Cell Injury, Cell Death PDF

INTRODUCTION INTRODUCTION TO PATHOLOGY  ‘Pathology’ is derived from two Greek words—pathos(suffering-disease) logos (study).  Pathology is, the scientific study of changes in the structure and function of the body in disease.  Etiology underlying causes and modifying factors  Pathogenesis: Mecha...

INTRODUCTION INTRODUCTION TO PATHOLOGY  ‘Pathology’ is derived from two Greek words—pathos(suffering-disease) logos (study).  Pathology is, the scientific study of changes in the structure and function of the body in disease.  Etiology underlying causes and modifying factors  Pathogenesis: Mechanisms of progression of disease development and  Thus, etiology refers to why a disease arises and pathogenesis describes how a disease develops. SUBDIVISIONS OF PATHOLOGY HISTOPATHOLOGY  CYTOPATHOLOGY  HAEMATOLOGY  CLINICAL BIOCHEMISTRY  MICROBIOLOGY  IMMUNOLOGY  MEDICAL GENETICS  MOLECULAR PATHOLOGY  Cell Injury  Cells are the basic units of tissues, which form organs and systems in the human body.  Cell injury is defined as the effect of a variety of stresses due to etiologic agents resulting in changes in internal and external environment.  The cellular response to stress depends upon following  i) Host factors i.e. the type of cell and tissue involved.  ii) Factors pertaining to injurious agent i.e. extent and type of cell injury. Cellular responses to cell injury may be as follows: 1. cellular adaptations. 2. reversible cell injury. 3. irreversible cell injury. 4. intracellular accumulations. CAUSES OF CELL INJURY  Hypoxia and ischemia. Hypoxia (oxygen deficiency) and ischemia, (reduced blood supply) are among the most common causes of cell injury.  Toxins. air pollutants, insecticides, CO, asbestos, cigarette smoke, ethanol, and drugs. Infectious agents. viruses, bacteria, fungi, and protozoans, injure cells. Immunologic reactions. Autoimmune reactions against one’s own tissues, allergic reactions against environmental substances, and excessive or chronic immune responses to microbes  Genetic abnormalities. congenital malformations, Down syndrome & sickle cell anemia. Nutritional imbalances A deficiency or an excess of nutrients may result in nutritional imbalances. (e.g. starvation, anaemia) Nutritional excess: obesity, atherosclerosis, heart disease and hypertension. Physical agents. Trauma, extremes of radiation, electric shock. Aging. temperature, MECHANISMS OF CELL INJURY AND CELL DEATH Hypoxia and Ischemia  Deficiency of oxygen leads to failure of many energy dependent metabolic pathways, and ultimately to death of cells by necrosis.  The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation, decreased intracellular pH, and decreased activity of many cellular enzymes.  Hypoxia per se increases the accumulation of ROS.  Hypoxia predisposes cells to ROSmediated damage if blood flow (and oxygen delivery) is reestablished, a phenomenon called reperfusion injury. Ischemia-Reperfusion Injury  Under certain circumstances, the restoration of blood flow to ischemic but viable tissues results, paradoxically, in increased cell injury.  New damage may be initiated during reoxygenation by increased generation of ROS. Oxidative Stress cellular abnormalities that are induced by ROS, which belong to a group of molecules known as free radicals.  Free radical-mediated cell injury is seen in chemical and radiation injury, hypoxia, cellular aging, tissue injury caused by inflammatory cells, and ischemiareperfusion injury.   Free radicals are chemical species with a single unpaired electron in an outer orbit (eg.superoxide (O2 ) & hydrogen peroxide (H2O2).  When generated in cells, they avidly attack nucleic acids as well as a variety of cellular proteins and lipids. Generation and Removal of Reactive Oxygen Species  The accumulation of ROS is determined by their rates of production and removal.  ROS are produced by two major pathways: - ROS are produced normally in small amounts in all cells during the reductionoxidation (redox) reactions Free radical scavengers,  superoxide dismutase (SOD).  Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from oxidative damage.  Catalase,  Endogenous or exogenous anti-oxidants (e.g., vitamins E, A, and C and β-carotene)  Cell Injury Caused by Reactive Oxygen Species  ROS causes cell injury by damaging multiple components of cells : Lipid peroxidation of membranes.  Crosslinking and other changes in proteins.  DNA damage.  Cell Injury Caused by Toxins  Toxins, including environmental chemicals and substances produced by infectious pathogens, induce cell injury and necrotic cell death. Different types of toxins induce cell injury by two general mechanism:  Direct-acting toxins.  Latent toxins.  Endoplasmic Reticulum Stress  The accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to cell death by apoptosis. DNA Damage  Exposure of cells to radiation or chemotherapeutic agents, intracellular generation of ROS, and acquisition of mutations may all induce DNA damage, which if severe may trigger apoptotic death. Inflammation  In all these situations, inflammatory cells, including neutrophils, macrophages, lymphocytes, and other leukocytes, secrete products that evolved to destroy microbes but also may damage host tissues. SEQUENCE OF EVENTS IN CELL INJURY AND CELL DEATH CELLULAR ADAPTATIONS TO STRESS  Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment.  Physiologic adaptations Represent responses of cells to normal stimulation by hormones or endogenous chemical mediators or to the demands of mechanical stress  Pathologic adaptations Are responses to stress that allow cells to modulate their structure and function and thus escape injury, but at the expense of normal function, such as squamous metaplasia of bronchial epithelium in smokers. Hypertrophy  Hypertrophy is an increase in the size of cells resulting in an increase in the size of the organ.   Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by growth factor or hormonal stimulation.  The massive physiologic enlargement of the uterus during pregnancy  the striated muscle cells in both the skeletal muscle and the heart undergo only hypertrophy because adult muscle cells have a limited capacity to divide.  pathologic hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease Heart hypertrophy in hypertension Hyperplasia  Hyperplasia is an increase in the number of cells in an organ that stems from increased proliferation.   Hyperplasia can be physiologic or pathologic. The two types of physiologic hyperplasia are:  (1) hormonal hyperplasia, exemplified by the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy.   (2) compensatory hyperplasia In which residual tissue grows after removal or loss of part of an organ.  Atrophy  Is shrinkage in the size of cells by the loss of cell substance.  Causes of atrophy include:  decreased workload (e.g., immobilization of a limb to permit healing of a fracture),  loss of innervation,  diminished blood supply,  inadequate nutrition,  loss of endocrine stimulation,  and aging (senile atrophy).  Metaplasia  Metaplasia is a change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.  Epithelial metaplasia is exemplified by the change that occurs in the respiratory epithelium of cigarette smokers REVERSIBLE CELL INJURY Reversible Cell Injury Reversible injury is the stage of cell injury at which the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed. In reversible injury, cells and intracellular organelles typically become swollen because they take in water as a result of the failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis. MORPHOLOGY 1 Cellular swelling Due to increased permeability of the plasma membrane. 2 Fatty change is manifested by the appearance of triglyceride containing lipid vacuoles in the cytoplasm. Cellular Swelling Fatty liver Other intracellular changes associated with cell injury include: (1) Plasma membrane alterations such as blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments. (2) Mitochondrial changes such as swelling and the appearance of phospholipid-rich amorphous densities. (3) Dilation of the ER with detachment of ribosomes and dissociation of polysomes. (4) Nuclear alterations, such as clumping of chromatin. (5)The cytoplasm may contain so-called “myelin figures,” which are collections of phospholipids resembling myelin sheaths that are derived from damaged cellular membranes. The biochemical and ultrastructural changes in reversible cell injury are: 1. Decreased generation of cellular ATP 2. Intracellular lactic acidosis: Nuclear clumping 3. Damage to plasma membrane pumps 4. Reduced protein synthesis Up to this point, withdrawal of acute stress that resulted in reversible cell injury can restore the cell to normal state. CELL DEATH IRREVERSIBLE CELL INJURY Persistence of ischaemia or hypoxia results in irreversible damage to the structure and function of the cell (cell death). Two essential phenomena distinguish irreversible from reversible cell injury: -Inability of the cell to reverse mitochondrial dysfunction on reperfusion or reoxygenation. - Disturbance in cell membrane function in general, and in plasma membrane in particular. Biochemical changes affects the ultrastructural components of the cell: 1.Calcium influx: Mitochondrial damage 2.Activatedphospholipases:Membrane damage 3. Intracellular proteases:Cytoskeletal damage. 4.Activated endonucleases: Nuclear damage 5. Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and phagocytosis Irreversible damage to the nucleus can be in three forms: i) Pyknosis: Condensation and clumping of nucleus which becomes dark basophilic. ii) Karyorrhexis: Nuclear fragmentation in to small bits dispersed in the cytoplasm. iii) Karyolysis: Dissolution of the nucleus. Ultrastructural changes during cell injury NECROSIS  Necrosis is a form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell.  Necrosis elicits a local host reaction, called inflammation MORPHOLOGY Necrotic cells show increased eosinophilia (i.e., they are stained red by the dye eosin—the E in the hematoxylin and eosin [H&E] stain), Nuclear changes:  Pyknosis  karyorrhexis  karyolysis  Microscopic view of the edge of the infarct, with normal kidney and necrotic cells in the infarct Morphologic Patterns of Tissue Necrosis Coagulative necrosis  is a form of necrosis in which the underlying tissue architecture is preserved for at least several days after death of cells in the tissue.  The affected tissues take on a firm texture.  Coagulative necrosis is characteristic of infarcts (areas of necrosis caused by ischemia) in all solid organs except the brain. Liquefactive necrosis  is seen in focal bacterial and, occasionally fungal infections because microbes stimulate rapid accumulation of inflammatory cells, and the enzymes of leukocytes digest (“liquefy”) the tissue.  Hypoxic death of cells within the central nervous system often evokes liquefactive necrosis.  If the process is initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus. Gangrenous necrosis  It usually refers to the condition of a limb (generally the lower leg) that has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers.  When bacterial infection is superimposed, the morphologic appearance changes to liquefactive necrosis because of the destructive contents of the bacteria and the attracted leukocytes (resulting in socalled “wet gangrene”). Wet gangrene Dry gangrene Caseous necrosis  Is most often encountered in foci of tuberculous infection.  Caseous means “cheeselike,” referring to the friable yellow-white appearance of the area of necrosis on gross examination Caseation of human tuberculosis granuloma Fat necrosis  refers to focal areas of fat destruction, Fibrinoid necrosis  Is a special form of necrosis. It usually occurs in immune reactions in which complexes of antigens and antibodies are deposited in the walls of blood vessels, Fat necrosis Apoptosis  Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.  Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off”).  The plasma membrane of the apoptotic cell remains intact, but the membrane is altered  apoptotic cell death does not elicit an inflammatory reaction. Causes of Apoptosis Physiologic apoptosis.  During normal development of an organism, some cells die and are replaced by new ones.  In mature organisms, highly proliferative and hormoneresponsive tissues undergo cycles of proliferation and cell loss that are often determined by the levels of growth factors.  In these situations, the cell death is always by apoptosis, ensuring that unwanted cells are eliminated without eliciting potentially harmful inflammation.  In the immune system, apoptosis eliminates excess leukocytes left at the end of immune responses  As well as lymphocytes that recognize self-antigens and could cause autoimmune diseases if they were not removed. Apoptosis in pathologic conditions  Apoptosis eliminates cells that are damaged beyond repair. This is seen when there is severe DNA damage, for example, after exposure to radiation and cytotoxic drugs.  The accumulation of misfolded proteins also triggers apoptotic death.  Certain infectious agents, particularly some viruses, induce apoptotic death of infected cells. Mechanisms of Apoptosis  Apoptosis is regulated by biochemical pathways that control the balance of death- and survival-inducing signals and ultimately the activation of enzymes called caspases. The mitochondrial (intrinsic) pathway  seems to be responsible for apoptosis in most physiologic and pathologic situations. The death receptor (extrinsic) pathway of apoptosis.  Many cells express surface molecules, called death receptors, that trigger apoptosis. Clearance of apoptotic cells.  Apoptotic cells and their fragments enter phagocytes by producing a number of eat-me” signals. MORPHOLOGY  In H&E-stained tissue sections, the nuclei of apoptotic cells show various stages of chromatin condensation and aggregation and, ultimately, karyorrhexis  The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies Apoptotic bodies Apoptotic bodies Autophagy  Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own components.  It is a survival mechanism in times of nutrient deprivation, so that the starved cell can live by eating its own contents and recycling these contents provide nutrients and energy. CELLULAR AGING  Individuals age because their cells age.  Age is one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease. CELLULAR AGING Results from a combination of multiple, progressive cellular alterations, including: 1- Accumulation of DNA damage and mutations 2- Replicative senescence: reduced capacity of cells to divide secondary to progressive shortening of chromosomal ends(telomeres) WERNER SYNDROME A rare disease characterized by premature aging  3-Defective protein homeostasis: loss of normal proteins and accumulation of misfolded proteins 4-Repeated environmental exposure to radiation 5-Progressive reduction of antioxidant defense mechanism Like Vit. E & glutathione peroxidase WERNER SYNDROME