Cell Injury PDF

= only for your understanding Lecture 1: Cell injury Dr Aisha Tabassum, MD Pathology Assistant Professor, Batterjee Medical college.  Overview of Cellular Responses to Stress and Noxious Stimuli R...

= only for your understanding Lecture 1: Cell injury Dr Aisha Tabassum, MD Pathology Assistant Professor, Batterjee Medical college.  Overview of Cellular Responses to Stress and Noxious Stimuli Reversible Cell Injury: Pathologic changes that can be reversed when the stimulus is removed or if the cause of injury is mild.  Irreversible Cell Injury: Pathologic changes that are severe and permanent → cause cellular death (necrosis or apoptosis).  Causes of Cell Injury A. Oxygen Deprivation: Hypoxia, Ischemia: Most common cause B. Chemical Agents and Drugs. C. Physical Agents: Trauma, extreme temperature, radiation, electric D. Infections Agents. E. Immunological Reactions. F. Genetic Defects. G. Nutritional Imbalances (deficiency or excess!). H. Aging.  The Progression of Cell Injury and Death Myocardial cells > noncontractile after 1 to 2 minutes of ischemia Do not die until 20 to 30 minutes of ischemia-Reversible Features of death of ischemic myocytes by electron microscopy within 2 to 3 hours after the death of the cells, but not evident by light microscopy until 6 to 12 hours later-Irreversible  Reversible Cell Injury Cellular swelling (hydropic change or vacuolar degeneration): Cells take in water as a result of the failure of energy-dependent ion pumps in the plasma membrane Plasma membrane: Blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments Fatty change: Manifested by the appearance of triglyceride containing lipid vacuoles in the cytoplasm Redder cytoplasm (eosinophilic)  Mitochondria: Swelling and the appearance of phospholipid-rich amorphous densities Dilation of the ER with detachment of ribosomes Myelin figures: Which are collections of phospholipids resembling myelin sheaths that are derived from damaged cellular membranes Nuclear alterations: Clumping of chromatin  Irreversible Cell Injury(Cell death) Mitochondria, Membranes and Nucleus (MMN)! 1.The inability to restore mitochondrial function 2.Breakdown of membranes: plasma membrane and intracellular membranes 3.The loss of DNA and chromatin structural integrity DCT: swollen reptured Normal Reversible Irreversible  Types of cell death With continuing damage, the injury becomes irreversible, at which time the cell cannot recover, and it dies.  There are two types of cell death— necrosis and apoptosis—which differ in their morphology, mechanisms, and roles in disease and physiology. Necrosis--changes produced by enzymatic digestion of dead cellular elements.  Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products  Necrosis Definition: Characteristics: Death of a group of cells within living organism. “Necrosis refers to a spectrum of Death of large groups of cells morphologic changes that follow cell followed by acute inflammation. death in living tissue, largely resulting Due to some underlying from progressive degradative action of pathologic process; never enzymes on the lethally injured cells”. physiologic. Divided into several types based on morphological features.  Necrosis: Morphological features  The necrotic cell is eosinophilic (pink) and glassy and may be vacuolated.  The cell membranes are fragmented.  Nuclear changes in necrotic cell include 3 forms: Pyknosis: shrinkage (small), dense nucleus. Karyorrheix: fragmentation: nucleus broken up into many clumps. Karyolysis : dissolved nucleus - DNase activity++.  Presence of Inflammatory cells.  Types of necrosis: 1. Coagulative Necrosis (most common). 2. Liquefactive Necrosis. 3. Caseous Necrosis. 4. Fat Necrosis. 5. Fibrinoid necrosis. 6. Gangrenous Necrosis  Coagulative Necrosis (most common) Occurs due to ischemia. This pattern of ischemic necrosis is called infract and seen in any solid organs, except the brain. Characterised by denaturation of structural proteins and enzymes.  Grossly: tissue is firm, often wedge-shaped and pale.  Microscopically: Cell outlines are preserved but details are lost, the nucleus disappears, cells look ghostly, and everything looks red (eosinophilic).  Example: Kidney infraction, Myocardial infarction.  Liquefactive Necrosis  Characterized by digestion of the dead cells, resulting in transformation of the tissue into a viscous liquid  Seen in focal bacterial or fungal infections  As microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells  Necrotic material is frequently creamy yellow due to excess of leukocytes and is called pus  Also in brain infarction  Caseous Necrosis Most often seen in tuberculosis,  Characteristically associated with the granulomatous inflammation.  Grossly: Soft and friable necrotic tissue with “cottage cheese –like” appearance(=Caseous) Microscopically:Necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance surrounded by a collection of macrophages and other inflammatory cells ”granuloma”  Fat Necrosis May be traumatic (e.g., breast) or enzymatic (e.g. acute pancreatitis).  Fatty acids released by trauma (e.g., breast) or lipase (e.g. acute pancreatitis) join with calcium via a process called saponification.  Grossly: chalky, white areas from the combination of the newly- formed free fatty acids with calcium (saponification).  Microscopically: shadowy outlines of dead fat cells surrounded by basophilic calcium deposits and inflammatory reaction. The digested fat loses its cellular outlines.  Fibrinoid necrosis Specified form of necrosis usually seen in immune reactions involving blood vessels.  Immune complexes (antigen-antibody complexes) and fibrin are deposited in vessel walls.  Characteristic of malignant hypertension and vasculitis.  Grossly: changes too small to see grossly.  Microscopically: vessel walls are thickened and pinkish-red, hence called fibrinoid necrosis.  Gangrenous Necrosis  Not a specific pattern , clinically used terminology  Usually applied to a limb, like lower leg, lost its blood supply (ischemia) and has undergone coagulative necrosis involving multiple tissue layers → dry gangrene.  Toes and foot in elderly people due to atherosclerosis.  When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes → called wet gangrene. Occurs in moist tissue (bowel, mouth cervix, vulva, lung) ; and in diabetic foot.  Apoptosis “Programmed cell death or suicide in which the cell membrane remains intact”  Involves single cells or small groups of cells.  Energy dependent process designed to switch off and eliminate unwanted cells.  No inflammatory reaction takes place.  Requires cellular signal i.e. protein cleavage within cell, causing cellular death.  Prevents neoplastic transformation.  Responsible for both physiological and pathological events Types of Apoptosis  Mechanism of Apoptosis Apoptosis is mediated by caspases that activate proteases and endonucleases Intrinsic Pathway: Cellular injury, DNA damage, loss of hormonal stimulation leads to inactivation of BCL2 Lack of BCL2 allows cytochrome c to leak from mitochondria and activates caspases Extrinsic Pathway: FAS ligand binds to FAS death receptor, activates caspases TNF receptor binds TNF, activates caspases Mechanism of Apoptosis Differences between necrosis and apoptosis * imp  Autophagy An adaptation to nutrient deprivation in which cells digest their own organelles and recycle them to provide energy and substrates If the stress is too severe for the process to cope with it, it results in cell death by apoptosis  Mechanism of cell injury  The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity  The consequences of an injurious stimulus also depend on the type, status, adaptability, and genetic makeup of the injured cell  Mechanism of cell injury 1) ATP Depletion. 2) Mitochondrial Membrane Damage “Permeability Transition” 3) Influx of Ca++ Ions & Loss of Calcium Homeostasis. 4) Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress). 5) Membrane Damage. 6) Protein misfolding and DNA Damage → triggers apoptosis. Mechanism of cell injury ATP depletion Mitochondrial Membrane Damage  Calcium ions normally serve as second messengers in several signaling pathways, but if released into the cytoplasm of cells in excessive amounts, are also an important source Influx of of cell injury. Ca++ Ions Intracellular Ca++ is sequestered in & Loss of Mitochondria & ER. Calcium Homeosta Increased cytosolic Ca++: sis  Activates various enzymes: ATPases, Phospholipases, Proteases, endonucleases → Membrane Damage  Also increases mitochondrial permeability.  Membrane damage Increased permeability of cellular membranes may affect:  Plasma membrane.  Lysosomal membranes.  Mitochondrial membranes.  Typically culminates in necrosis.  References: Kumar V. et al, 2021. Robbins & Cotran Pathologic basis of disease, 10th ed. Chapter 2, P 33-70 WWW.Amboss.com https://youtu.be/1vaEVcMfa1E?si=MRD3xEpdD81dVXrs https://youtu.be/9xFk99C0gyk?si=757YQsakB2Qymx7A https://youtu.be/iNmMEfV-7w0?si=nXfaIT0fGvDhwQot Thank You