CELL INJURY, DEATH, ADAPTATION NML.pptx

Cell cycle and control Dr Bernard Petershie  Cellproliferation is fundamental to organism development, to maintenance of steady-state tissue homeostasis, and to replacement of dead or damaged cells.  Thekey elements of cellular proliferation are accurate DNA replication, coordi...

Cell cycle and control Dr Bernard Petershie  Cellproliferation is fundamental to organism development, to maintenance of steady-state tissue homeostasis, and to replacement of dead or damaged cells.  Thekey elements of cellular proliferation are accurate DNA replication, coordinated synthesis of other cellular components, and equal apportionment of DNA and organelles to daughter cells through the processes of mitosis and cytokinesis. DNA REPLICATION Mitosis Cytokinesis  The sequence of events that results in cell proliferation is called the cell cycle; it consists of G1 (gap 1), S (DNA synthesis), G2 (gap 2), and M (mitotic) phases.  Quiescentcells that are not actively cycling are in the G0 (gap 0) state.  Cells can enter G1 either from the G0 quiescent cell pool or after completing a round of mitosis.  Each stage requires completion of the previous step, as well as activation of necessary factors.  Nonfidelity of DNA replication or cofactor deficiency results in arrest at various transition points.  The cell cycle is regulated by activators and inhibitors.  Cell cycle progression is chaperoned by proteins called cyclins (named for the cyclic nature of their production and degradation) and cyclin-associated enzymes called cyclin dependent kinases (CDKs).  Constitutively synthesized CDKs acquire kinase activity—that is, the ability to phosphorylate protein substrates—by forming complexes with the relevant cyclins.  Transiently increased synthesis of a particular cyclin thus leads to increased kinase activity of the appropriate CDK binding partner.  Asthe CDK completes its round of phosphorylation, the associated cyclin is degraded and CDK activity abates.  Consequently, as cyclin levels rise and fall, activity of associated CDKs will likewise wax and wane  More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs.  Thecell cycle thus resembles a relay race in which each leg is regulated by a distinct set of cyclins  As one collection of cyclins leaves the track, the next set takes over.  Surveillancemechanisms primed to sense DNA or chromosomal damage are embedded within the cell cycle.  These quality control checkpoints ensure that cells with genetic imperfections do not complete replication.  Thus the G1-S checkpoint monitors DNA integrity before irreversibly committing cellular resources to DNA replication.  Laterin the cell cycle, the G2-M restriction point insures that there has been accurate genetic replication before the cell actually divides.  When cells do detect DNA irregularities, checkpoint activation delays cell cycle progression and triggers DNA repair mechanisms.  Ifthe genetic derangement is too severe to be repaired, cells either undergo apoptosis or enter a nonreplicative state called senescence— primarily through p53-dependent mechanisms.  Enforcingthe cell cycle checkpoints is the job of CDK inhibitors (CDKIs); they accomplish this by modulating CDK-cyclin complex activity.  There are several different CDKIs. One family of CDKIs—composed of three proteins called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C)— broadly inhibits multiple CDKs. Another family of CDKIs has selective effects on cyclin CDK4 and cyclin CDK6; these proteins are called p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D). Defective CDKI checkpoint proteins allow cells with damaged DNA to divide, resulting in mutated daughter cells at risk for malignant transformation.  An equally important aspect of cell growth and division is the biosynthesis of the membranes, cytosolic proteins, and organelles necessary to make two daughter cells.  Thus as growth factor receptor signaling stimulates cell cycle progression, it also activates events that promote the metabolic changes that support growth.  Chiefamong these is the switch to aerobic glycolysis (with the counter-intuitive reduction in oxidative phosphorylation), also called the Warburg effect. These alterations in cell metabolism are an important element in cancer cell growth. CELL INJURY, CELL DEATH & ADAPTATIONS (Pathophysiology of cell adaptations) Introduction Cells are classified according to their proliferative potential into:  Labile cells  Stable cells  Permanent cells I.Labile Cells These are continually dividing cells which pass directly from M to G1 E.g.  -Epidermis of the skin  -Surface epithelium of GI and GU systems  -Hemopoietic cells II. Stable Cells  These are in quiescent state (Go state). They can divide when they are activated. E.g. are:  Hepatocytes  Renal tubular cell  Glandular cells  Mesenchymal cells (smooth muscle, III. Permanent Cells  These cells have left the cell cycle and cannot undergo mitotic division. E.g. are : Neurons Cardiac muscle cells Skeletal muscle cells Types of Cell Adaptations  Atrophy  Hypertrophy  Hyperplasia  Metaplasia Hypertrophy  It is an increase in the size of the parenchymal cells, which will eventually lead to an increase in the size of the organ. It results in increased protein in organelles. They are typically not pathologic. Causes of Hypertrophy  Increased functional demand. E.g. uterus during pregnancy  Stimulation by hormones and growth factors  Increased protein synthesis within cells, or decreased protein breakdown Mechanism of Hypertrophy  Increased production of cellular proteins  And this is due to the increased activation of genes responsible for the production of the proteins  Sometimes a subcellular organelle may undergo selective hypertrophy.  E.g. Patients on barbiturates show hypertrophy of the smooth endoplasmic reticulum (ER) in hepatocytes, an e.g. of an adaptive response Classification of Hypertrophy Basically two types:  Physiologic hypertrophy  Pathologic hypertrophy I.Physiologic Hypertrophy  Enlarged size of the uterus in pregnancy. This is largely due to estrogenic hormones, leading to stimulation of estrogen receptors on smooth muscle. This results in an increased smooth muscle proteins. And this gradually cause the increase in size of the organ  Hypertrophy of breast during lactation (due to hormones like estrogen and lactic)  Skeletal muscle hypertrophy in body builders and athletes Pathologic Hypertrophy E.g. I. Cardiac Muscle Hypertrophy This can be divided into;  Pressure load in diseases (e.g. Hypertension, coarctation of aorta), or  Volume load (e.g. Valvular disease such as mitral, tricuspid, aortic, pulmonary or valvular)  Cardiomyopathy (familial, viral, toxic, metabolic) II. Skeletal Muscle Hypertrophy  It is as a result of a compensation following the loss or atrophy of surrounding muscle due to myopathic or neuropathic disorder.  In this case, the muscle fibers will be abnormal in pathologic hypertrophy III. Smooth Muscle Hypertrophy  Typically seen in the bladder wall due to increased resistance to outflow of urine from the bladder  E.g. In cases of enlarged prostate Hypertrophy of the Heart Increased thickness of left ventricular wall, often exceeding >1.5 cm (normal ventricular wall thickness) Hyperplasia  An increase in the number of cells in an organ. It is due to increased cell division faster than death.  It takes place if the cell population is capable of dividing.  It cannot occur in permanent cells like cardiac and skeletal muscle or nerves, since they are not capable of dividing.  It however occurs in labile cells and stable cells. Mechanism of Hyperplasia Results from growth factor induced proliferation of mature cells or, Increased output of new cells from stem cells Classification of Hyperplasia Categorized into two groups 1. Physiologic 2. Pathologic I.Physiologic Hyperplasia E.g.  Enlarged size of the uterus in pregnancy  Breast-puberty, pregnancy and lactation Compensatory Hyperplasia Regeneration of liver, bone marrow hyperplasia (e.g. In anemia) II. Pathologic Hyperplasia 1. Endometrial hyperplasia 2. Nodular hyperplasia of the prostate 3. Hyperplasia of the epidermis in warts(papillomavirus) Metaplasia  It is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. Mechanism of Metaplasia  Basically due to reprogramming of the precursor cells present in the normal tissue or the mesenchymal tissues (e.g. reprogramming of squamous epithelial cells to columnar epithelium)  In metaplasia, there will be a differentiation into a new cell lineage  This is due to signals generated by various cytokines, growth factors and extracellular matrix components in the cell environment.  In other words, there will be expression of genes that promote differentiation Metaplasia Can be classified as:  Epithelial metaplasia  Mesenchymal metaplasia I. Epithelial Metaplasia E.g.  Squamous metaplasia  E.g. Bronchus (in smokers), uterine cervix, gall bladder, renal pelvis  Columnar metaplasia  E.g. Barrett’s esophagus, intestinal & gastric metaplasia II. Mesenchymal Metaplasia E.g. 1.Osseous metaplasia e.g. arterial wall, myositis ossificans, stroma of tumor, cartilage of larynx in elderly 2. Cartilaginous metaplasia e.g. healing of fractures Atrophy Reduction in the size of an organ or tissue due to a decrease in cell size and number. Physiologic atrophy occurs in fetal development and decrease in uterine size after parturition. Causes of Pathologic Atrophy  Decreased use  Decreased blood supply  Decreased nutrition  Change in hormones e.g. puberty  Loss of innervation  Pressure Cell injury I. Reversible  Cells are generally able to continue functioning despite changing their environment. When cells are threatened, they react by;  Drawing on reserves to keep functioning  Adaptive changes or cellular dysfunction II. Irreversible Prolonged stress or changes can injure or kill cells e.g.; I. If stressors outlasts cellular resources, cell death occurs II. Adaptations has failed and thus, cell unable to maintain homeostasis There is no known point of no return. This depends on;  Type, state, adaptive ability of cell  Type, severity, duration of injury or stimulus Causes of Cell injury Oxygen deprivation, Hypoxia , Ischaemia  Cardiorespiratory failure, anaemia, CO poisoning  Physical Agents: (mechanical trauma, burns, frostbite, sudden changes in pressure (barotrauma), radiation, electric shock).  Chemical Agents: glucose, salt, water, poisons (toxins), drugs, pollutants, insecticides, herbicides, carbon monoxide, asbestos, alcohol, narcotics, tobacco. Causes of Cell injury  InfectiousAgents: prions, viruses, rickettsiae, bacteria, fungi, parasites.  Immunologic Reactions: anaphylaxis, autoimmune disease.  GeneticDerangements: Congenital malformations, normal proteins (hemoglobinopathies), enzymes (storage diseases).  Nutritional Imbalances: protein-calorie deficiencies, vitamin deficiencies; excess food intake (obesity, atherosclerosis). Mechanism of cellular injury  Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components Most important target of cellular injury  (1) aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP  (2) the integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends  (3) protein synthesis  (4) the cytoskeleton  (5) the integrity of the genetic apparatus of the cell.  ATP DEPLETION  High-energy phosphate in the form of ATP is required for many synthetic and degradative processes within the cell.  These include membrane transport, protein synthesis, lipogenesis,and the deacylation– reacylation reactions necessary for phospholipid turnover  ATP is produced in two ways.  The major pathway in mammalian cells is oxidative phosphorylation of adenosine diphosphate  The second is the glycolytic pathway, which can generate ATP in the absence of oxygen using glucose derived either from body fluids or from the hydrolysis of glycogen. CONSEQUENCE OF ATP DEPLETION  Theactivity of the plasma membrane energy- dependent sodium pump (ouabain-sensitive Na+,K+-ATPase) is reduced. ----K moves out and Na moves in accompanied by water leading to cellular swelling  Cellular energy metabolism is altered. -----Anaerobic glycolysis is favoured, glycogenolysis increases, there is lactic acid and inorganic phosphate accumulation leading to reduce pH  Failure of the Ca2+ pump leads to influx of Ca2+ -----With damaging effects on numerous cellular components  structural disruption of the protein synthetic apparatus due to prolonged or worsening depletion of ATP -------manifested as detachment of ribosomes from the rough endoplasmic reticulum and dissociation of polysomes into Monosomes  proteins may become misfolded in cells deprived of oxygen or glucose -------misfolded proteins trigger a cellular reaction called the unfolded protein response that may lead to cell injury and even death.  Mitochondrial damage  Mitochondria can be damaged by increases of cytosolic Ca2+, oxidative stress, breakdown of phospholipids through phospholipase A2 and sphingomyelin pathways,and by lipid breakdown products such as free fatty acids and ceramide. ------There is formation of a high-conductance channel,the so-called mitochondrial permeability transition, in the inner mitochondrial membrane This is initially reversible but may progress to irreversibility if injury persist  INFLUX OF INTRACELLULAR CALCIUM AND LOSS OF CALCIUM HOMEOSTASIS  Cytosolic free calcium is maintained at extremely low concentrations (