Ch.1 Baby Robbins Outline

CH. 1 Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death (BABY ROBBINS OUTLINE w/ some big Robbins: page numbers and pictures reference big Robbins) INTRODUCTION: (p.4)  PATHOLOGY: is the study of the structural and functional causes of human disease o 4 aspects of a disease process that form the core of pathology are:  ETIOLOGY: cause of a disease  PATHOGENESIS: mechanism(s) of disease development  MORPHOLOGIC CHANGE: structural alteration induced in cells and tissues by the disease (pathophysiology)  CLINICAL SIGNIFICANCE: functional consequences of the morphologic changes (lesion)

Fig. 1-1 Stages of the cellular response to stress and injurious stimuli

OVERVIEW: (p.5)  HOMEOSTASIS: a steady state  INJURY: More excessive stresses, or adverse pathology stimuli result in: o 1) ADAPTATION o 2) REVERSIBLE INJURY o 3) IRREVERSIBLE INJURY and CELL DEATH [Table 1-1]  ADAPTATION: occurs when physiologic or pathologic stressors induce a new state that changes the cell but otherwise preserves its viability in the face of the exogenous stimuli. These changes include: o HYPERTROPHY: increased cell mass (size) o HYPERPLASIA: increased cell # o ATROPHY: decreased cell mass o METAPLASIA: change from 1 mature cell type to another mature cell type  REVERSIBLE INJURY: denotes pathologic cell changes that can be restored to normalcy in the stimulus is removed or if the cause of injury is mild.  IRREVERSIBLE INJURY: occurs when stressors exceed the capacity of the cell to adapt (beyond a “POINT OF NO RETURN”) and denotes permanent pathologic changes that cause cell death (necrosis)

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CELL DEATH: occurs primarily thru 2 morphologic and mechanistic patterns denoted NECROSIS and APOPTOSIS (Table 1-2) NECROSIS: the more common type of cell death involving: o Severe cell swelling o Denaturation and coagulation of proteins o Breakdown of cellular organelles o Cell rupture o INFLAMMATION* o Usually, a large number of cells in the adjoining tissue are affected APOPTOSIS: occurs when a cell dies by activation of an internal “SUICIDE” PROGRAM, involving: o An orchestrated disassembly of cellular components o Minimal disruption of the surrounding tissue o NO (or minimal) INFLAMMATION* AUTOPHAGY: and adaptive response of cells to nutrient deprivation; a “self-cannibalization” to maintain viablility

CAUSES OF CELL INJURY: (p.11)  HYPOXIA: oxygen deprivation o Affects AEROBIC Respiration  ATP synthesis o Common cuase of cell injury and death occurs as a result of:  ISCHEMIA: loss of blood supply  Inadequate oxygenation (e.g., cardiorespiratory failure)  Loss of O2-carrying capacity of the blood (e.g., anemia, CO poisoning)  PHYSICAL AGENTS  CHEMICAL AGENTS and DRUGS  INFECTIOUS AGENTS  IMMUNOLIGIC REACTIONS  GENETIC DERAGEMENTS  NUTRITIONAL IMBALANCES MORPHOLOGIC ALTERATIONS IN CELL INJURY: (p.12)  REVERSIBLE INJURY: o CELL SWELLING o FATTY CHANGE o The ultrastructure changes of reversible cell injury include:  1) Plasma membrane alterations  2) Mitochondrial changes  3) Dilation of the ER  4) Nuclear alterations  NECROSIS: is the sum of the morphologic changes that follow cell death in living tissue or organs o 2 processes underlie the basic morphologic changes:  1) Denaturation of proteins  2) Enzymatic digestion of organelles and other cytosolic components o There are several distinctive features:  Eosinophilic (pink)  Appear “glassy” and may be Vacuolated  Cell membranes are fragmented  May attract calcium salts, esp. necrotic FAT cells (form FATTY SOAPS)  Nuclear changes include:  PYKNOSIS: small, dense nucleus  KARYOLYSIS: faint, dissolved nucleus  KARYORRHEXIS: fragmented nucleus

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General tissue patterns of NECROSIS:  COAGULATIVE NECROSIS: most common pattern* o INFARCT = a localized area of coagulative necrosis o HETEROLYSIS: digestion by lysosomal enzymes of invading leukocytes o AUTOLYSIS: digestion by its own lysosomal enzymes  LIQUEFACTIVE NECROSIS: most frequently seen in localized bacterial infections (ABSCESSES) and in the brain o PUS = dead leukocytes  GAGRENOUS NECROSIS: coagulative necrosis as applied to an ischemic limb; superimposed bacterial infection  WET gangrene  CASEOUS NECROSIS: characteristic of TB lesions*; “CHEESY” o GRANULOMA = focus of inflammation  FAT NECROSIS: (seen in adipose tissue) lipase activation releases fatty acids from triglycerides + Ca2+  SOAPS o Grossly = white, chalky areas (FAT SAPONIFICATION) o Histologically = vague cell outlines and Ca2+ deposition  FIBRINOID NECROSIS: is a pathologic pattern resulting from IMMUNE COMPLEX (Ag-Ab) deposition in blood vessels o Histologically = bright-pink amorphous material (protein deposition) in arterial walls, often with associated inflammation and thrombosis

MECHANISMS OF CELL INJURY: (p.17)  Responses to injurious stimuli depend on the: o TYPE of injury o DURATION o SEVERITY  The consequences of injury depend on the: o TYPE o STATE o ADAPTABILITY of the injured cell  Cell injury results from perturbations of any of 5 essential cellular elements: o 1) ATP production (mostly fro aerobic respiration) o 2) Mitochondrial integrity independent of ATP production o 3) Plasma membrane integrity, responsible for ionic and osmotic homeostasis o 4) Protein synthesis, folding, degradation, and refolding o 5) Integrity of the genetic apparatus 

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DEPLETION of ATP: decreased ATP synthesis and ATP depletion are common consequences of both ischemic and toxic injury o ATP is critical for membrane transport, maintenance of ionic gradients (Na+, K+, and Ca2+) and protein synthesis MITOCHONDRIAL DAMAGE: can occur directly due to hypoxia or toxins, or as a consequence of increased cystolic Ca2+, oxidative stress, or phospholipid breakdown o MITOCHONDRIAL PERMEABILITY TRANSITION PORE – a high-conductance channel that leaks protons and dissipates the electromotive potential that drive oxidative phosphorylation o Also leak cytochrome c  triggers apoptosis INFLUX OF Ca2+ AND LOSS OF Ca2+ HOMEOSTASIS: cystolic Ca2+ is maintained at extremely low levels by energy-dependent transport

Ischemia and Toxins  Ca2+ influx across the plasma membrane and release of Ca2+ from mitochrondria and ER o Increased cystolic Ca2+ activates phospholipases that degrade membrane phospholipids; proteases that breakdown membrane and cytoskeletal problems; ATPases that hasten ATP depletion; and endonucleases that cause chromatin fragmentation ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS): o FREE RADICALS - are stable, partially reduce molecules with unpaired electrons in outer orbitals that make them particularly reactive with other molecules; also called reactive oxygen species (ROS)  Most common and biological systems  Major forms:  Superoxide anion (O2, 1 extra e )  Hydrogen peroxide (H2O2, 2 extra e )  Hydroxyl ions (OH, 3 extra e )  Peroxynitrate ion (ONOO ; [NO] and O2)  Free Radical generation occurs by:  Normal metabolic processes such as the reduction of O2  H2O during respiration  Absorption of radiant energy  Production by leukocytes during inflammation to sterilize sites of infection  Enzymatic metabolism of exogenous chemicals or drugs  TRANSITION METALS can catalyze free radical formation  NO, an important chemical mediator can act directly as a free radical or be converted to other highly reactive forms  Free Radicals inherently unstable and generally DECAY SPONTANEOUSLY  Systems that contribute to Free Radical inactivation:  ANTIOXIDANTS (vit. E & A, ascorbic acid, and glutathione)  Levels of TRANSITION METALS binding to storage and transport proteins  Free Radical scavenging ENZYME systems catabolize H 2O2 and O2 DEFECTS IN MEMBRANE PERMEABILITY: membranes can be damaged directly or indirectly o Increased plasma membrane permeability affects intracellular osmolarity as well as enzymatic activity DAMAGE TO DNA AND PROTEINS: damage to DNA that exceeds normal repair capacity leads to activation of apoptosis o W/in limits, all the changes of cell injury described previously = REVERSIBLE INJURY o However, persistent or excessive injury causes cells to pass a threshold into IRREVERSIBLE INJURY associated w/:  Extensive cell membrane damage  Lysosomal swelling  Mitochondrial vacuolization w/ deficient ATP synthesis o REVERSIBLE  IRREVERSIBLE = 2 phenomena consistently characterize IRREVERSIBILITY  1) Inability to reverse mitochondrial dysfunction (lack of ATP generation) even after resolution of the original injury  2) Development of profound disturbances in membrane function o

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EXAMPLES OF CELL INJURY AND NECROSIS: (p.23)  ISCHEMIC AND HYPOXIC INJURY: o Most common forms of cell injury in clinical medicine = ISCHEMIA and HYPOXIA  HYPOXIA – is reduced O2-carrying capacity  HYPOXIA leads to loss of ATP generation by mitochondria; ATP depletion has multiple, initially reversible effects o OSMOTIC LOAD  CELL SWELLING o CELLULAR ENERGY METABOLISM is altered  Hypoxia  ANAEROBIC GLYCOLYSIS -> GLYCOGEN STORES ARE RAPIDLY DEPLETED and REDUCED INTRACELLULAR pH o Reduced protein synthesis  ISCHEMIA – (causes hypoxia*) is due to reduced blood flow o ALL the aforementioned changes are reversible and oxygenation is restored o If ISCHEMIA persists  IRREVERSIBLE INJURY, a transition largely dependent upon the extent of ATP DEPLETION and MEMBRANE DYSFUNCTION  ATP depletion induces the pore transition change in the mitochondrial membrane  diffusion of solutes  ATP depletion also RELEASES CYTOCHROME C, a soluble component of the ETC that is a key regulator in driving apoptosis  Increased cytosolic calcium activates membrane phopholipases, leading to progressive loss of phospholipids and membrane damage; decreased ATP also leads to diminished phospholipid synthesis  Increased cytosolic calcium ACTIVATES INTRACELLULAR PROTEASES causing degradation of intermediate cytoskeletal elements  cell swelling  Cell membrane stretching and rupture  FFAs and lysophospholipids accumulate in ischemic cells as a result of phospholipid degradation = directly toxic to membranes  ISCHEMIA-REPERFUSION INJURY: o REPERFUSION INJURY = Depending on the intensity and duration of the ischemic insult, additional cells may die AFTER blood flow resumes, involving either necrosis or apoptosis  Clinically important in MI, acute renal failure, and stroke o Several mechanisms potentially underlie reperfusion injury:  New damage may occur during reoxygenation by increased generation of ROS  INCREASED local inflammatory cell infiltration  COMPLEMENT activation  cell injury and inflammation  CHEMICAL (TOXIC) INJURY: o Occurs by 2 general pathways:  1) DIRECTLY

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2) INDIRECTLY

APOPTOSIS: (p.25)  APOPTOSIS = PROGRAMMED CELL DEATH – occurs when a cell dies thru activation of a tightly regulated internal SUICIDE program  FUNCTION OF APOPTOSIS – is to eliminated unwanted cells selectively, with minimal disturbance to surrounding cells and the host  DOES NOT elicit an INFLAMMATORY REACTION** – dead cell is rapidly cleared before its contents have leaked out o Therefore, FUNDAMENTALLY DIFFERENT FROM NECROSIS, which is characterized by loss of membrane integrity, enzymatic digestion of cells, and frequently a host reaction 

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CAUSES OF APOPTOSIS: can be PHYSIOLOGIC OR PATHOLOGIC o PHYSIOLOGIC CAUSES:  Programmed destruction of cells during embryongenesis  Hormone-dependent involution of tissues in the adult  Cell deletion in proliferating cell populations to maintain a constant cell #  Death of cells that have served their useful purpose  Deletion of potentially harmful self-reactive lymphocytes o PATHOLOGIC CAUSES:  DNA damage  Mild = may induce apoptosis  Larger/more severe (of same stimuli) = may result in necrosis  Accumulation of misfolded proteins  Cell death in certain viral infections (either directly or by cytotoxic T cells)  Cytotoxic T cells (for tumors and transplanted tissues)  Pathologic atrophy in parenchymal organs after duct obstruction (i.e., pancreas) MORPHOLOGIC AND BIOCHEMICAL CHANGES IN APOPTOSIS: o MORPHOLOGIC FEATURES OF APOPTOSIS: (Table 1-2)  Cell shrinkage  Chromatin condensation and fragmentation  Cellular blebbing and fragmentation into apoptotic bodies  Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages o Lack of inflammation makes it difficult to detect apoptosis histologically  Protein breakdown occurs thru a family of proteases called CASPASES (have an active site cysteine and cleave at asparatate residues)  Internucleosomal cleavage of DNA into fragments  Plasma membrane alterations allow recognition of apoptotic cells for phagocytosis MECHANISMS OF APOPTOSIS: (Fig. 1-4) o APOPTOSIS is a cascade of molecular events that can be initiated by a variety of triggers. o Process of APOPTOSIS is divided into:  INITIATION phase – when caspases become active  EXECUTION phase – when the enzymes cause cell death o Initiation of Apoptosis occurs thru 2 distinct but convergent pathways:  1) the INTRINSIC MITOCHONDRIAL PATHWAY  2) the EXTRINSIC (DEATH RECEPTOR-MEDIATED) PATHWAY o The essence of the INTRINSIC pathway is a balance b/t pro-apoptotic and anti-apoptotic molecules that regulate mitochondrial permeability

^^Fig. 1-4: Mechanisms of apoptosis

^^Fig. 1-8: Schematic illustration of the morphologic changes in cell injury culminating in necrosis or apoptosis. 

APOPTOSIS IN HEALTH AND DISEASE: o GROWTH FACTOR DEPRIVATION o DNA DAMAGE o PROTEIN MISFOLDING o TNF FAMILY RECEPTORS o CYTOTOXIC T LYMPHOCYTES o

DISORDERS ASSOCIATED WITH DYSREGULATED APOPTOSIS:  Dysregulated (“too much or too little”) apoptosis underlies multiple disorders:  Disorders with defective apoptosis and increased cell survival o 1) CANCERS (esp tumors with p53 mutations, or hormonedependent tumors, such as breast, prostate, or ovarian cancers) o 2) AUTOIMMUNE DISORDERS – when autoreactive lymphocytes are not eliminated  Disorders with increased apoptosis and excessive cell death o 1) NEURODEGERNERATIE DISEASES – with drop out of specific sets of neurons o 2) ISCHEMIC INJURY – such as myocardial infarction or stroke o 3) DEATH OF VIRUS-INFECTED CELLS

INTRACELLULAR ACCUMULATIONS: (p.32)  1) a normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it  2) an abnormal endogenous substance, typically the product of a mutated gene, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently  3) a normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance  4) an abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites  In many cases, if the overload can be controlled or stopped, the accumulation is reversible  In inherited storage diseases accumulation is progressive, and the overload may cause cellular injury, leading in some instances to death of the tissue and the patient LIPIDS:  Tryglycerides (most common),  Cholesterol and cholesterol esters, &  Phospholipids can accumulate in cells 

STEATOSIS (FATTY CHANGE): o An abnormal accumulation of triglycerides within parenchymal cells either due to excessive injury or defective metabolism and export o It can occur in heart, muscle, and kidney, but the most common is in the LIVER o Fatty change is typically reversible, but it can lead to inflammation and fibrosis o The condition is caused by excessive entry or defective metabolism or export of lipids:  Increased fatty acids entering the liver (starvation, corticosteroids)  Decreased fatty acid oxidation (hypoxia)  Increased triglyceride formation (alcohol)

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 Decreased apoprotein synthesis (carbon tetrachloride poisoning, starvation)  Impaired lipoprotein secretion from the liver (alcohol) CHOLESTEROL AND CHOLESTEROL ESTERS: o Atherosclerosis o Xanthomas  Hyperlipidemias  Foamy macrophages o Cholesterolosis o Niemann-Pick disease, type C PROTEINS: o Intracellular protein accumulation may be due to excessive synthesis, absorption, or defects in cellular transport. o In some disorders (e.g., amyloidosis), abnormal proteins deposit primarily in the EXTRACELLULAR space  REABSORPTION DROPLETS of proteins accumulate in proximal renal tubules in the setting of chronic proteinuria  REVERSIBLE  The droplets are metabolized and clear if the proteinuria resolves  NORMALLY SECRETED PROTEINS can accumulate if produced in excessive amounts  RUSSELL BODIES  DEFECTIVE INTRACELLULAR TRANSPORT AND SECRETION (e.g., Alpha 1antitrypsin deficiency, which can also lead to emphysema)  ACCUMULATED CYTOSKELETAL PROTEINS  Excess intermediate filaments (e.g., keratin or certain neurofilaments) are HALLMARKS of CELL INJURY; thus, keratin intermediate filaments coalesce into cytoplasmic eosinophilic inclusions called ALCOHOLIC HYALINE, and the NEUROFIBRILLARY TANGLE in Alzheirmer’s disease  AGGREGATES OF ABNORMAL PROTEINS  Can be intracellular and/or extracellular (e.g., extracellular amyloid) HYALINE CHANGE: o HYALINE CHANGE – refers to any deposit that imparts a homogeneous, glassy, pink appearance in H&E-stained histologic sections  INTRACELLULAR HYALINE CHANGE  EXTRACELLULAR HYALINE CHANGE GLYCOGEN: o GLYCOGEN is commonly stored within cells as ready energy source o EXCESSIVE intracellular deposits are seen with abnormalities of glycogen storage (socalled GLYCOGENOSES) and glucose metabolism (DIABETES MELLITUS) PIGMENTS: o PIGMENTS – colored substances that can be exogenous (e.g., coal dust) or endogenous (e.g., melanin or hemosiderin) o EXOGENOUS PIGMENTS: include carbon or coal dust (most common); when visibly accumulated within pulmonary macrophages and LNs, these deposits are called ANTHRACOSIS  Pigments from tattooing are taken up by macrophages and persist for the life of the cell o ENDOGENOUS PIGMENTS include:  LIPOFUSCIN – the “wear and tear” pigment, usually associated with cellular and tissue atrophy (BROWN ATROPHY)  MELANIN – is a normal, endogenous, brown-black pigment formed in melanocytes

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HOMOGENTISIC ACID – is a black pigment formed in patients with alkaptonuria that deposits in skin and connective tissue; the pigmentation is called OCHRONOSIS HEMOSIDERIN – is a hemoglobin-derived, golden--yellow-brown, granular intracellular pigment composed of aggregated ferritin  LOCALIZED accumulation – macrophage-mediated breakdown of blood in a bruise  SYSTEMIC accumulation – resulting from increased dietary iron absorption (primary hemochromatosis), impaired utilization (e.g., thalassemia), hemolysis, or chronic transfusions

PATHOLOGIC CALCIFICATION:  PATHOLOGIC CALCIFICATION – the abnormal tissue deposition of calcium salts --- occurs in 2 forms: o DYSTROPHIC CALCIFICATION – arises in nonviable tissues in the presence of normal calcium serum levels o METASTATIC CALCIFICATION – happens in viable tissues in the setting of hypercalcemia 

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DYSTROPHIC CALCIFICATION: o Occurs arteries in atherosclerosis, and damaged heart valves, and in areas of necrosis o Calcium can be intracellular and extracellular o INITIATION (NUCLEATION):  EXTRACELLULAR initiation – occurs on membranes-bound vesicles from dead or dying cells that concentrate calcium due to their content of charged phospholipids  INTRACELLULAR initiation – calcification occurs in mitochondria dead or dying cells o PROPAGATION of crystal formation depends on:  The concentration of calcium and phosphates  The presence of inhibitors, and  Structural components of the extracellular matrix METASTATIC CALCIFICATION: o Results from hypercalcemia, which has four principal causes:  1) ELEVATED PARATHYROID HORMONE  2) BONE DESTRUCTION, as in primary marrow malignancies or by diffuse skeletal metastasis, by accelerated bone turnover (Paget’s disease), or immobilization  3) VITAMIN D-RELATED DISORDERS, including vitamin D intoxication and systemic sarcoidosis  4) RENAL FAILURE, causing secondary hyperparathyroidism due to phosphate retention and the resulting hypocalcemia

CELLULAR AGING:  With increasing age, degenerative changes impact the structure and physiologic function of all organs systems  The tempo and severity of such changes in any given individual are influenced by genetic factors, diet, social conditions, and the impact of other comorbidities, such as atherosclerosis, diabetes, and osteoarthritis  CELLULAR AGING – reflecting the progressive accumulation of sublethal cellular and molecular damage due to both genetic and exogenous influences --- leads to cell death and diminished capacity to respond to injury

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AGING – appears to be a regulated process influenced by a limited number of genes; this, in turn, implies that aging can potentially be parsed into definable mechanistic alterations: o CELLULAR SENESCENCE (esp TELOMERE SHORTENING) o ACCUMULATED METABOLIC AND GENETIC DAMAGE Increased ROS production The recognition and repair of damaged DNA is also a critical counterbalance o In patients with Werner syndrome, there is a premature aging due to defective DNA helicase with accelerated accumulation of chromosomal damage Genetic instability is also characteristic of other disorders associated with premature aging (e.g., ATAXIATELANGIECTASIA) THE MOST EFFECTIVE WAY TO PROLONG THE LIFESPAN IS CALORIC RESTRICTION