Cell Injury Dr Ban 2024-2025 PDF

Cell Adaptation, Cell Injury and Cell Death Prof. Dr. Ban J. Qasim MBChB, MSc, PhD Path Objectives The students will understand: ´ Concept of adaptation and cell injury ´ Reversible vs. irreversible cell injury ´ Causes and mechanisms of cell injury ´ Apoptosis vs. necrosis  Extra...

Cell Adaptation, Cell Injury and Cell Death Prof. Dr. Ban J. Qasim MBChB, MSc, PhD Path Objectives The students will understand: ´ Concept of adaptation and cell injury ´ Reversible vs. irreversible cell injury ´ Causes and mechanisms of cell injury ´ Apoptosis vs. necrosis  Extracellular stresses homeostasis Adapt atrophy hypertrophy X hyperplasia metaplasia Cell death necrosis apoptosis Cell injury  Adaptations ´ are reversible changes in the cells in response to changes in their environment. ´ When the stress is eliminated the cell can recover to its original state.  HYPERTROPHY ´Is an increase in the size of cells, resulting in an increase in the size of the organ. ´No new cells, just bigger cells enlarged by an increased amount of structural proteins and organelles. ´Hypertrophy and hyperplasia (increase in cell number) can also occur together, and result in an enlarged (hypertrophic) organ. ´Enlargement of the uterus during pregnancy occurs as a consequence of estrogen- stimulated smooth muscle hypertrophy and smooth muscle hyperplasia. ´ In contrast, the striated muscle cells in both the skeletal muscle and the heart can undergo only hypertrophy in response to increased demand because in the adult they have limited capacity to divide. Can be: ´ Physiological Ø Muscles hypertrophy of bodybuilders caused by increased workload. Ø Enlargement of the uterus during pregnancy caused by estrogen. ´ Pathological: myocardial muscle fibers hypertrophy resulting from hypertension.  HYPERPLASIA ´Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased mass of the organ or tissue. ´Occurs in cells capable of replication ´Hyperplasia can be physiologic or pathologic.  Physiologic Hyperplasia ´The proliferation of the glandular epithelium of the female breast in puberty and pregnancy. ´When a liver is partially resected, mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal weight.  Pathologic Hyperplasia ´Endometrial hyperplasia due to increases in the amount of estrogen, with consequent hyperplasia of the endometrial glands. This is a common cause of abnormal menstrual bleeding. ´Benign prostatic hyperplasia induced by androgens. Benign prostatic hyperplasia Normal uterus Pathologic Hyperplasia Dr.T.Krishna MD, www.mletips.com ´Pathologic hyperplasia constitutes a risk for cancerous proliferation. ´Thus, patients with hyperplasia of the endometrium are at increased risk of developing endometrial cancer.  ATROPHY ´Shrinkage of the size of the cell by the loss of cell substance. ´When a sufficient number of cells involved , the entire tissue or organ diminishes in size , becoming atrophic. ´Although atrophic cells may have diminished function, they are not dead. ´Atrophy results from decreased protein synthesis and increased protein degradation in cells.  The common causes of atrophy are the following: q Decreased workload (disuse atrophy). skeletal muscle atrophy due to immobilization caused by fractured bone q Loss of innervation (denervation atrophy). Nerve damage q Diminished blood supply (ischemia). brain atrophy in elderly because of reduced blood supply as a result of atherosclerosis. q Inadequate nutrition. is associated with the use of skeletal muscle as a source of energy after other reserves such as adipose stores have been depleted. q Loss of endocrine stimulation. loss of hormone stimulation after menapause leads to endometrial atrophy. q Aging. senile atrophy  Blood supply Nerve Supply Nutrition Does A Function  METAPLASIA ´Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. ´It may represent substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment.  METAPLASIA ´It is a genetic “reprogramming” of stem cells and not changing of already differentiated cells. ´Metaplastic cells survive but protective mechanism is lost. ´If the influences are persistent, there is an increased chance of malignant transformation.  Types of metaplpasia 1) Epithelial metaplasia ´A) Metaplasia from columnar to squamous (Squamous metaplasia). E.g.,In the habitual cigarette smoker, the normal ciliated columnar epithelial cells of the trachea and bronchi are often replaced by stratified squamous epithelial cells. ´ Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucus secretion and ciliary clearance. Lung cancer (squamous cell carcinoma) may arise later in areas of squamous metaplasia. ´ B) Metaplasia from squamous to columnar type may also occur, as in Barrett esophagus, in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells under the influence of refluxed gastric acid. ´ Cancers may arise in these areas; these are typically glandular (adeno)carcinomas Barrett esophagus 2) Mesenchymal tissue metaplasia Bone is occasionally formed in soft tissues in foci of injury. Formation of Scar bone in fibrous tissue in case of healing of a Bone wound  Cell Injury and Cell Death ´Cell injury occurs when cells are exposed to severe stress or damaging agents that they are no longer able to adapt. ´Cell injury is reversible up to a certain point, but if the stimulus persists or is severe, the cell suffers irreversible injury and ultimately cell death. Reversible cell injury In early stages or mild forms of injury, the changes are reversible if the damaging stimulus is removed. At this stage, although there may be significant structural and functional abnormalities, the injury has not progressed to severe membrane damage and nuclear dissolution. ´ The hallmarks of reversible injury is depletion of energy stores (ATP), and cellular swelling. Irreversible cell injury (cell death) ´With continuing damage, the injury becomes irreversible, at which time the cell cannot recover and it dies. ´When large numbers of cells die the tissue or organ is said to be necrotic. ´Necrosis is the major pathway of cell death in many injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma. ´Severe depletion of ATP and loss of membrane integrity are typically associated with necrosis ´There is membrane damage of necrotic cells ;their contents leak out, this can result in an inflammation in the surrounding tissue. ´ The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells (autolysis). ´Cellular function may be lost long before cell death occurs, and the morphologic changes of cell injury (or death) occur later. ´For example, myocardial cells become noncontractile after 1 to 2 minutes of ischemia, although they do not die until 20 to 30 minutes have passed. Causes of Cell Injury Changes of REVERSIBLE INJURY ´ Two features of reversible cell injury can be recognized under the light microscope: ´ 1.Cellular swelling (hydropic degeneration) is the result of failure of energy-dependent ion pumps in the plasma membrane. ´ 2. Fatty change :It is the appearance of lipid vacuoles in the cytoplasm. It is seen in cells dependent on fat metabolism, such as hepatocytes and myocardial cells. Changes of reversible cell injury by electron microscopy (ultrastructural changes):  Changes of irreversible cell injury “necrosis” By light microscopy : ´Cytoplasm show increased eosinophilia. ´Nuclear changes are: ´Pyknosis: nuclear shrinkage and increased basophilia. ´Karyorrhexis: nuclear fragmentation. ´Karyolysis: The basophilia of the chromatin may fade and nucleus totally disappears.  Changes of irreversible cell injury “necrosis” normal pyknosis karyolysis karyorrhexis Liver cell necrosis Changes of irreversible cell injury “necrosis” by electron microscopy (ultrastructural changes): Changes of irreversible cell injury “necrosis”  Patterns (types) of Tissue Necrosis ´1.Coagulative necrosis :the architecture of dead tissues is preserved. The cells are eosinophilic, anucleated cells. ´Cause :Ischemia in all organs except the brain. ´ A localized area of coagulative necrosis is called an infarct. Normal cardiac muscle ´2.Liquefactive necrosis: is characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid. Examples : ´Hypoxic cell death of the brain ´Abscess ´3.Gangrenous necrosis :It is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone necrosis (coagulative necrosis). ´4.Caseous necrosis :is seen in tuberculous infection.The term “caseous” (cheeselike) is derived from the friable white appearance of the area of necrosis.  5.Fat necrosis : ´ Enzymatic fat necrosis: occurs in acute pancreatitis ,pancreatic enzymes leak out and liquefy the fat cells in the peritoneum. The derived fatty acids, combine with calcium to produce chalky-white areas (fat saponification). ´ Traumatic fat necrosis :e.g.fat necrosis of breast after trauma which induces rupture of fat cells. The released fat causes chronic inflammation and foreign body reaction resulting in a hard mass mistaken as malignant tumor.  Mechanisms of Cell Injury 1.DEPLETION OF ATP ´The major causes are reduced supply of oxygen (ischemia) and nutrients, and some toxins (e.g., cyanide). ´Depletion of ATP to less than 5% to 10% of normal levels has widespread effects on many critical cellular systems: 2.INFLUX OF CALCIUM Ischemia and certain toxins cause an increase in cytosolic calcium concentration. Increased cytosolic Ca2+ activates a number of enzymes, including:  3. ACCUMULATION OF OXYGEN- DERIVED FREE RADICALS (OXIDATIVE STRESS) ´Free radicals are chemical species with a single unpaired electron in an outer orbital. ´Such chemical states are extremely unstable and readily react with inorganic and organic chemicals; ´ when generated in cells they avidly attack nucleic acids as well as a variety of cellular proteins and lipids (cell membrane). ´ Reactive oxygen species (ROS) are a type of oxygen-derived free radical whose role in cell injury is well established. ´They are produced normally in cells during mitochondrial respiration and energy generation. ´Free radicals are unstable and decay spontaneously or are degraded and removed by cellular defense systems: Ø Superoxide dismutases (SODs) Ø Glutathione (GSH) peroxidase Ø Catalase Ø Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C, and β- carotene) ´When the production of ROS increases, the result is an excess of these free radicals, leading to a condition called oxidative stress. ´Cell injury results from damage by free radicals in the following situations: ischemia-reperfusion , chemical and radiation injury, oxygen toxicity, infection, and inflammation.  Apoptosis ´Apoptosis is a pathway of cell death induced by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading the cells' own nuclear DNA and nuclear and cytoplasmic proteins. ´Fragments of the apoptotic cells then break off (apoptosis: falling off). ´The plasma membrane of the apoptotic cell remains intact, its fragments become avid targets for phagocytes. ´Therefore cell death by this pathway does not elicit an inflammatory reaction in the host.  MORPHOLOGIC CHANGES IN APOPTOSIS ´Cell shrinkage. ´The nucleus break up into small fragments. ´Formation of apoptotic bodies composed of cytoplasm ,nuclear fragments and organelles ´The apoptotic bodies are rapidly ingested by phagocytes. ´ On histologic examination, in tissues stained with hematoxylin and eosin, the apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin fragments.  CAUSES OF APOPTOSIS Physiologic ´ During embryogenesis ´ Involution of hormone-dependent tissues upon hormone withdrawal, such as, the regression of the lactating breast after weaning ´ Cell loss in proliferating cell populations, such as, epithelial cells in intestinal crypts, to maintain a constant number.  CAUSES OF APOPTOSIS Physiologic ´ Death of cells that served their purpose: Neutrophils in an acute inflammatory response ´ Elimination of potential harmful self-reactive lymphocytes (Prevents reaction against one’s own tissue). ´ Cell death by cytotoxic T lymphocytes , a defense mechanism against viruses and tumors. Pathologic q DNA damage. Radiation, cytotoxic anticancer drugs q Accumulation of misfolded proteins. because of mutations in the genes or free radicals. q Viral infections e.g. viral hepatitis in which apoptotic cells are known as councilman bodies. q Pathologic atrophy in paranchymal organs after duct obstruction such pancreas and parotid gland. Feature Necrosis Apoptosis Cell size Enlarged Reduced (shrinkage) (swelling) Nucleus Pyknosis ➙ Fragmentation into karyorrhexis ➙ nucleosome-size fragments karyolysis Plasma Disrupted Intact membrane Cellular contents Enzymatic Intact digestion; may leak out of cell Adjacent Frequent No inflammation Physiologic or pathologic Often physiologic, pathologic role may be pathologic after some forms of cell injury, especially DNA damage