Lec 1 and 2. Cell Injury I and II, Dr. Broderick Jones- Full Slides.pdf

Broderick C. Jones, MD, MSc 954 262 1325 Offc 1325 Terry [email protected] Lymph node with caseous necrosis Pathology What is Pathology? Pathology Study of Disease Examines – Structural Biochemical Functional Changes in - Cells Tissues Organs - that underlie disease Pathology Study of Disease Tools Mo...

Broderick C. Jones, MD, MSc 954 262 1325 Offc 1325 Terry [email protected] Lymph node with caseous necrosis Pathology What is Pathology? Pathology Study of Disease Examines – Structural Biochemical Functional Changes in - Cells Tissues Organs - that underlie disease Pathology Study of Disease Tools Molecular Microbiologic Immunologic Morphologic – Techniques To explain the signs and symptoms manifested by patients Provides a rational basis for clinical care and therapy Pathology Clinical Medicine Basic Sciences Etiology Pathogenesis Morphology Clinical Importance The four aspects of a disease process Pathology General Pathology Systemic Pathology Disease Process and Clinical Manifestations Systemic Pathology Cardiovascular Hematopathology Respiratory Gastrointestinal Renal Reproductive Endocrine Dermatopathology Musculoskeletal Central Nervous System Pathology Diagnosis of Disease Guide Treatment of Disease Autopsy Tissue Examination Clinical Laboratory Pathology Study of Disease Diagnosis of Disease Guide Treatment of Disease Autopsy Tissue Examination Clinical Laboratory Cell Injury Cell Injury and Death  What causes cell injury?  Injurious Stimulus Cell Response to Injury Cell Adaptations  Adaptations  Response to changes in cell environments  Reversible Changes –Size –Number –Phenotype –Metabolic activity –Functions Cell Adaptations Atrophy  Hypertrophy  Hyperplasia  Metaplasia  Intracellular Accumulations  Aging  Cell Adaptations   An 89-year-old male who was seen in clinic 1 month ago with a family member with increased forgetfulness, difficulty recalling immediate events. Recently, he fell and broke his hip and was admitted to the hospital where he developed pneumonia and expired. An autopsy was performed. Patient’s brain is shown on the following slide. Cell Adaptations  Which of the following brains is from the 89-yearold male? A. A B. B Cell Adaptations  Atrophy Reduced size of an organ  Results from a decrease in cell size and number  Cell Adaptations  Atrophy - Decrease in cell size (reduction in organ and/or tissue size) - JL’s Case - Multi-infarct dementia Alzheimer Disease Parkinson Disease Cell Adaptations  Atrophy (Physiological) – reduction in size of uterus after delivery  Atrophy (Pathological) - Decrease in Cell Size - Decreased workload (atrophy of disuse) Loss of innervation (denervation atrophy) Diminished blood supply Inadequate nutrition Loss of endocrine stimulation Local pressure Denervation Autophagy (Intracellular Accumulations) Cell Adaptations  Atrophy  Mechanisms of Atrophy - Intracellular Factors - Decreased protein synthesis - Increased protein degradation – Cellular protein degradation by ubiquitinproteasome pathways Nutrient Deficiency and Disuse – Activate ubiquitin ligases – Ubiquitin-tagged structures degraded in proteasomes Cell Adaptations  Atrophy  Cellular protein degradation by ubiquitin-proteasome pathways Cell Adaptations  Atrophy  Mechanisms of Atrophy  Autophagy Starved cell cannabalism for survival Undigested cell debris creates lipofuscin granules Autophagy. Cellular stresses, such as nutrient deprivation, activate an autophagy pathway that proceeds through several phases (initiation, nucleation, and elongation of isolation membrane) and eventually creates double-membrane-bound vacuoles (autophagosome) in which cytoplasmic materials, including organelles, are sequestered and then degraded after fusion of the vesicles with lysosomes. In the final stage, the digested materials are released for recycling of metabolites. See text for details. LC3, Light chain 3. (Modified from Choi, AMK, Ryter S, Levine B: Autophagy in human health and disease, N Engl J Med 368:651, 2013.) Cell Adaptations  Past Medical History (PMHx)  A 63 year old man diagnosed with essential hypertension 30 years ago. Since that time MH has been noncompliant with medication to control blood pressure.  Recently he reported funny feelings in chest but did not seek medical attention. MH developed ventricular fibrillation (v-fib) and expired. The patient’s heart is shown on the following slide. Cell Adaptations  What does this patient’s heart show? A. Thickened right ventricle B. Thickened left ventricle C. Left chamber dilation D. Right chamber dilation E. Normal heart Left Ventricular Hypertrophy Cell Adaptations  Hypertrophy  Enlargement of Cells   Increase in the size of cells Resulting in increase size of the organ Increased size of the cells Due to synthesis of more structural components Cell Adaptations  Hypertrophy  Enlargement of Cells Physiological  Pathological  Cell Adaptations  Hypertrophy (Physiological)  Enlargement of cells  Growth Factors Transforming growth factor (TGF-β) Insulin-like growth factor-1 [IGF-1] Fibroblast growth factor Vasoactive agents – α-adrenergic agonists – Endothelin-1 – Angiotensin II Skeletal Muscle Biochemical mechanisms of myocardial hypertrophy. The major known signaling pathways and their functional effects are shown. Mechanical sensors appear to be the major triggers for physiologic hypertrophy, and agonists and growth factors may be more important in pathologic states. ANF, Atrial natriuretic factor; GATA4, transcription factor that binds to DNA sequence GATA; IGF1, insulin-like growth factor; NFAT, nuclear factor activated T cells; MEF2, myocardial enhancing factor 2. Cell Adaptations  Hypertrophy (Pathological)  Enlargement of cells  Growth Factors TGF-β [IGF-1] Fibroblast growth factor Vasoactive agents – α-adrenergic agonists – Endothelin-1 – Angiotensin II Left Ventricular Hypertrophy Normal Heart Cell Adaptations  A 62-year- old male who came to clinic because of difficulty urinating. Digital rectal exam (DRE) revealed an enlarged boggy prostate gland. Biopsies were collected.  Biopsies revealed increased stromal and glandular cells  Diagnosis  – Benign Prostatic Hyperplasia (BPH) Cell Adaptations  TS is a 62-year-old male who came to clinic because of difficulty urinating. Digital rectal exam (DRE) revealed an enlarged boggy prostate gland. Biopsies were collected.  Biopsies revealed increased stromal and glandular cells.  Diagnosis  – Benign Prostatic Hyperplasia Cell Adaptations  Hyperplasia  Increase in Cell Numbers  Hormonal  Compensatory   Physiological Breast – Puberty – Pregnancy Pathological Uterus – Endometrial hyperplasia Skin - Psoriasis Prostate - BPH Uterus - Endometrial Hyperplasia Normal Epithelium Psoriasis (Skin) Cell Adaptations  A 35-year-old female cigarette smoker is concerned because she is experiencing hoarseness in her speech. She read an article in a magazine which indicated this might be an early sign of throat cancer.  A biopsy from the oropharynx was obtained and revealed a squamous poulation of cells Cell Adaptations  Metaplasia  Stem Cell Reprogramming   Stem cells exist in normal tissues Undifferentiated mesenchymal cells present in connective tissue Reversible  Adaptive Substitution of Cells  Cell Adaptations  Metaplasia  Stimuli promote gene expression Cells driven toward a specific differentiation pathway Resistant cell to harsh environment  Differentiation Cytokines Growth factors Extracellular matrix components Cell Adaptations  Metaplasia     Columnar → squamous epithelium Reprogramming of stem cells Response to chronic irritation Resistant population of cells Nicotene replacement therapy doubles the chance that a cigarette smoker will quit. True False Cell Adaptations  Intracellular Accumulations   Metabolic derangements in a cell leading to accumulation of abnormal amounts of various substances Caused by     Abnormal Metabolism Protein folding and transport Lack of an enzyme Ingestion of indigestible material Cell Adaptations  Intracellular Accumulations  Lipids  Cholesterol  Proteins  Glycogen  Pigments Cell Adaptations  A 23-year-old medical student aced the first pathology exam. Later at an outing to celebrate with other students who aced the exam. They had a few drinks and began to wonder what happens in the liver when it metabolizes alcohol and is alcohol consumption healthy?  The affects of the alcohol began to kick in when MT decided to try and answer the question on alcohol metabolism. Which of the following is MT’s answer? A. Alcohol is really good for you B. Alcohol has gotten bad reviews C. Alcohol interferes with lipid metabolism D. Alcohol increases water absorption by the kidneys E. Alcohol is transported into the CNS by a carrier protein Cell Adaptations  Intracellular Accumulations  Result of abnormal metabolism     Triglyceride accumulation ↑ Reduced NAD Defective export Example  Liver / Steatosis Cell Adaptations  Intracellular Accumulations   Result of abnormal metabolism Example  Steatosis  A 42-year-old female is in clinic today because of declining exercise tolerance. She runs 2 miles everyday and works out at the gym. But over the year she began to notice shortness of breath during distance running and exercise.  Labs  ↑ Hematocrit ↑ Hemoglobin  ↓ α1-antitrypsin (anti-elastase) CXR  Hyperinflation  A/P CXR Hyperinflation Cell Adaptations  Intracellular Accumulations Mutations in proteins can slow folding of protein for transport Example  α-1-antitrypsin deficiency (Anti  elastase) Cell Adaptations  Intracellular Accumulations (other examples)    Lipofuscin granules  In cardiac myocytes Hemosiderin granules  In liver cells Protein reabsorption droplets  In the renal tubular epithelium Cell Adaptations  Intracellular Accumulations    Accumulations most often are reversible Overload can cause cell injury or cell death Patient death may occur without medical intervention Cell Response to Injury Cell Injury and Death  Causes of Cell Injury  Oxygen deprivation (Hypoxia)  Physical Agents  Chemical Agents and Drugs  Infectious Agents  Immunological Reactions  Genetic Derangements  Nutritional Imbalances Cell Injury and Death  Causes of Cell Injury        Oxygen deprivation (Hypoxia) Physical Agents Chemical Agents and Drugs Infectious Agents Immunological Reactions Genetic Derangements Nutritional Imbalances How do these adverse stimuli injure cells? What is the mechanism? The principal forms and sites of damage in cell injury. ATP, Adenosine triphosphate; ROS, reactive oxygen species. Cell Injury  Mechanisms of Cell Injury  Loss of ATP  Mitochondrial damage  Influx of Calcium  Free radical accumulation  Damage to DNA and proteins  Membrane damage Mechanisms of Cell Injury  Cascade of Events (Ischemia)  ↓ Oxidative Phosphorylation ↓ ATP  ↓ Membrane pumps Influx – H2O Results in – - Cellular swelling – Ca+2 - Organelle swelling – Na+ Efflux – K+ Mechanisms of Cell Injury  Cascade of Events (Ischemia)  ↑ Anerobic glycolysis  ↓ Glycogen  ↓ pH Clumping of chromatin Enzyme function abnormalities  Mechanisms of Cell Injury  Loss of ATP  Mechanisms of Cell Injury  Mitochondrial Damage   Inability to generate ATP → Necrosis Membrane leakage  Mechanisms of Cell Injury  Influx of Calcium  Activates intracellular enzymes  Cellular damage SOD; Superoxide Dismutase Hydroxyl Radical Most damaging to cell The generation, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and deoxyribonucleic acid (DNA), resulting in cell injury.  Mechanisms of Cell Injury  Membrane Damage Cell Response to Injury  Reversible Cell Injury Cell Injury  Magnitude of Cell Injury    Nature of Injury Cell Factors Type State Adaptability Biochemical Mechanisms Determine if cellular damage is Reversible or Irreversible Cell Functions and Response to Injury  Reversible Cell Injury (Cellular Changes)   Plasma membrane alterations  Blebbing  Blunting  Loss of microvilli Mitochondrial changes  Swelling  Appearance of small amorphous densities Cell Functions and Response to Injury  Reversible Cell Injury  Cellular swelling and ↑ vacuoles (Hydropic change)     Dilation of the ER  Detachment of polysomes Intracytoplasmic myelin Nuclear alterations Disaggregation of granular and fibrillar elements Cell Response to Injury  Irreversible Cell Injury Cell Functions and Response to Injury  Irreversible Cell Injury (Cellular Necrosis)  Increased eosinophilia   Myelin figures accumulate    Denaturation of proteins Damaged cellular membranes Mitochondrial amorphous densities increase Nuclear changes  Pyknosis (Nuclear shrinkage and increased basophilia)  Karyolysis (Enzymatic degradation by endonucleases)  Karyorrhexis (Pyknotic nucleus undergoes fragmentation) Cell Functions and Response to Injury  Irreversible Cell Injury (Cellular Necrosis)  Viable Cardiac Cells Increased eosinophilia or  Decreased basophilia Cardiac Cells Post MI Morphologic changes in reversible cell injury and necrosis (A) Normal kidney tubules with viable epithelial cells. (B) Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. (C) Necrosis (irreversible injury) of epithelial cells, with loss of nuclei, fragmentation of cells, and leakage of contents. (Courtesy Drs. Neal Pinckard and M.A. Venkatachalam, University of Texas Health Sciences Center, San Antonio, Tex.) Cell Functions and Response to Injury / Irreversible Injury Clinical Correlation Blood Vessel Cell Death Extracellular Space Labs Normal Cell Cell Contents Troponin CPK-MB AST ALT  If a cell cannot adapt and becomes irreversibly injured, it must _____? A. B. C. D. E. Seek help Keep trying Die or undergo necrosis Give up Recycle itself Cell Response to Stress  Cell Death  Necrosis Necrosis and Cell Death  Coagulative Necrosis Liquefactive Necrosis Caseous Necrosis Fat Necrosis Fibrinous Gangrenous  Apoptosis      Coagulative Necrosis Coagulative necrosis. (A) A wedge-shaped kidney infarct (yellow). (B) Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I) showing preserved cellular outlines with loss of nuclei and an inflammatory infiltrate (seen as nuclei of inflammatory cells in between necrotic tubules). Necrosis and Cell Death  Liquefactive Necrosis    Occurs in focal bacterial or, occasionally, fungal infections  Accumulation of leukocytes  Liberation of enzymes Tissue → liquid viscous mass  Digestion of dead cells Infarction of brain Liquefactive Necrosis Brain CVA ; Liquefactive Necrosis Necrosis and Cell Death  Caseous Necrosis    Foci of tuberculous infection “Caseous” (Cheeselike)  Friable white areas of necrosis Focus of Inflammation  Granuloma Collection of fragmented cells Amorphous granular debris Enclosed within an inflammatory border “Caseation” Lung tissue Necrosis and Cell Death  Fat Necrosis    Occurs with acute pancreatitis Pancreatic lipases released into peritoneal cavity  Liquefy the membranes of fat cells in the peritoneum  Lipases split the triglyceride esters  Fatty acids combine with calcium Visible chalky-white areas (fat saponification) Result - focal areas of fat destruction  Fatty acids + calcium = fat saponification Produce chalky-white areas Fat Necrosis involving omentum (Gross) Necrosis and Cell Death  Fibrinous Necrosis     Necrosis involving blood vessels Antigen and antibody deposition in arterial walls  Immune complexes Pro-inflammatory Fibrin leaks into vessel walls Produces a bright pink amorphous deposit in vessel walls Fibrinous Necrosis Blood Vessel; Fibrinoid Necrosis Necrosis and Cell Death  Gangrenous Necrosis     Clinical designation Refers to an infarcted limb involving multiple tissue planes Coagulative necrosis has occurred Superimposed bacterial infection  Can produce a liquefactive necrosis Gangrenous Necrosis Cell Response to Stress  Apoptosis Cell Death and Necrosis  Apoptosis    Tightly regulated suicide pathway program Elimination of cells that are no longer needed Maintains a steady number of various cell populations in tissues Cell Death and Necrosis  Apoptosis  Physiological     Programmed destruction of cells during embryogenesis Involution of hormone-dependent tissues upon hormone withdrawal Cell loss in proliferating cell populations Maintains a steady number of various cell populations in tissues Cell Death and Necrosis  Apoptosis  Pathological  Eliminates cells injured beyond repair DNA damage Accumulation of mis-folded proteins Cells infected by viruses Cell Death and Necrosis  Morphologic Features  Apoptosis      Cell shrinkage Chromatin condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies, by macrophages Similar to cell death due to irreversible injury Cell Death and Necrosis  Mechanism  Apoptosis  Intrinsic (Mitochondrial Pathway) Caspases become active  Extrinsic (Death receptor–Initiated Pathway) Caspases trigger the degradation of critical cellular components Cell Death and Necrosis   Mechanism Apoptosis  Intrinsic / Mitochondrial Pathway Cell Death and Necrosis  Apoptosis (Mechanism)  Intrinsic / Mitochondrial Pathway 1. Lack of growth and survival signals / injury 2. Activate Bim, Bid, and Bad sensors 3. Bim, Bid, and Bad activate Bax and Bak 4. Bax and Bak insert channels into Mitochondrial leakage of cytochrome C 5. Cytochrome C activation of caspases 9 and others 6. Executioner caspases activation Cell Death and Necrosis  Apoptosis (Mechanism)  Extrinsic / Death Receptor–Initiated Pathway  TNF and Fas related proteins    FasL to Fas binding Cytoplasmic domains form a binding site for FADD FADD activates caspase 8 and other caspases Cell Death and Necrosis  Mechanism  Apoptosis  Extrinsic / Death receptor–initiated pathway Apoptosis  Execution Phase  Executioner Caspases  Caspases (3 and 6)  Act on many cellular components Indirectly activate DNase – Cleavage of DNA into nucleosomesized pieces  Executioner Caspases Degradation and fragmentation of nuclear matrix Mechanisms of apoptosis. Although the two pathways of apoptosis differ in their induction and regulation, they both culminate in the activation of caspases. In the mitochondrial pathway, proteins of the BCL2 family, which regulate mitochondrial permeability, become imbalanced such that the ratio of pro-apoptotic versus anti-apoptotic proteins results in the leakage of various substances from mitochondria that lead to caspase activation. In the death receptor pathway, signals from plasma membrane receptors lead to the assembly of adaptor proteins into a “death-inducing signaling complex,” which activates caspases, and the end result is the same.  Necroptosis     Caspase-independent Depends on the RIPK1 and RIPK3 complex. RIPK1–RIPK3 signaling leads to: Phosphorylation of MLKL, which then forms pores in the plasma membrane. Necroptosis Apoptosis Pathologic Calcification  Abnormal Tissue Deposition  Calcium salts  Iron  Magnesium other mineral salts  Types  Dystrophic calcification  Metastatic calcification Pathologic Calcification  Pathogenesis  Membrane Damage +2 binds to the phospholipids in membrane  Ca vesicles  Phosphate groups bind calcium +2 and phosphate binding cycle repeated  Ca +2 and phosphate groups generate  Ca microcrystals +2  Ca deposition 99 Pathologic Calcification  Dystrophic Calcification  Pathology  Encountered in areas of necrosis  Macroscopic Fine, white granules or clumps, gritty deposits Pathologic Calcification  Dystrophic Calcification  Pathology  Encountered in areas of necrosis  Macroscopic White granules Clumps Gritty deposits Dystrophic Calcification of Aortic Valve Pathologic Calcification  Metastatic Calcification   Results from conditions that produce hypercalcemia Principal causes of Hypercalcemia  Increased secretion of Parathyroid Hormone (PTH)    Destruction of Bone tissue     Ectopic secretion PTH-related protein by malignant tumors Secondary to primary tumors of bone marrow (e.g., multiple myeloma, leukemia) Diffuse skeletal metastasis (e.g., breast cancer) Vitamin D Related Disorders Renal Failure  Causes retention of phosphate, leading to secondary hyperparathyroidism Pathologic Calcification  Metastatic Calcification  Occur widely throughout the Body  Affects Interstitial Tissues Gastric mucosa Kidneys Lungs Systemic arteries Pulmonary veins  These tissues excrete acid which creates an internal alkaline compartment that predisposes them to metastatic calcification Do you want to take a quiz?? YES! Harmless Quiz  Use any of the following terms to answer the questions in the quiz – Hypertrophy – Hyperplasia – Atrophy – Dystrophic calcification – Metaplasia – Coagulative Necrosis – Liquefactive Necrosis – Gangrenous Necrosis – Caseous Necrosis – Intracellular accumulations * * Terms can be used more than once too! Case 1  A. B. C. D. E. Which of the following best describes the condition of the heart labelled B. (A is a normal heart). Dilated cardiomyopathy Hypertrophy Metaplasia Coagulative necrosis Fibrin deposition B A C Case 2  Patient TK underwent a complete thyroidectomy. Thyroid gland revealed an increase in number of cells (normal gland and microscopy – 1 and 2, thyroidectomy – 3 and 4. what condition does this represent? 1 2 A. Metaplasia B. Dysplasia 3 C. Hypertrophy D. Hyperplasia E. Storage disease 4 Case 3 Unfortunately, MT continued to consume large quantities of alcohol throughout his professional career as a doctor and later succumbed to conditions related with liver failure. At autopsy the liver appeared yellow and microscopy of the liver revealed abundant lipid droplets. What does this pathology represent? A. B. C. D. E. Atrophy Liquefactive necrosis Metaplasia Fatty necrosis Intracellular accumulation Case 4  53 yo man with PMHx of lung cancer. Presents to clinic with chills and a low-grade fever. Patient expired from myocardial infarction while waiting to see physician. Autopsy revealed the following lesion in the upper L. lobe. Which of the following is this lesion consistent with? A. Dystrophic calcification B. Coagulative Necrosis C. Liquefactive Necrosis D. Gangrenous Necrosis E. Caseous Necrosis The Day the Earth Stood Still (1951) Thank You!