxygen Species (ROS)<\/strong> are unstable, highly reactive molecules characterized by an <strong>unpaired electron<\/strong>.\u00a0 Examples include superoxide, hydrogen peroxide, and hydroxide ions.\u00a0 Although ROS are produced normally by <strong>mitochondria<\/strong> as part of <strong>metabolic signaling<\/strong> (including regulation of <strong>vascular tone<\/strong> - the balance between vasoconstriction and vasodilation), they are kept in check by the cell's own neutralizing <strong>antioxidants.<\/strong>\u00a0\u00a0<\/span>\r\n\r\nProblems arise when ROS production exceeds the cell's capacity to neutralize them - a state called <strong>oxidative stress<\/strong>.\u00a0 In this scenario, ROS cause damage to cell membranes, proteins, and DNA, promoting <strong>inflammation<\/strong> and contributing to cell death.\r\n<table class=\"grid landscape\" style=\"border-collapse: collapse;width: 100%;height: 30px\" border=\"0\">\r\n<tbody>\r\n<tr style=\"height: 15px\">\r\n<td class=\"border\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Causes of oxidative stress<\/strong><\/span><\/td>\r\n<td style=\"width: 82.0463%;height: 15px\">Ischemia, UV radiation, ionizing radiation (e.g., gamma rays from nuclear sources), cigarette smoking, and excessive alcohol consumption.<\/td>\r\n<\/tr>\r\n<tr style=\"height: 15px\">\r\n<td class=\"shaded\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Role in disease<\/strong><\/span><\/td>\r\n<td class=\"shaded\" style=\"width: 82.0463%;height: 15px\">ROS accumulation is implicated in ALS (Lou Gehrig's disease), normal aging, stroke, heart attack, and fatty liver disease.<\/td>\r\n<\/tr>\r\n<tr>\r\n<td class=\"border\" style=\"width: 17.9537%\"><span style=\"color: #032c80\"><strong>Antioxidants<\/strong><\/span><\/td>\r\n<td style=\"width: 82.0463%\">Molecules that neutralize ROS.\u00a0 Produced naturally by cells; also found in food such as dark chocolate and green tea.\u00a0 Beneficial when ROS levels are elevated, but not necessarily required in excess for a healthy individual with a balanced diet.<\/td>\r\n<\/tr>\r\n<\/tbody>\r\n<\/table>\r\n<div class=\"textbox textbox--examples\"><header class=\"textbox__header\">\r\n<p class=\"textbox__title\"><strong>\u2217 Real World Story:\u00a0 The Dangers of Radiation - Fukushima and Chernobyl <\/strong><\/p>\r\n\r\n<\/header>\r\n<div class=\"textbox__content\">\r\n\r\nIn 2011, a major earthquake off the coast of Japan triggered a tsunami that severely damaged the <strong>Fukushima Daiichi nuclear reactor<\/strong>.\u00a0 The resulting release of <strong>ionizing radiation<\/strong> (specifically gamma rays) caused significant environmental contamination and posed serious health risks to people in the affected area.\u00a0 A similar disaster occurred at <strong>Chernobyl<\/strong> in 1986.\r\n\r\nIonizing radiation damages cells through three interconnected mechanisms:\u00a0 it causes direct <strong>DNA damage<\/strong>, which can lead to genetic mutations and cancer; it triggers the caspase cascade, leading to <strong>apoptosis<\/strong> of irradiated cells; and it stimulates the production of <strong>ROS,<\/strong> which cause further membrane, protein, and DNA damage, eventually leading to <strong>necrosis<\/strong> of large areas of tissue.\u00a0 Individuals exposed to high doses of ionizing radiation may develop <strong>acute radiation sickness<\/strong>.\r\n\r\n<\/div>\r\n<\/div>\r\n<h3><span style=\"color: #1f5c99\"><strong>Causes of Cell Damage and Death:\u00a0 A Summary<\/strong><\/span><\/h3>\r\nA variety of agents can damage or kill cells:\r\n<ul>\r\n \t<li><strong>Physical damage:<\/strong>\u00a0 Wounds, cuts, extreme heat (e.g., burns, electrical burns), and extreme cold (e.g., frostbite).\u00a0 Electric shocks cause burns due to heat from electrical resistance.\u00a0 High temperatures over 40\u00b0C induce vascular injury, disruption of cell membrane and cause blood and protein coagulation leading to cell death and downstream ischemia.\u00a0 During frostbite, blood vessels in exposed skin vasoconstrict to protect internal organs, depriving skin tissue of oxygen and nutrients and leading to necrosis of the affected tissue.<\/li>\r\n \t<li><strong>Radiation:<\/strong>\u00a0 Ionizing radiation (X-rays, gamma rays) cause DNA damage, ROS production and cell death.<\/li>\r\n \t<li><strong>Mechanical damage: <\/strong> Tearing or crushing of tissue<\/li>\r\n \t<li><strong>Chemical toxins:<\/strong>\u00a0 Exogenous toxins (e.g., acids, mercury, lead) or endogenous toxic accumulations (e.g., lipids, abnormal proteins) as discussed above.<\/li>\r\n \t<li><strong>Reperfusion injury:<\/strong>\u00a0 Restoration of blood flow to ischemic tissue causing intracellular calcium flooding, loss of cell membrane integrity, cell lysis, and ROS-mediated damage.<\/li>\r\n \t<li><strong>Microorganisms:<\/strong>\u00a0 Bacteria, viruses, fungi (e.g., yeast), helminths, and protozoa cause cellular damage through direct infection and\/or inflammatory responses<\/li>\r\n \t<li><strong>Abnormal metabolic diseases: <\/strong> Rare conditions in which toxic waste products accumulate inside cells (e.g., inherited Tay Sachs Disease)<\/li>\r\n \t<li><strong>Malnutrition:<\/strong>\u00a0 Cells deprived of essential building blocks cannot maintain normal function and may deteriorate and die.<\/li>\r\n \t<li><strong>Fluid and electrolyte imbalance:<\/strong>\u00a0 Disruptions in the balance of water and electrolytes can be severely damaging to the heart, brain, and kidneys.<\/li>\r\n<\/ul>\r\n&nbsp;\r\n\r\n[caption id=\"attachment_6355\" align=\"alignnone\" width=\"300\"]<a href=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand.jpg\" target=\"_blank\" rel=\"noopener\"><img class=\"wp-image-6355 size-medium\" src=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand-300x227.jpg\" alt=\"Electrical burns may show erythema and bullae from the heat of arcing current or may be non-descript with severe internal damage between the points of contact and exit of the electrical current.\" width=\"300\" height=\"227\" \/><\/a> Electrical burns may show erythema and bullae from the heat of arcing current or may be non-descript with severe internal damage between the points of contact and exit of the electrical current.[\/caption]\r\n\r\n[caption id=\"attachment_2233\" align=\"alignnone\" width=\"250\"]<a href=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound.jpg\" target=\"_blank\" rel=\"noopener\"><img class=\"wp-image-2233 size-full\" src=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound.jpg\" alt=\"Electrical burn exit wound. Current flows through the body from the entrance point, until finally exiting where the body is closest to the ground. This foot suffered massive internal injuries, which weren't readily visible, and had to be amputated a few days later.\" width=\"250\" height=\"168\" \/><\/a> Electrical burn exit wound. Current flows through the body from the entrance point, until finally exiting where the body is closest to the ground. This foot suffered massive internal injuries, which weren't readily visible, and had to be amputated a few days later.[\/caption]\r\n\r\n&nbsp;\r\n<div class=\"textbox textbox--examples\"><header class=\"textbox__header\">\r\n<p class=\"textbox__title\"><strong>\u2217 A Real-World Story:\u00a0 Water Intoxication - 'Don't Wee for a Wii'<\/strong><\/p>\r\n\r\n<\/header>\r\n<div class=\"textbox__content\">\r\n\r\nIn 2007, a US radio show hosted a \"Hold Your Wee for a Wii\" content where contestants competed for a video game console by drinking water bottles every 15 minutes while not being allowed to use the washroom.\u00a0 Unfortunately, the radio station ignored calls from a nurse and other listeners about the lethal dangers of <strong>water intoxication<\/strong>.\u00a0 One contestant, a 28 year old mother of three, left the contest complaining of swollen stomach and severe head pain, dying later the same day.\r\n\r\nWhat the organizers did not realize is that consuming large volumes of water in a short period of time causes a dangerous drop in blood electrolyte concentrations - a condition known as water intoxication (or <strong>hyponatremia,<\/strong> due to diluted blood sodium levels).\u00a0 The resulting electrolyte imbalance can lead to impaired heart and brain function and be fatal, by causing brain swelling or heart attacks.\r\n\r\nThis tragic case illustrate why extreme dietary behaviours - including overconsumption of water - can be just as dangerous as deprivation.\r\n\r\n<\/div>\r\n<\/div>","rendered":"<p><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\">Cell death is a normal and essential part of life.\u00a0 However, not all cell death is the same.\u00a0 There are two fundamentally different types:\u00a0 <strong>planned cell death<\/strong> (apoptosis) and <strong>unplanned cell death<\/strong> (necrosis).\u00a0 Understanding the difference between them &#8211; and the conditions that trigger each &#8211; is central to understanding how disease affects the body.\u00a0 \u00a0\u00a0<\/span><\/p>\n<h3><span style=\"color: #1f5c99\"><strong>Apoptosis:\u00a0 Planned Cell Death<\/strong><\/span><\/h3>\n<p><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Apoptosis<\/strong> (sometimes called programmed cell death) is a tightly regulated, orderly process in which aging or damaged cells are eliminated to make room for new, more functional ones.\u00a0 It is driven by an <strong>internal enzymatic cascade<\/strong> involving proteins called <strong>caspases,<\/strong> and it results in a clean, contained death that does not trigger inflammation.<\/span><\/p>\n<p><strong><span style=\"color: #2e75b6\">Apoptosis in Normal Life<\/span><\/strong><\/p>\n<p>Apoptosis is not a sign of disease &#8211; it is a routine, continuous process that keeps tissues healthy.\u00a0 Consider the following examples:<\/p>\n<ul>\n<li><strong>Red blood cell (RBC) turnover:<\/strong>\u00a0 RBCs live approximately 120 days.\u00a0 Millions undergo apoptosis every day and are simultaneously replaced by new cells produced in the bone marrow.\u00a0 This balance keeps the RBC population stable.<\/li>\n<li><strong>Skin cell turnover: <\/strong> Skin cells replace themselves approximately every 30 days through a cycle of apoptosis and mitosis.\u00a0 Similarly, the epithelial cells lining the <strong>mucosa membranes<\/strong> of the <strong>respiratory<\/strong> and <strong>digestive tracts<\/strong> experience frequent turnover (every 30-50 days and every 3-5 days respectively).<\/li>\n<li><strong>Embryonic development: <\/strong> Apoptosis plays a critical role in shaping the body before birth.\u00a0 For example, the webbing between <strong>fingers<\/strong> and <strong>toes<\/strong> during fetal development is removed through apoptosis, sculpting the final form of the hands and feet.\u00a0 <strong>Heart<\/strong> development and the remodeling of other organs during fetal stages also rely on apoptosis.<\/li>\n<li><strong>Breast tissue remodeling: <\/strong> During pregnancy, breast tissue grows to support lactation.\u00a0 After breastfeeding ends, apoptosis returns breast tissue to its pre-pregnancy size.<\/li>\n<\/ul>\n<p>Note that some cell types &#8211; particularly neurons &#8211; do not undergo ongoing turnover.\u00a0 After birth, the number of neurons a person has is largely fixed for life, which is one reason that neurological damage can be so significant.<\/p>\n<p><strong><span style=\"color: #2e75b6\">Triggers of Apoptosis<\/span><\/strong><\/p>\n<p>While apoptosis is normal, it can also be triggered by a variety of stressors.\u00a0 Triggers are classified as either <strong>extrinsic<\/strong> (coming from outside the cells) or <strong>intrinsic<\/strong> (arising from within the cell):<\/p>\n<table class=\"grid landscape\" style=\"border-collapse: collapse;width: 100%;height: 30px\">\n<tbody>\n<tr style=\"height: 15px\">\n<td class=\"border\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Extrinsic triggers<\/strong><\/span><\/td>\n<td style=\"width: 82.0463%;height: 15px\"><strong>Bacterial LPS<\/strong> (lipopolysaccharide):\u00a0 A component of the bacterial cell membrane that activates a &#8216;death receptor&#8217; on the surface of human cells initiating the caspase cascade.<\/p>\n<p>Some <strong>pro-inflammatory cytokines<\/strong> released by White Blood Cells can also activate the &#8216;death receptor&#8217; stimulating the apoptotic enzyme cascade, providing an important defence mechanism against pathogens that have infected cells.<\/td>\n<\/tr>\n<tr style=\"height: 15px\">\n<td class=\"shaded\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Intrinsic triggers<\/strong><\/span><\/td>\n<td class=\"shaded\" style=\"width: 82.0463%;height: 15px\"><strong>Reactive Oxygen Species (ROS)<\/strong> increased levels<\/p>\n<p><strong>DNA damage<\/strong><\/p>\n<p><strong>Hypoxia<\/strong> (low oxygen \/ low ATP)<\/p>\n<p><strong>Senescence<\/strong> (cellular aging)<\/p>\n<p>All of these activate the intrinsic pathway of the caspase cascade within the cell.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<div class=\"textbox textbox--key-takeaways\">\n<header class=\"textbox__header\">\n<p class=\"textbox__title\"><strong>Why Does DNA Damage Trigger Apoptosis?<\/strong><\/p>\n<\/header>\n<div class=\"textbox__content\">\n<p>When a cell detects that its DNA has been mutated, apoptosis serves as a critical <strong>safety net<\/strong>.\u00a0 A cell with a mutated genome is at risk of dividing and passing on those mutations potentially leading to either <strong>cancer<\/strong> or <strong>loss of normal organ function.<\/strong>\u00a0 By eliminating itself, the cell prevents this from happening.\u00a0 Similarly a cell experiencing chronically low ATP due to <strong>hypoxia<\/strong> becomes less functional and potentially more prone to mutation &#8211; making apoptosis a logical and protective response.<\/p>\n<\/div>\n<\/div>\n<div class=\"textbox textbox--exercises\">\n<header class=\"textbox__header\">\n<p class=\"textbox__title\"><strong>Telomere Shortening and Cellular Aging<\/strong><\/p>\n<\/header>\n<div class=\"textbox__content\">\n<p>Each time a cell divides, the <strong>telomeres<\/strong> &#8211; protective caps at the ends of chromosomes &#8211; shorten slightly.\u00a0 After approximately 50 rounds of cell division telomeres reach a critical minimal length.\u00a0 At this point, the cell recognized that it is &#8216;old&#8217; and becomes susceptible to DNA damage and cancer.\u00a0 Telomere shortening therefore acts as a built-in trigger for <strong>apoptosis,<\/strong> ensuring that aged cells make way for newer, healthier replacements.<\/p>\n<p>The <strong>Hayflick limit<\/strong> refers to the number of times a human cell can divide before it stops and enters a state of <strong>cellular senescence<\/strong>.\u00a0 The Hayflick limit varies depending on the specific cell type.\u00a0 Senescence is a state of cell cycle arrest, that differs from maturation and differentiation.\u00a0 Senescent cells remain metabolically active and while cleared by young healthy immune systems, they can remain as &#8220;<strong>zombie cells<\/strong>&#8221; that accumulate, secrete harmful chemicals, and contribute to tissue deterioration in chronic disease and aging.<\/p>\n<\/div>\n<\/div>\n<p>&nbsp;<\/p>\n<p><strong><span style=\"color: #2e75b6\">The Apoptotic Process:\u00a0 What it Looks Like<\/span><\/strong><\/p>\n<p>Under a microscope, apoptosis follows a recognizable sequence of steps:<\/p>\n<ul>\n<li><strong>Step 1 &#8211; Cell shrinkage:<\/strong>\u00a0 The cell shrinks and rounds up.<\/li>\n<li><strong>Step 2 &#8211; Chromatin condensation: <\/strong> The DNA condenses and forms compact patches against the inner surface of the nuclear envelope.<\/li>\n<li><strong>Step 3 &#8211; Nuclear disintegration: <\/strong> The nuclear envelope breaks down and the DNA fragments.<\/li>\n<li><strong>Step 4 &#8211; Membrane blebbing and apoptotic body formation: <\/strong> The cell membrane bubbles outward forming small, membrane bound vesicles called <strong>apoptotic bodies<\/strong>.\u00a0 Each apoptotic body carries transmembrane &#8216;flag&#8217; proteins that signal <strong>macrophages<\/strong> to engulf and recycle it.<\/li>\n<\/ul>\n<p>The process is clean and efficient.\u00a0 Macrophages rapidly phagocytose the apoptotic bodies, recycling their components without triggering an inflammatory response &#8211; a key distinction from unplanned cell death.<\/p>\n<figure id=\"attachment_2276\" aria-describedby=\"caption-attachment-2276\" style=\"width: 300px\" class=\"wp-caption alignnone\"><a href=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis.png\" target=\"_blank\" rel=\"noopener\"><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-2276 size-medium\" src=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-300x286.png\" alt=\"Structural changes of cells undergoing necrosis or apoptosis\" width=\"300\" height=\"286\" srcset=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-300x286.png 300w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-768x731.png 768w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-65x62.png 65w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-225x214.png 225w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis-350x333.png 350w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/necrosis_vs_apoptosis.png 840w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/a><figcaption id=\"caption-attachment-2276\" class=\"wp-caption-text\">Apoptosis consists of regulated cell death that does not result in inflammation, while necrosis is unregulated cell death that results in an uncontrolled release of inflammatory agents, causing inflammation.<\/figcaption><\/figure>\n<h3><span style=\"color: #1f5c99\"><strong>Unplanned Cell Death:\u00a0 Necrosis<\/strong><\/span><\/h3>\n<p><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Necrosis<\/strong> occurs when cells are damaged so severely that they burst and die in an uncontrolled manner.\u00a0 Unlike apoptosis, necrotic cell death is messy &#8211; cells <strong>lyse<\/strong> (rupture), spilling their contents into the surrounding tissue.\u00a0 This triggers <strong>inflammation:<\/strong> white blood cells, such as <strong>neutrophils<\/strong> are recruited to the area and, while they help clean up the debris, they can also cause collateral damage to neighbouring cells through the release of <strong>Reactive Oxygen Species (ROS)<\/strong>.<\/span><\/p>\n<h3><span style=\"color: #1f5c99\"><strong>The Number One Cause of Unplanned Cell Death:\u00a0 Ischemia<\/strong><\/span><\/h3>\n<p><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Ischemia<\/strong> &#8211; the interruption of blood flow to a tissue &#8211; is the leading cause of unplanned cell death in humans.\u00a0 When blood flow is blocked or reduced (e.g., by a blocked or compressed blood vessel), three harmful conditions arise simultaneously:<\/span><\/p>\n<ul>\n<li><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Oxygen deprivation (hypoxia): <\/strong> Hypoxia (hypo- = below, -oxia = oxygen) means reduced oxygen in tissues.\u00a0 Without oxygen, cells cannot perform aerobic cellular respiration and ATP production falls dramatically.<\/span><\/li>\n<li><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Nutrient deprivation: <\/strong> Glucose, vitamins, and other building blocks essential for cellular function are no longer delivered.\u00a0\u00a0<\/span><\/li>\n<li><strong>Waste accumulation:<\/strong>\u00a0 Metabolic waste products build up and become toxic to cells.<\/li>\n<\/ul>\n<p>Together, these three factors cause far more cell injury than oxygen deprivation alone.<\/p>\n<div class=\"textbox textbox--key-takeaways\">\n<header class=\"textbox__header\">\n<p class=\"textbox__title\"><strong>Which Organs are Most Sensitive to Hypoxia?<\/strong><\/p>\n<\/header>\n<div class=\"textbox__content\">\n<p>The organs most vulnerable to hypoxia are those with the highest energy demands &#8211; the <strong>brain, heart,<\/strong> and <strong>kidneys.<\/strong> None of these organs can store oxygen; they depend on a continuous blood supply.\u00a0 Brain cells (neurons) can survive only approximately <strong>3-5 minutes<\/strong> without oxygen before they begin to die.\u00a0 This is why strokes and cardiac arrest must be treated immediately to minimize permanent damage.<\/p>\n<\/div>\n<\/div>\n<p><strong><span style=\"color: #2e75b6\">How Ischemia Damages Cells:\u00a0 A Step-by-Step Breakdown<\/span><\/strong><\/p>\n<p>The cellular consequences of <strong>ischemia<\/strong> follow a predictable, escalating cascade:<\/p>\n<ul>\n<li><strong>Low ATP \u2192 pump failure: <\/strong> Cells maintain their internal environment using two critical ion pumps that both require ATP:\u00a0 the sodium-potassium pump (which moves 3 Na<sup>+<\/sup> out and 2 K<sup>+<\/sup> in) and a calcium-sodium exchanger (which expels Ca<sup>2+<\/sup>).\u00a0 Without sufficient ATP, both pumps fail.<\/li>\n<li><strong>Calcium accumulation: <\/strong> Ca<sup>2+<\/sup> floods into the cell and inappropriately activates two destructive enzymes:\n<ul>\n<li><strong>Phospholipase: <\/strong> degrades the phospholipids of the cell membrane, cause the cell to lose <strong>membrane integrity<\/strong> and become leaky.<\/li>\n<li><strong>Protease:<\/strong>\u00a0 degrades cytoskeletal proteins (the cell&#8217;s internal scaffolding), causing the cell to lose its supportive structure and shape.<\/li>\n<\/ul>\n<\/li>\n<li><strong>Membrane phospholipid depletion:<\/strong>\u00a0 A third enzyme &#8211; <strong>phospholipid reacylation synthase<\/strong> &#8211; normally replaces phospholipids in the membrane during natural turnover.\u00a0 This enzyme requires ATP and therefore also fails during ischemia, meaning damaged phospholipids cannot be replenished.<\/li>\n<li><strong>Sodium and water influx: <\/strong> As the membrane becomes leaky, sodium and water rush into the cell.\u00a0 The cell swells and may ultimately burst.<\/li>\n<li><strong>Anerobic metabolism and intracellular acidosis:<\/strong>\u00a0 in an attempt to survive, the cell has switched to anaerobic cellular respiration (glycolysis alone).\u00a0 The generates some ATP but also produces large amounts of lactic acid, lowering intracellular pH.\u00a0 Enzyme function declines as the cell becomes increasingly acidic.<\/li>\n<\/ul>\n<div class=\"textbox textbox--key-takeaways\">\n<header class=\"textbox__header\">\n<p class=\"textbox__title\"><strong>Ischemia, Reperfusion, and Calcium Flooding<\/strong><\/p>\n<\/header>\n<div class=\"textbox__content\">\n<p>Restoring blood flow <strong>(reperfusion)<\/strong> to ischemic tissue is necessary for recovery but carries its own risks.\u00a0 When blood rushes back into a leaky, calcium-starved cell, the high <strong>calcium<\/strong> concentration of blood floods in through the damaged membrane.\u00a0 This triggers a surge of <strong>phospholipase<\/strong> and <strong>protease<\/strong> activity, accelerating membrane destruction and cell death.<\/p>\n<p>Additionally, reperfusion brings a wave of <strong>white blood cells<\/strong> (WBCs) to the area.\u00a0 While WBCs such as <strong>neutrophils<\/strong> and <strong>macrophages<\/strong> are essential for clearing debris, they also release <strong>Reactive Oxygen Species<\/strong> (ROS, e.g., peroxide, superoxide, hydroxide ions) &#8211; highly reactive molecules with unpaired electrons that can damage cell membranes, proteins, and DNA.\u00a0 This collateral damage to neighbouring cells is known as <strong>reperfusion injury<\/strong>.\u00a0 For this reason, reperfusion is carried out at a controlled pace in clinical settings.<\/p>\n<\/div>\n<\/div>\n<h3><span style=\"color: #1f5c99\"><strong>Reactive Oxygen Species (ROS) and Oxidative Stress<\/strong><\/span><\/h3>\n<p><span class=\"transcription-time-part\" style=\"text-align: initial;font-size: 1em\" data-time-start=\"1537.339\" data-time-end=\"1539.71\"><strong>Reactive Oxygen Species (ROS)<\/strong> are unstable, highly reactive molecules characterized by an <strong>unpaired electron<\/strong>.\u00a0 Examples include superoxide, hydrogen peroxide, and hydroxide ions.\u00a0 Although ROS are produced normally by <strong>mitochondria<\/strong> as part of <strong>metabolic signaling<\/strong> (including regulation of <strong>vascular tone<\/strong> &#8211; the balance between vasoconstriction and vasodilation), they are kept in check by the cell&#8217;s own neutralizing <strong>antioxidants.<\/strong>\u00a0\u00a0<\/span><\/p>\n<p>Problems arise when ROS production exceeds the cell&#8217;s capacity to neutralize them &#8211; a state called <strong>oxidative stress<\/strong>.\u00a0 In this scenario, ROS cause damage to cell membranes, proteins, and DNA, promoting <strong>inflammation<\/strong> and contributing to cell death.<\/p>\n<table class=\"grid landscape\" style=\"border-collapse: collapse;width: 100%;height: 30px\">\n<tbody>\n<tr style=\"height: 15px\">\n<td class=\"border\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Causes of oxidative stress<\/strong><\/span><\/td>\n<td style=\"width: 82.0463%;height: 15px\">Ischemia, UV radiation, ionizing radiation (e.g., gamma rays from nuclear sources), cigarette smoking, and excessive alcohol consumption.<\/td>\n<\/tr>\n<tr style=\"height: 15px\">\n<td class=\"shaded\" style=\"width: 17.9537%;height: 15px\"><span style=\"color: #032c80\"><strong>Role in disease<\/strong><\/span><\/td>\n<td class=\"shaded\" style=\"width: 82.0463%;height: 15px\">ROS accumulation is implicated in ALS (Lou Gehrig&#8217;s disease), normal aging, stroke, heart attack, and fatty liver disease.<\/td>\n<\/tr>\n<tr>\n<td class=\"border\" style=\"width: 17.9537%\"><span style=\"color: #032c80\"><strong>Antioxidants<\/strong><\/span><\/td>\n<td style=\"width: 82.0463%\">Molecules that neutralize ROS.\u00a0 Produced naturally by cells; also found in food such as dark chocolate and green tea.\u00a0 Beneficial when ROS levels are elevated, but not necessarily required in excess for a healthy individual with a balanced diet.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<div class=\"textbox textbox--examples\">\n<header class=\"textbox__header\">\n<p class=\"textbox__title\"><strong>\u2217 Real World Story:\u00a0 The Dangers of Radiation &#8211; Fukushima and Chernobyl <\/strong><\/p>\n<\/header>\n<div class=\"textbox__content\">\n<p>In 2011, a major earthquake off the coast of Japan triggered a tsunami that severely damaged the <strong>Fukushima Daiichi nuclear reactor<\/strong>.\u00a0 The resulting release of <strong>ionizing radiation<\/strong> (specifically gamma rays) caused significant environmental contamination and posed serious health risks to people in the affected area.\u00a0 A similar disaster occurred at <strong>Chernobyl<\/strong> in 1986.<\/p>\n<p>Ionizing radiation damages cells through three interconnected mechanisms:\u00a0 it causes direct <strong>DNA damage<\/strong>, which can lead to genetic mutations and cancer; it triggers the caspase cascade, leading to <strong>apoptosis<\/strong> of irradiated cells; and it stimulates the production of <strong>ROS,<\/strong> which cause further membrane, protein, and DNA damage, eventually leading to <strong>necrosis<\/strong> of large areas of tissue.\u00a0 Individuals exposed to high doses of ionizing radiation may develop <strong>acute radiation sickness<\/strong>.<\/p>\n<\/div>\n<\/div>\n<h3><span style=\"color: #1f5c99\"><strong>Causes of Cell Damage and Death:\u00a0 A Summary<\/strong><\/span><\/h3>\n<p>A variety of agents can damage or kill cells:<\/p>\n<ul>\n<li><strong>Physical damage:<\/strong>\u00a0 Wounds, cuts, extreme heat (e.g., burns, electrical burns), and extreme cold (e.g., frostbite).\u00a0 Electric shocks cause burns due to heat from electrical resistance.\u00a0 High temperatures over 40\u00b0C induce vascular injury, disruption of cell membrane and cause blood and protein coagulation leading to cell death and downstream ischemia.\u00a0 During frostbite, blood vessels in exposed skin vasoconstrict to protect internal organs, depriving skin tissue of oxygen and nutrients and leading to necrosis of the affected tissue.<\/li>\n<li><strong>Radiation:<\/strong>\u00a0 Ionizing radiation (X-rays, gamma rays) cause DNA damage, ROS production and cell death.<\/li>\n<li><strong>Mechanical damage: <\/strong> Tearing or crushing of tissue<\/li>\n<li><strong>Chemical toxins:<\/strong>\u00a0 Exogenous toxins (e.g., acids, mercury, lead) or endogenous toxic accumulations (e.g., lipids, abnormal proteins) as discussed above.<\/li>\n<li><strong>Reperfusion injury:<\/strong>\u00a0 Restoration of blood flow to ischemic tissue causing intracellular calcium flooding, loss of cell membrane integrity, cell lysis, and ROS-mediated damage.<\/li>\n<li><strong>Microorganisms:<\/strong>\u00a0 Bacteria, viruses, fungi (e.g., yeast), helminths, and protozoa cause cellular damage through direct infection and\/or inflammatory responses<\/li>\n<li><strong>Abnormal metabolic diseases: <\/strong> Rare conditions in which toxic waste products accumulate inside cells (e.g., inherited Tay Sachs Disease)<\/li>\n<li><strong>Malnutrition:<\/strong>\u00a0 Cells deprived of essential building blocks cannot maintain normal function and may deteriorate and die.<\/li>\n<li><strong>Fluid and electrolyte imbalance:<\/strong>\u00a0 Disruptions in the balance of water and electrolytes can be severely damaging to the heart, brain, and kidneys.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<figure id=\"attachment_6355\" aria-describedby=\"caption-attachment-6355\" style=\"width: 300px\" class=\"wp-caption alignnone\"><a href=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand.jpg\" target=\"_blank\" rel=\"noopener\"><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-6355 size-medium\" src=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand-300x227.jpg\" alt=\"Electrical burns may show erythema and bullae from the heat of arcing current or may be non-descript with severe internal damage between the points of contact and exit of the electrical current.\" width=\"300\" height=\"227\" srcset=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand-300x227.jpg 300w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand-65x49.jpg 65w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand-225x170.jpg 225w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2026\/05\/Electrical_burn_on_hand.jpg 325w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/a><figcaption id=\"caption-attachment-6355\" class=\"wp-caption-text\">Electrical burns may show erythema and bullae from the heat of arcing current or may be non-descript with severe internal damage between the points of contact and exit of the electrical current.<\/figcaption><\/figure>\n<figure id=\"attachment_2233\" aria-describedby=\"caption-attachment-2233\" style=\"width: 250px\" class=\"wp-caption alignnone\"><a href=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound.jpg\" target=\"_blank\" rel=\"noopener\"><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-2233 size-full\" src=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound.jpg\" alt=\"Electrical burn exit wound. Current flows through the body from the entrance point, until finally exiting where the body is closest to the ground. This foot suffered massive internal injuries, which weren't readily visible, and had to be amputated a few days later.\" width=\"250\" height=\"168\" srcset=\"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound.jpg 250w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound-65x44.jpg 65w, https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-content\/uploads\/sites\/1961\/2024\/09\/Electrical_burn_exit_wound-225x151.jpg 225w\" sizes=\"auto, (max-width: 250px) 100vw, 250px\" \/><\/a><figcaption id=\"caption-attachment-2233\" class=\"wp-caption-text\">Electrical burn exit wound. Current flows through the body from the entrance point, until finally exiting where the body is closest to the ground. This foot suffered massive internal injuries, which weren&#8217;t readily visible, and had to be amputated a few days later.<\/figcaption><\/figure>\n<p>&nbsp;<\/p>\n<div class=\"textbox textbox--examples\">\n<header class=\"textbox__header\">\n<p class=\"textbox__title\"><strong>\u2217 A Real-World Story:\u00a0 Water Intoxication &#8211; &#8216;Don&#8217;t Wee for a Wii&#8217;<\/strong><\/p>\n<\/header>\n<div class=\"textbox__content\">\n<p>In 2007, a US radio show hosted a &#8220;Hold Your Wee for a Wii&#8221; content where contestants competed for a video game console by drinking water bottles every 15 minutes while not being allowed to use the washroom.\u00a0 Unfortunately, the radio station ignored calls from a nurse and other listeners about the lethal dangers of <strong>water intoxication<\/strong>.\u00a0 One contestant, a 28 year old mother of three, left the contest complaining of swollen stomach and severe head pain, dying later the same day.<\/p>\n<p>What the organizers did not realize is that consuming large volumes of water in a short period of time causes a dangerous drop in blood electrolyte concentrations &#8211; a condition known as water intoxication (or <strong>hyponatremia,<\/strong> due to diluted blood sodium levels).\u00a0 The resulting electrolyte imbalance can lead to impaired heart and brain function and be fatal, by causing brain swelling or heart attacks.<\/p>\n<p>This tragic case illustrate why extreme dietary behaviours &#8211; including overconsumption of water &#8211; can be just as dangerous as deprivation.<\/p>\n<\/div>\n<\/div>\n<div class=\"media-attributions clear\" prefix:cc=\"http:\/\/creativecommons.org\/ns#\" prefix:dc=\"http:\/\/purl.org\/dc\/terms\/\"><h2>Media Attributions<\/h2><ul><li about=\"https:\/\/commons.wikimedia.org\/wiki\/File:Structural_changes_of_cells_undergoing_necrosis_or_apoptosis.png\"><a rel=\"cc:attributionURL\" href=\"https:\/\/commons.wikimedia.org\/wiki\/File:Structural_changes_of_cells_undergoing_necrosis_or_apoptosis.png\" property=\"dc:title\">Private: necrosis_vs_apoptosis<\/a>  &copy;  National institute on alcohol abuse and alcoholism (NIAAA)    is licensed under a  <a rel=\"license\" href=\"https:\/\/creativecommons.org\/publicdomain\/mark\/1.0\/\">Public Domain<\/a> license<\/li><li about=\"https:\/\/commons.wikimedia.org\/wiki\/File:Electrical_burn_on_hand.jpg#\/media\/File:Electrical_burn_on_hand.jpg\"><a rel=\"cc:attributionURL\" href=\"https:\/\/commons.wikimedia.org\/wiki\/File:Electrical_burn_on_hand.jpg#\/media\/File:Electrical_burn_on_hand.jpg\" property=\"dc:title\">Electrical_burn_on_hand<\/a>  &copy;  National Institute for Occupational Safety and Health (NIOSH)    is licensed under a  <a rel=\"license\" href=\"https:\/\/creativecommons.org\/publicdomain\/mark\/1.0\/\">Public Domain<\/a> license<\/li><li about=\"https:\/\/commons.wikimedia.org\/wiki\/File:Electrical_burn_exit_wound.jpg\"><a rel=\"cc:attributionURL\" href=\"https:\/\/commons.wikimedia.org\/wiki\/File:Electrical_burn_exit_wound.jpg\" property=\"dc:title\">Private: Electrical_burn_exit_wound<\/a>  &copy;  Occupational Safety and Health Administration    is licensed under a  <a rel=\"license\" href=\"https:\/\/creativecommons.org\/publicdomain\/mark\/1.0\/\">Public Domain<\/a> license<\/li><\/ul><\/div>","protected":false},"author":1370,"menu_order":9,"template":"","meta":{"pb_show_title":"on","pb_short_title":"","pb_subtitle":"","pb_authors":["zoe-soon"],"pb_section_license":"cc-by-nc-sa"},"chapter-type":[],"contributor":[60],"license":[57],"class_list":["post-6265","chapter","type-chapter","status-web-only","hentry","contributor-zoe-soon","license-cc-by-nc-sa"],"part":3,"_links":{"self":[{"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/chapters\/6265","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/chapters"}],"about":[{"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/wp\/v2\/types\/chapter"}],"author":[{"embeddable":true,"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/wp\/v2\/users\/1370"}],"version-history":[{"count":10,"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/chapters\/6265\/revisions"}],"predecessor-version":[{"id":6641,"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/chapters\/6265\/revisions\/6641"}],"part":[{"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/parts\/3"}],"metadata":[{"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/chapters\/6265\/metadata\/"}],"wp:attachment":[{"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/wp\/v2\/media?parent=6265"}],"wp:term":[{"taxonomy":"chapter-type","embeddable":true,"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/pressbooks\/v2\/chapter-type?post=6265"},{"taxonomy":"contributor","embeddable":true,"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/wp\/v2\/contributor?post=6265"},{"taxonomy":"license","embeddable":true,"href":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/wp-json\/wp\/v2\/license?post=6265"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}