Cellular injury, Cell death and Adaptations Flashcards
The normal cell:
○ Capable of handling physiologic demands ○ Maintains a steady state of homeostasis ○ Capable of adaptation ■ Reversible functional and structural responses to physiologic state ■ Pregnancy (Physiologic stress) ● The uterus will be stimulated to grow big and accommodate the baby
Cellular injury can be:
Reversible and Irreverisible
Reversible
We are able to identify the stress early into the cellular injury and the cell can go back to its normal state
Irreversible
Why does hypertension cause hypertrophy of myocytes?
In hypertension, there is an increase in workload. The myocyte needs to adapt. Since the myocyte is a permanent cell, it cannot divide or reproduce itself. The myocyte adapts in such a way that it could carry out the increased load. Hence, it hypertrophies
Appears as Enlarged heart
In AMI, there is decreased blood flow to the heart → decreased oxygenation → cells will be compromised. If this persists, it will involve more of the population of the myocytes → cell death
OXYGEN DEPRIVATION
● The major and important cause of cell injury
● Causes:
○ Reduced blood flow
○ Cardiorespiratory failure ○ Decreased oxygen-carrying capacity of blood
PHYSICAL AGENTS
● Mechanical trauma
● Extremes of temperature (burns and deep cold)
● Sudden changes in atmospheric pressure
● Radiation
● Electric shock
CHEMICAL AGENTS AND DRUGS
● Can create burns, skin irritation
● Drugs in abnormal dosage
○ Chemotherapeutic drugs are programmed to kill cells
INFECTIOUS AGENTS
IMMUNOLOGIC REACTIONS
● The immune system serves an essential function in defense against infectious pathogens, but immune reactions may also cause cell injury ● Injurious reactions to endogenous self-antigens are responsible for autoimmune diseases ● Allergic reactions
GENETIC ABNORMALITIES
● Deficiency of enzymes and proteins can produce toxic substances and can cause injury
NUTRITIONAL IMBALANCES
● Protein-calorie deficiency ● Vitamin Deficiency
THE PROGRESSION OF CELL INJURY AND CELL DEATH CURVE
● All stresses and noxious influences exert their effects first at the molecular or biochemical level ●
Biochemical alterations → Ultrastructural changes
● The early changes are subtle and are only detected with highly sensitive methods of examination
● With histochemical, ultrastructural, or biochemical techniques, changes may be seen minutes to hours after injury, whereas changes visible by light microscopy or the naked eye may take considerably longer (hours to days) to appear. As would be expected, the morphologic manifestations of necrosis take more time to develop than those of reversible damage
REVERSIBLE CELL INJURY
● A functional and structural alteration in early stages or mild forms of injury
● Features: ○ Generalized swelling of the cell and its organelles
■ Results from influx of water
■ This is usually caused by failure of the ATP-dependent Na-K plasma membrane pump due to depletion of ATP resulting from oxygen deficiency
○ Blebbing of the plasma membrane ○ Detachment of ribosomes ○ Clumping of nuclear chromatin
Explain the injury
● In the middle picture, there is early cellular injury
○ Swelling
■ Vacuoles on top of the cells or Hydropic changes or Vacuolar degeneration
○ Eosinophilia
■ Some of the cells are pinker than the others due to RNA loss
● In the last picture, the cell shows irreversible injury ○ Disintegration of the lining of the cells ○ Some cells do not have their nuclei ○ Vacuolations are bigger
Structural changes in Plasma membrane
Blebbing,
Blunting
Loss of Microvilli
Structural changes in Mitochondria
Swelling
Small densities
Myelin Figures in the Cytoplasm
Derived from phospholipids of damaged membranes
Dilation of ER Detachment of Polysomes
Nuclear Alterations
Disaggregation of granular and fibrillar elements
Electron Microscopy of Normal Cell
Electron micrograph of a normal cell ○ Several microvilli protruding in the apical surface ○ Organelles are arranged in an organized fashion
EM of Reversible injury
○ Presence of blebs ○ Loss of microvilli
Irreversible injury EM
○ Formation of vacuoles, blebs, and deposits ○ Enlargement of organelles (Swelling) ○ Disintegrated nucleus ○ Fragmentation of nucleus and organelles ○ Haphazard arrangement of organelles
Cell Death
Necrosis, apoptosis
NECROSIS
A pathologic process that is the consequence of severe injury
Causes of Necrosis
○ Ischemia ○ Exposure to microbial toxins ○ Burns and other forms of chemical and physical injury ○ Unusual situations in which active proteases leak out of the cells and damage surrounding tissues
Necrosis is characterized by
○ Denaturation of cellular proteins ○ Leakage of cellular contents through damaged membranes ○ Local inflammation ○ Enzymatic digestion
Some specific substances released from the injured cells have been called
damage-associated molecular patterns (DAMPs)
Cardiac specific troponins
detected in the blood as early as 2 hours after myocardial cell necrosis, bile duct epithelium expresses a specific isoform of the enzyme alkaline phosphatase and hepatocytes express transaminase (e.g. SGPT
Karyolysis
basophilia of the chromatin may fade; presumably reflects loss of DNA because of enzymatic degradation by endonucleases
Pyknosis
characterized by nuclear shrinkage and increased basophilia, chromatin condenses into a dense, shrunken basophilic mass (also seen in apoptotic cell death)
Karyorrhexis
pyknotic nucleus undergoes fragmentation
COAGULATIVE NECROSIS
● Architecture of dead tissue is preserved for a span of at least some days only with loss of Nuclei ● Affected tissue has a firm texture ● Injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells; as a result, intensely eosinophilic cells with indistinct or reddish nuclei may persist for days or weeks
The brain undergoes which type of necrosis in ischemia
Liquefactive
LIQUEFACTIVE NECROSIS
● Digestion of the dead cells, resulting in the transformation of the tissue in a viscous liquid
● Seen in focal bacterial or, occasionally, fungal infections
● Accumulation of leukocytes (predominantly neutrophils) and the liberation of enzymes from these cells known as pus
● Seen in ischemic death of brain cells
GANGRENOUS NECROSIS
● not a specific pattern of cell death, but the term is commonly used in clinical practice, usually applied to a limb ● When bacterial infection is superimposed giving rise to so-called wet gangrene
CASEOUS NECROSIS
● Encountered most often in foci of tuberculous infection
● Term caseous (cheeselike) is derived from the friable white appearance of the area of necrosis
Granuloma
Necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation
FAT NECROSIS
● Focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity ● Occurs in acute pancreatitis
Fatty acids released grossly appear as,
Chalky-white (Fat saponification)
FIBRINOID NECROSIS
● Special form of vascular damage usually seen in immune reactions involving blood vessels
● Occurs when complexes of antigens and antibodies are deposited in the walls of arteries called “fibrinoid” (fibrin-like)
APOPTOSIS
● Basically cell shrinkage or reduce size ● Induced by tightly regulated suicide program ● Cells are destined to die ● Activation of intrinsic enzymes to degrade the genomic DNA and nuclear and cytoplasmic proteins ● No inflammatory reaction ● Programmed cell death
PHYSIOLOGIC CAUSES OF APOPTOSIS
● Eliminates cells that are no longer needed ● Removal of supernumerary cells during development ● Involution of hormone-dependent tissues on hormone withdrawal ● Cell turnover in proliferating cell populations ● Elimination of potentially harmful self-reactive lymphocytes.
The pathway that is most involved in Physiologic and pathologic apoptosis
Mitochondria
PATHOLOGIC CAUSES OF APOPTOSIS
PATHOLOGIC CAUSES OF APOPTOSIS
● Eliminates cells that are beyond repair ● No host reaction ● DNA damage in radiation and anti-cancer drugs ● Accumulation of misfolded proteins ● Certain infections, viral infections, cytotoxic T lymphocytes. Also eliminate lymphocytes and some dead cells ● Pathologic atrophy in parenchymal organs after duct obstruction. It could be fibrosis, inflammation or presence of stones
MECHANISM OF APOPTOSIS
Activation of capsases
Inititation phase
Execution phase
Removal phase
Initiation phase
■ Caspases become active
Mitochondrial Pathway -
INITIATED BY CASPASE 9
● Intrinsic pathway ● Responsible for apoptosis in most situations ● Results from increased permeability of mitochondrial outer membrane with consistent release of death-inducing (pro-apoptotic) molecules from the mitochondrial space into the cytoplasm
Micochondrial pathway is controlled by which protein
BCL2 family of proteins
Death receptor Pathway -
NITIATED BY CASPASE 8, 10
Extrinsic pathway of apoptosis
Initiated by engagement of plasma membrane death receptors that are members of the TNF receptor family [TNFR1, fas (CD95)]
Execution phase
Capsapses trigger cellular fragmentation
Removal of dead cells
■ Apoptotic cells and their fragments also undergo several changes in their membranes that actively promote their phagocytosis
■ Apoptotic bodies may also become coated with natural antibodies and proteins of the complement system, notably C1q, which are recognized by phagocytes
NECROPTOSIS
Physiologic: occurs during the formation of the mammalian bone growth plate
● Pathologic: cell death in steatohepatitis, acute pancreatitis, ischemia-reperfusion injury, and neurodegenerative diseases such as Parkinson disease
Necroptosis pathology
Acts as a backup mechanism in host defense against certain viruses that encode caspase inhibitors (e.g., cytomegalovirus)
PYROPTOSIS (remember Pyrexia or Fever, Heat)
● Form of apoptosis that is accompanied by the release of the fever-inducing cytokine IL-1 (pyro refers to fever)
● Mechanism by which some microbes cause the death of infected cells and at the same time trigger local inflammation
FERROPTOSIS (remember Ferrum, ROS- Reactive O2 Species)
● Discovered in 2012
● Triggered when excessive intracellular levels of iron or reactive oxygen species overwhelm the glutathione-dependent antioxidant defenses to cause unchecked membrane lipid peroxidation
AUTOPHAGY
● process in which a cell eats its own contents
● implicated in many physiologic states (e.g., aging and exercise) and pathologic processes
● survival mechanism whereby, in states of nutrient deprivation, starved
● cells live by cannibalizing themselves and recycling the digested contents
useful marker of autophagy
LC3
Nucleation and formation of an isolation membrane, also called a phagophore derived from
ER
Role of autophagy in Turnover of organelle
like the ER, mitochondria, and lysosomes and the clearance of intracellular aggregates that accumulate during aging, stress, and various disease states.
Autophagy in Cancer
both promote cancer growth and act as a defense against cancers but still under investigation
Autophagy in Neurodegenerative disorder
Many neurodegenerative disorders are associated with dysregulation of autophagy. Alzheimer disease is characterized by impaired autophagosome maturation, and in mouse models of the disease genetic defects in autophagy accelerate neurodegeneration
In Huntington disease, mutant huntingtin impairs autophagy
Autophagy in Infectious diseases
pathogens are degraded by autophagy; including mycobacteria, Shigella spp., and HSV-1. This is one way by which microbial proteins are digested and delivered to antigen presentation pathways. Macrophage-specific deletion of Atg5 increases susceptibility to tuberculosis
○ Inflammatory bowel diseases Autophagy
Genome-wide association studies have linked both Crohn disease and ulcerative colitis to single-nucleotide polymorphisms (SNPs) in the autophagy-related gene ATG16L1.
MITOCHONDRIAL DAMAGE
Mitochondria are critical players in all pathways leading to cell injury and death
ATP depletion:
Decreased ATP synthesis and ATP depletion are frequently associated with both hypoxic and chemical (toxic) injury. It produces ATP utilizing oxidative phosphorylation and glycolytic pathway (in the absence of oxygen)
mitochondrial permeability transition pore
Mitochondrial damage often results in the formation of a high-conductance channel in the mitochondrial membrane
Detachment of ribosomes from the RER and dissociation of polysomes, result in,
reduction in protein synthesis or increased protein misfolding
Incomplete oxidative phosphorylation also leads to the formation of
ROS
initial step in apoptosis by the intrinsic pathway
Leakage of mitochondrial proteins due to channel formation by pro-apoptotic BAX and BAK
Membrane damage
● Early loss of selective membrane permeability, leading ultimately to overt membrane damage, is a consistent feature of most forms of cell injury (except apoptosis)
● May be the result of ATP depletion and calcium-mediated activation of phospholipases.
● ROS. Oxygen free radicals cause injury to cell membranes by lipid peroxidation
DAMAGE TO DNA
● May be caused by exposure to radiation, chemotherapeutic (anticancer) drugs, and ROS, or may occur spontaneously as a part of aging, due largely to deamination of cytosine residues to uracil residues
● Damage to nuclear DNA activates sensors that trigger p53-dependent pathways which arrests cells in the G1 phase of the cell cycle and activates DNA repair mechanisms (important in development of tumors)
ROS
Cell injury induced by free radicals, particularly ROS, is an important mechanism of cell damage in many pathologic conditions (Read in text)
DISTURBANCE IN CALCIUM HOMEOSTASIS
Study
ENDOPLASMIC RETICULUM STRESS
Study from book
CLINICOPATHOLOGIC CORRELATIONS
ISCHEMIA
Ischemia is the most common cause of cell injury in clinical medicine ○ Results from hypoxia induced by reduced blood flow, most often due to a mechanical arterial obstruction ○ It can also occur due to reduced venous drainage ○ In ischemic tissues, not only does aerobic metabolism cease but anaerobic energy generation also fails after glycolytic substrates are exhausted or glycolysis is inhibited by the accumulation of metabolites ○ Ischemia causes more rapid and severe cell and tissue injury
Hypoxia
Blood flow is maintained and during which energy production by anaerobic glycolysis can continue, ischemia compromises the delivery of substrates for glycolysis
ISCHEMIA REPERFUSION INJURY
● Restoration of blood flow to ischemic tissues can promote recovery of cells in reversible injury
● However, it can also exacerbate cell injury and cause cell death of the previously viable tissues or cells
Oxidative Stress in IRI
○ During reoxygenation, there is increased generation of Reactive Oxygen Species
○ These free radicals may be produced in reperfused tissue as a result of incomplete reduction of oxygen leukocytes, and in damaged endothelial cells and parenchymal cells
○ Compromise of cellular antioxidant defense mechanisms during ischemia may sensitize cells to free radical damage
Intracellular Calcium Overload
○ Intracellular and mitochondrial calcium overload begins during reperfusion due to influx of calcium resulting from cell membrane damage and ROS-mediated injury to sarcoplasmic reticulum ○ Calcium overload favors opening of the mitochondrial permeability transition pore with resultant ATP depletion
Inflammation
Ischemic injury is associated with inflammation as a result of “danger signals” released from: ■ Dead cells ■ Cytokines secreted by resident immune cells such as macrophages ■ Increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells ● All of which act to recruit circulating neutrophils to reperfused tissue
Activation of Complement Pathway
○ For unknown reasons, some IgM antibodies have a propensity to deposit in ischemic tissues
○ When blood flow is resumed, complement proteins bind to the deposited antibodies, are activated, and exacerbate cell injury and inflammation
CHEMICAL (TOXIC) INJURY
● A major limitation to drug therapy
● Because many drugs are metabolized in the liver, this organ is a major target of drug toxicity
● Toxic liver injury is often the reason for terminating the therapeutic use or development of a drug
Direct Toxicity
○ Chemicals combine with critical molecular components ○ Mercuric Chloride poisoning ■ Mercury binds to the sulfhydryl groups of cell membrane proteins, causing increased membrane permeability and inhibition of ion transport
Conversion to Toxic Metabolites
○ Most toxic chemicals are not biologically active in their native form, but must be converted to reactive toxic metabolites, which then act on target molecules
○ This modification is usually accomplished by the cytochrome P-450 mixed-function oxidases in the smooth ER of the liver and other organs
○ The toxic metabolites cause membrane damage and cell injury mainly by formation of free radicals and subsequent lipid peroxidation
HYPERTROPHY
Increase in size of cells and organ
PHYSIOLOGIC HYPERTROPHY
● Increased functional demand (body builders)
● Stimulation by hormones and growth factors (pregnancy and lactation) ○ Pregnancy ○ Body builders
PATHOLOGIC HYPERTROPHY
● Common to permanent cells - nondividing cells (skeletal muscles, myocytes, brain cells)
● Increased workload
● Synthesis of more protein by increasing the number of myofilaments per cell, increase the amount of force, more strength and work capacity
MECHANISM OF HYPERTROPHY
● Hypertrophy is a result of increased cellular protein production
● Mechanical sensors detect the increased load -> activate a complex downstream web of signaling pathways, including PI3K/AKT pathway (physiologic) and G-protein-coupled receptor-initiated pathways (pathologic) -> stimulate increased production of growth factors and vasoactive agents -> activate transcription factors [GATA4, NFAT, MEF2] which increase the expression of genes that encode muscle proteins
● Increase in number of proteins in the cell -> becomes bigger -> performance will be stronger
● Sometimes induction of embryonic genes [cardiac proteins, atrial natriuretic factor, actin] can also increase or help in the synthesis or formation of proteins, particularly proteins of growth factors
HYPERPLASIA
● Increase in number of cells and (consequently) organ
● Usually occur together with hypertrophy (especially in physiologic)
● Can only take place if the tissue contains cells capable of dividing
PHYSIOLOGIC HYPERPLASIA
● Action of hormones or growth factors ● Increase functional capacity of the organ ● Compensatory increase after damage or resection EXAMPLES ○ Hormonal hyperplasia - development of the female breast during puberty and pregnancy ○ Compensatory hyperplasia - liver regeneration
*Pathologic hyperplasia caused by virus
MECHANISM OF HYPERPLASIA
Result of growth factor-driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells
ATROPHY
● Reduction in size of organ or tissue
● Decrease in cell size and number
PHYSIOLOGIC ATROPHY
● Regression of the uterus after pregnancy
● Regression of the breast after pregnancy and lactation
● Regression of the thyroglossal duct - (during development) originates at the base of the tongue and transports the thyroid to the anterior neck; this duct normally regress
● Common during normal development
PATHOLOGIC ATROPHY Causes
● Decreased workload ○ Immobilization ○ Prolonged disuse Initially, changes are reversible but becomes irreversible with continued disuse
● Loss of innervation
● Diminished blood supply - in contrast with ischemia, is in milder form because it does not allow ischemia to be symptomatic; happen to organs that are not that vital to produce significant manifestations; chronic type of ischemia
● Inadequate nutrition
● Loss of endocrine stimulation
● Pressure - exemplified when you have a developing tumor and then compressing the adjacent normal tissue
MECHANISM OF ATROPHY
● Result from decreased protein synthesis (because of reduced trophic signals) and increased protein degradation in cells
● Degradation of proteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disuse may activate ubiquitin ligases.
● In many situations, atrophy is also accompanied by increased autophagy.
METAPLASIA
Reversible change in which one differentiated cell type is replaced by another cell type (change should be from a stronger or more stable type of cell)
MECHANISMS of METAPLASIA
● Reprogramming of local tissue stem cells (there is transition of the cells to a more durable cells depending on the condition that stimulated the metaplastic reaction)
● Colonization by differentiated cell population from adjacent sites (extension of squamous epithelium going into the endocervical region and replacing glandular epithelium)
BARRETT’S METAPLASIA
Esophagus - squamous epithelium; gastric - glandular epithelium -> glandular epithelium is starting to replace your squamous epithelium because glandular epithelium is more resistant to acid
INTRACELLULAR ACCUMULATIONS
● Manifestations of metabolic derangements ● Harmless or can cause injury ● Location- cytoplasm, organelles, or nucleus ● Endogenous or exogenous
MECHANISMS OF ABNORMAL INTRACELLULAR ACCUMULATIONS
○ Inadequate Removal of a normal substance
■ Defects in packaging and transport
■ EXAMPLES ● Lipids ● Proteins ● Hyaline change ● Glycogen ● Pigments
LIPIDS ACCUMULATION
Triglycerides - steatosis (abnormal accumulations of triglycerides within parenchymal cells)
● Cholesterol and cholesterol esters - atherosclerosis, xanthomas, cholesterolosis, and niemann pick disease type c
Steatosis
accumulation of lipids or triglycerides in the hepatocytes; bigger the size, more lipids are accumulated
*Atheroma - (blood vessel) there is deposition of cholesterol esters in the wall; sometimes there is corresponding fibrosis *some cholesterol are engulfed in macrophages - foamy histiocyte
*gallbladder - yellow bright color in the mucosa because of the deposition of your cholesterol esters *there is aggregation of histiocytes containing cholesterol esters
PROTEINS ACCUMULATION
● Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm.
● They can be amorphous, fibrillar, or crystalline in appearance under electron microscopy.
● In some disorders, such as certain forms of amyloidosis, abnormal proteins deposit primarily in extracellular spaces.
● Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria).
● In the kidney, small amounts of protein filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal tubule
The ER becomes hugely distended, producing large, homogeneous eosinophilic inclusions called
Russell bodies
Protein accumulation can be seen as rounded pink droplets (within the cytoplasm) or vacuoles and proteins usually stain in H&E . seen in proteinuria. Initial stage; reversible
