Pathology EXAM 1 Plasma Protease Diagram

Complement Diagram

Eicosanoids Innate Vs. Acquired Diagram

Cell Injury Chapter 1 *adaptive responses fight to keep the cell alive under stress and are a short term fix!!!* Pathology Terms Morphology Appearance of cells/tissue/organ under stress

Etiology Causative factors and hardest level of correlation. Ex. Smoking causes lung cancer (all proof is epidemiologic)

Pathogenesis Mechanism of cell/tissue/organ injury how and why shit falls apart

Cells encounter many stresses as a result of changes in their internal and external environments. If an injury exceeds the adaptive capacity of the cell, the cell dies. A cell exposed to persistent sublethal injury has limited available responses.In general, mammalian cells adapt to injury by conserving resources: decreasing or ceasing differentiated (mature cell) functions and focusing exclusively on its own survival. Ex. Sickle cell anemia ridged rbc cant squeeze through caps like regular ones (jam cap and u get ischemia) thrown out by spleen. Health Pathology Perspective: Broad Perspective: Absence of disease A state where mind and body function Disease: Any disturbance of structure or function. Structure & function are dependent on each other : one cant exist w/o the other

efficiently and harmoniously as an integrated unit Symptoms: Signs: Subjective manifestations such Objective manifestations/physical as weakness or pain. Ex. findings such as body Diarrhea temperature

Reactions to Persistent Stress and Cell Injury Stress on cells stress on organ stress on organism. Persistent stress (temp, virus, toxin, etc.) often leads to chronic cell injury. Permanent organ injury is associated with the death of individual cells. By contrast, the cellular response to persistent sublethal injury, whether chemical or physical, reflects adaptation of the cell to a hostile environment. These changes are, for the most part, reversible on discontinuation of the stress. On the other hand : no stress = no cell injury Proteasomes: Cell Homeostasis, Response to Stress, and Adaptation to Altered Extracellular Environment We can only regulate/maintain homeostasis in a very narrow margin. Adaptation is extremely limited and not all cells have the same adaptive capacities ex. Different cells react differently to the same stressor. Original theories of adaptation to stress focused on analyzing changes in gene expression and protein production. New theories focus on the regulation of protein degradation. Homeostasis requires mechanisms that allow the cell to destroy certain proteins selectively. The best understood mechanism by which cells target specific proteins for elimination is the ubiquitin (Ub) - proteasome apparatus. Proteosome - Ubiquitin importance: It may comprise up to 1% of the total protein of cells. Proteasomes are evolutionarily highly conserved, and are present in all eukaryotic cells. Dysfunctions of normal proteasomal function, are lethal. Ub is a 76-amino acid protein that is almost identical in yeast and humans. Ubiquitin function: 1. Proteins targeted for destruction are modified, and recognized by one 19S proteasome subunit. 2. They are degraded in an ATP requiring process by the 20S subunit. 3. The products of this process are peptides that are 3 to 25 amino acids in size, and are released through the lower 19S subunit. Ubiquitin and Ubiquitination Proteins to be degraded are flagged by attaching small chains of ubiquitin molecules to them. It is the key to selective protein elimination: it is conjugated to proteins as a flag to identify those proteins to be destroyed. The process of attaching Ub to proteins is called ubiquitination. Side note: all organs have 2 cell types: Parenchyma Functional cells of the organ ex. Myocardial cells

Stroma Ct holds it together

Cellular Adaptations to Stress In response to persistent stress, a cell dies or adapts to remove it. It fails when the stress is excessive/long termThe major adaptive responses are: Atrophy Hypertrophy Hyperplasia size size number Metaplasia Dysplasia Intracellular storage Cell type change Dysfunctional growth to get rid of stress Cellular Atrophy An adaptation to stress resulting from reduced metabolic need or resources for a cell's activities. It is mostly irreversible if u get rid of the stressor. Clinically, atrophy is often noted as decreased size or function of an organ. It may occur under both pathologic and physiologic circumstances. Atrophy is an adaptive response resulting from accommodations to changes in environment, while remaining viable. Reduction in an organ's size may reflect reversible cell atrophy or irreversible loss of cells. Atrophy of the brain in Alzheimers disease is

secondary to extensive cell death; the size of the organ cannot be restored. Ex. Widening of gyri and flattening of sulci. The neurons cant undergo atrophy the brain has no adaptive capacity so when the brain atrophies it is dying, not shrinking (ppl using terminology wrong). Causes of Cell Atrophy Reduced functional demand Ex. Muscle when leg breaks Interruption of trophic signals

Inadequate oxygen supply (ischemia) Persistent cell injury

Insufficient nutrient delivery Aging

Atrophy Is an Active Process Atrophy involves changes both in production and destruction of cellular constituents. In essence, atrophy is a cell's reversible restructuring of its activities to maximize survival and adapt to conditions of diminished use. Ubiquitin comes into play...Ex. polio myelitis attack anterior horn cell and those contain alpha motor neuronsbasically, youre fucked. Responses to muscle unloading: Decrease in protein synthesis Selective increase in protein degradation Selective changes in gene transcription Selective decrease in free fatty acid utilization Fiber Type Grouping Only happens in denervation (carwreck, polio, etc.) You have 2 spinal nerves : one goes to a group of type I muscle fibers and one goes to a group of type II muscle fibers (there is no such thing as a mixed motor nerve) there is denervation atrophy/damage at a type II motor fiber and the fiber going to type I muscle will reroute itself and innervate type II muscles eventually the type II muscle fibers change to type I muscle fibers meaning that muscle type is determined by innervation not skeletal muscle genetics!!! Hypertrophy increase in cellular size Hyperplasia Increase in cell number Metaplasia Change in cell type

Cellular Hypertrophy Hypertrophy is a response to sublethal stress involving changes in metabolic activity resulting in an increase in cellular size. Cellular remodeling occurs in hypertrophy when theres an increased proteasomal degradation of proteins that do not contribute to the specific functional response. Elevation in the production of proteins that do contribute to increases in functional response. Selective degradation of protein. Signaling Mechanisms in Hypertrophy Skeletal muscle hypertrophy illustrates some critical general principles. Many types of stress may lead to cell hypertrophy: Growth factor stimulation Ex. androgens (est & prog) for Increased load (muscle) Neuroendocrine stimulation uteus 2 different adaptive patterns to SHORT term stress The following look different because the muscle fiber type being stressed is different! Both processes ae reversible.

Others

Pic of big dude

Stressed T2 fibers adaption = myosin & actin fibers Yes skeletal muscle hypertrophy, no cardiac hypertrophy anaerobic processes only

Pic of bix winner

Stressed T1 fibers adaption = mitos No skeletal muscle hypertrophy, just cardiac hypertrophy in aerobic endurance = mitos

The heart responds to pathologic and physiologic stress the same way. Two situations, why they respond the same but are different:

Short term running

Long term heart disease

ok b/c its short term not ok b/c its long term Heart muscle is working against angiogenesis and mitos Heart muscle is working against 24/7 in BP Why the heart will fail in the long term heart stress: the adaptation has now become injurious and the #1 problem: 1. its too thick and inelastic to contract (elasticity contraction) 2. more dependent 3. grooves for cardiac vessels are compressed restricting own blood flow 4. conduction problems

Smooth m. and hypertrophy Uterus undergoes reversible hypertrophy & hyperplasia during pregnancy smooth muscle can undergo hyperplasia and sk m. and c. m. cant. Hyperplasia Hyperplasia Is an Increase in the Number of Cells in an Organ or Tissue. Hypertrophy and hyperplasia can occur independently or concurrently. Hyperplasia occurs so that theres a bigger army to counteract a given stressor. The specific stimuli that induce hyperplasia vary greatly from one tissue and cell type to the next. Basically, hyperplasia involves stimulating resting (G0) cells to enter the cell cycle (G1) and then to multiply. This may be a response to altered endocrine stimulation, increased functional demand or chronic injury. Ex. skin cells in response to stress consistent abrasion bunion and corns thickened epidermins to increase the # of squamous cells. Psoriasis in summer its better b/c of uv light Hyperplasia of bone marrow RBC count increases doping on EPi bix runners, etc. WBC count increases . Kemia and lymphoma cancer and infection Prostate hyperplasia increase p on urethra is reversible. Hormonal Stimulation Increased Functional Demand Chronic Injury *prolonged meta and dys-plasia are increased risk factors for cancer* Metaplasia Metaplasia Is Conversion of One Differentiated Cell Type to Another. Metaplasia is usually an adaptive response to chronic, persistent injury. Mostcommonly, glandular epithelium is replaced by squamous epithelium. Columnar or cuboidal lining cells may be committed to mucus production, but may not be adequately resistant to the effects of chronic irritation or a pernicious chemical. For example, prolonged exposure of the bronchial epithelium to tobacco smoke leads to squamous metaplasia. In molecular terms, metaplasia involves replacing the expression of one set of differentiation genes with another. The process is not restricted to squamous differentiation. With chronic gastric reflux the squamous epithelium of the esophagus may be replaced by stomach-like glandular mucosa (Barrett epithelium) GERD. The presence of barret epithelium indicates that metaplasia has taken place. Metaplasia may also consist of replacement of one glandular epithelium by another. In chronic gastritis atrophic gastric glands are replaced by cells resembling those of the small intestine. The adaptive value of this condition, known as intestinal metaplasia, is not clear. Metaplasia is unique and not many cells can do it. It is basically cells changing to a better defensive cell brought on by a specific stress. Its the presence of normal cells in an abnormal environment and it increases the risk for cancer and adenocarcinomas develop.

Metaplasia Examples
Columnar secretory epithelium squamous epithelium CSE usually lines the bronchii and secretes mucous but in some smokers the mucous system doesnt work so it changes to SE which contains keratin and is chemically resistant Squamous epithelium columnar secretory epithelium SE usually lines the esophagus but in GERD/chronic reflux patients they change to CSE which is a gastric epithelium that is well designed to protect from acid

Lung Cancer = Bronchogenic Cancer The #1 lung tumor was squamous cell carcinoma (SE) but now its adenocarcinomas (CSE)People who dont smoke can develop lung cancerright now, smoking is related to lung cancer bc there are lots of smokers who have quit and the squamous metaplasia reverted back to columnar secreteory epithelium mutations in basal cell population are now expressed. Epithelial Tissue Is The Main Site Males Females 1 prostate 1 ovarian / cervical? 2 lung 2 lung 3 - colorectal 3 - colorectal

Dysplasia Dysplasia is Disordered Growth and Maturation of the Cellular Components of a Tissue Epithelial tissues normally exhibit uniformity of size and shape. Moreover, they are arranged in a regular fashion, for example, a squamous epithelium progresses from plump basal cells to flat superficial cells. In dysplasia, normal tissue architecture is disturbed by: 1. variation in cell size and shape 2. nuclear enlargement, irregularity, and hyperchromatism 3. disarray in the arrangement of cells within the epithelium Dysplasia occurs most often in hyperplastic squamous epithelium, as seen in epidermal actinic keratosis (caused by sunlight) and in areas of squamous metaplasia, such as in the bronchus or the cervix. Like metaplasia, dysplasia is a response to a persistent stress and will usually regress, for example, on cessation of smoking or the disappearance of human papillomavirus from the cervix. Dysplasia shares many cytologic features with cancer. It may be difficult to distinguish severe dysplasia from early cancer of the cervix. Dysplasia is a preneoplastic lesion, thought to be a necessary stage in the multistep cellular progression to cancer. Displastic cells are trying to survive stress its reversible. D = a pre-neoplastic change & disruption of order. Leukoplakia tobacco chewers, pipe and cigar smokers. Epidermal actinic keratosis means youre turning a squamous cell into a basal cell a d this is extremely non-malignant. Melanoma starts out as a dysplasia. Ex. papilloma virus. Full thickness dysplasia = carcinoma-in-situ from basement membrane surface of epi b/c BM isnt directly involved in a dysplasia means its curable. Once it reache s the BM u have full blown carcinoma {cancer at site of ____ = hasnt spread}. Cell storage is @ the end. Mechanisms of Cell Injury All cells have efficient mechanisms to deal with shifts in environmental conditions (to a point!). Thus, ion channels open or close, harmful chemicals are detoxified, metabolic stores such as fat or glycogen may be mobilized, and catabolic processes lead to the segregation of internal particulate materials. It is when environmental changes exceed the cell's capacity to maintain normal homeostasis that we recognize acute cell injury. If the stress is removed in time or if the cell can withstand the assault, cell injury is reversible, and complete structural and functional integrity is restored. When circulation to the heart is interrupted for less than 30 minutes, all structural and functional alterations are reversible. Cells can also be exposed to persistent sublethal stress, as in mechanical irritation of the skin or exposure of the bronchial mucosa to tobacco smoke. In such instances, the cell has time to adapt to reversible injury in a number of ways, each of which has its morphologic counterpart. If the stress is severe, irreversible injury leads to cell death. The precise moment at which reversible injury gives way to irreversible injury, the point of no return. Injurious stimulus Reversible cell injury Reversible stage? Necrosis Apoptosis Ischemia If you dont have ATP in a cell you have no Na/K pump which leads to swelling / hydropic change. The cytoskeleton determines the shape of the cell. H2O flows into the cell and it swells when Ca2+ enters the cell (a highly impermeable ion 10,000Ca outside/1Ca inside) the cell dies, its THE DEATH ION. Calcium and phosphate are stored in the bone. Calcium regulation is necessary for neurotransmittance/neural activity and muscle contraction. Reversible Injury Reduced oxygen availability leads to a decrease in ATP generation. Thus reduction in ATP synthesis then systems: A. Na/K pump - acute cellular swelling (Hydropic B. Glycogen C. Ribosome Change)This is the cellular process that consumes depletion - detachment - reduced most ATP 20% of it. intracellular pH protein synthesis

affects a number of other D. Cytoskeletal disruption Most important because it causes more diffusion and swelling

Two Ischemic Events That Respond Differently To The Same Stressor Brain dies first, heart dies second. Heart attack Recovery > 30 min of heart after ischmia

Stroke No recovery of brain after ischemia

Irreversible Injury The continuation of cell stress leads to changes that are not repairable: A. Mitochondrial disruption B. Plasma membrane disruption and calcium influx* C. Release of lysosomal hydrolases *Note: The loss of plasma membrane integrity and subsequent influx of calcium are believed to be the most important events that cause "irreversible" injury. Reactive Oxygen Species (ROS)/Oxygen Radicals ROS have been identified as the likely cause of cell injury in many diseases. The inflammatory process, whether acute or chronic, can cause considerable tissue destruction. Partially reduced oxygen species produced by phagocytic cells are important mediators of cell injury. Damage to cells resulting from oxygen radicals formed by inflammatory cells has been implicated in diseases of the joints and of many organs, including the kidneys, lungs, and heart. The toxicity of many chemicals may reflect the formation of toxic oxygen species. The killing of cells by ionizing radiation is most likely the result of the direct formation of hydroxyl (OH) radicals from the radiolysis of water (H2O). There is also evidence of a role for oxygen species in the formation of mutations during chemical carcinogenesis. Finally, oxidative damage has been implicated in biological aging. Non-biological example of O2 reactiveness = rust and fire. Oxygen (O2) has a major metabolic role as the terminal acceptor for mitochondrial electron transport. Cytochrome oxidase catalyzes the four-electron reduction of O2 to H2O. The resultant energy is harnessed as an electrochemical potential across the mitochondrial inner membrane. Complete reduction of O2 to H2O involves the transfer of four electrons. There are three partially reduced species that are intermediate between O2 and H2O, representing transfers of varying numbers of electrons. They are O2-, superoxide, H2O2, hydrogen peroxide and OH (most harmful), the hydroxyl radical. These ROS are produced principally by leaks in mitochondrial electron transport. Sources of Free Radicals Aerobic respiration #1 source! From ets (its not 100% efficient!)

Immune cell activation Immune system uses these as weapons! It becomes an issue if the inflammation is uncontrolled

Radiant Energy

Environment

Chemicals

Reactions of Free Radicals Formation Degradation P-450 Cytochrome Oxidases Superoxide dismutase NADPH Oxidase Catalase Xanthine Oxidase Glutathione Peroxidase Myeloperoxidase (From neutrophils and forms a hypochlorous radial basically bleach!) Reaction Glutathione peroxidase catalyzes: Glutathione reductase then reduces the oxidized glutathione to complete the cycle: 2GSH + H2O2 GSSG + 2H2O GSSG + NADPH + H+ 2 GSH + NADP+. Impact of Free Radicals Membrane Lipid Peroxidation

DNA Fragmentation

Protein Fragmentation and Cross linking

Cellular Defenses against Oxygen Free Radicals Cells have potent antioxidant defenses against ROS, including detoxifying enzymes and exogenous free radical scavengers (vitamins). The major enzymes that convert ROS to less reactive molecules are superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX). Detoxifying Enzymes SOD is the first line of defense against O2-, converting it to H2O2 and O2. (H+ = hydrogen ion) 2 O2- + 2 H+ O2 + H2O2.

Catalase principally located in peroxisomes, is one of two enzymes that complete the dissolution of O2- by eliminating H2O2 and, therefore, its potential conversion to OH. 2 H2O2 2 H2O + O2

GPX catalyzes the reduction of H2O2 and lipid peroxides in mitochondria and the cytosol. H2O2 + 2 GSH 2 H2O + GSSG

Scavengers of ROS Vitamin E (-tocopherol) is a terminal electron acceptor and, therefore, blocks free-radical chain reactions. Because it is fat soluble, it exerts its activity in lipid membranes, protecting them against lipid peroxidation.

Vitamin C (ascorbate) is water soluble and reacts directly with O2, OH, and some products of lipid peroxidation. It also serves to regenerate the reduced form of vitamin E. A, C, E!

Retinoids the precursors of vitamin A, are lipid soluble and function as chainbreaking antioxidants.

Ischemia/Reperfusion Injury Reflects Oxidative Stress 6

Ischemia/reperfusion (I/R) injury is a common clinical problem that arises in occlusive cardiovascular disease, infection, shock, and many other settings. I/R injury reflects the interplay of transient ischemia, consequent tissue damage, and exposure of damaged tissue to the oxygen that arrives when blood flow is reestablished (reperfusion). Initially, ischemic cellular damage leads to damge of electron transport systems. Reperfusion then provides molecular O2 to activating damaged mitochondria with release of high levels of ROS. Depletion of cellular nitric oxide has also been implicated in tissues decreased ability to respond to stress as well as a potential agent of stress induced tissue injury. Vascular actions of NO (important vasodilator) include the following: Direct vasodilation Indirect vasodilation (flow dependent and receptor mediated) by inhibiting vasoconstrictor influences (ex. inhibits angiotensin II & S vasoconstriction) Anti-thrombotic effect Anti-inflammatory effect inhibits platelet adhesion to the vascular inhibits leukocyte adhesion to vascular endothelium;scavenges superoxide anion endo Anti-proliferative effect inhibits smooth muscle hyperplasia Patterns of Cell Death: Necrosis and Apoptosis Necrosis pathologic Apoptosis physiologic pathologic

Cell Death An understanding of the mechanisms underlying cell death is not simply an academic exercise; manipulation of cell viability by biochemical and pharmacologic intervention is currently a major area of research. Understand the biochemistry of ischemic myocardial cell death, responsible for the leading cause of death in the Western world, may lead to prolonged cardiac survival. Paradoxically, an organism's survival requires sacrifice of individual cells. Physiologic cell death is integral to the transformation of embryonic tissues to fully developed organs. It is also crucial for regulation of cell numbers in a variety of tissues, including the epidermis, gastrointestinal tract, and hematopoietic system. Physiological cell death involves activation of an internal suicide program, which results in cell killing by a process termed apoptosis. Necrosis Pathologic cell death is not regulated and is invariably injurious to the organism. It may result from a variety of insults to cellular integrity (e.g., ischemia, burns, and toxins). Necrosis occurs when an insult interferes with a vital structure or function of an organelle (plasma membrane {via C12+ entrance}, mitochondria, etc.) and does not trigger apoptosis. Pathologic cell death can also result from apoptosis, as exemplified by viral infections {well talk about} and ionizing radiation {damages DNA}. This results primarily from enzymatic digestion (heterolysis and autolysis) and protein denaturation. Cellular necrosis: Pyknosis Karyorrhexis Karyolysis Nuclear condensation Nuclear fragmentation Nuclear disintegration Visible change in dead cell Visible change in dead cell Visible change in dead cell nuclei: nuclei: nuclei: Donut One dot Lots of little dots Stains No stain Gross Patterns of necrosis: Coagulative Liquefactive Gangrenous Caseous Fat 1 patterns of necrosis across all cells most General term for coagulative necrosis important Ex. Mountain climbers get frostbite no disease Coagulative Necrosis Protein degradation. Ex of liquefaction Cooking an egg. At the end of cooking it there is no persistance of architecture. You arent changing the protein LEVELS so why does the color and texture change? Its clear and viscous (because there are spaces between the cells that the light is leaking through) and the water molecules inside it is highly organized. Add heat. The heat changes the charge because it randomizes the water molecules. This results in breakage of the H bonds (weak bonds) between the protein and the water. Its now opaque and solid {solid b/cThe album binds tighter because the protein is unwound and the adhesion area increases}. pH works the same way as heat H bonds change and the change in shape changes the state of the molecules. Has to do with a general process of coagulation and prtein denaturation. Review of Protein Bonds Organization The whole time youre cooking the egg youre minimizing the energy it contains. The ultimate minimalization of E is breaking the 3 bonds. You dont break the 2 bonds because theyre strong (covalent). 1 structure 2 structure 3 structure 4 structure aa alpha helices and beta pleated sheets aa-R H bonds combining >1 protein. 7

group bonds. covalent disulfide bridges Things that create cell death: Ph change Changes how the nuclear material binds

(non-covalent bonds)

Release of endonucleases Chew dna

Example Muscle Cell Outside The CNS Kill it with ischemia. It has the ability to unergo anaerobic glycolysis (cell is storing E as glycogen) Ischemia induces glycogenolysis and glucose undergoes glycolysis anaerobic heart muscle can survive for 30 minutes, skeletal muscle will survive for hours under ischemia. This produces lactic acid that builds up (no blood flow to wash it away) and its called metabolic acidosis {which is termporary b/c u have fluids sloshing around, etc.}.). Whether or not the lysosome (has lipases, proteases and endonucleases) degrades detemerines th kind of necrosis u r faced with. If the L is ruptured, the enzymes are released into the metabolic acidosis. In the acidic environment, the enzymes are denatured and function is lost. Neurons (are lysosome rich) that undergo ischemia theres no metabolic acidosis b/c they cant undergo any glycogenolysis so when the lysosomes are released and rupture the enzymes chew shit up collagen is the most abundan protein in the body but theres none IN the brain (in meninges OUTSIDE the brain). The protein concentration in the brain is very low so if the lysosomal enzymes are released by neurons in the brain its super easy for them to eat through it. The tissue during metabolic acidosis is prime for infextion. Liquesfaction can occur anywhere in body after 2 infection. How does the bacteria get in and stay during this? They eat you with enzymes and make energy and its easy in this mean time to eat you b/c you have dead tissue. 1. Bacteria come in and 2 they use acidic tempered enzymes to eat u.

Gangrene There are 3 terms for this. Dry gangrene Wet gangrene Coagulative necrosis Liquefaction/liquifactive Ex. Result of renal infarct {death of a t. due to ischemia}. how to tell the difference between coagulative vs. liquefactive gangrene What we focus on Coagulative/2 for a period of time after cell death the cell outline/cytoarchitecture is still obvious/in tact Usually outside the CNS

Gas gangrene Infection via chlostridium

Liquefactive/1 or 2 no persistance of cytoarchitecture usually inside the CNS

There is an exception to this ruse any tissue outside the CNS can undergo secondary liquefaction after undergoing coagulative necrosis b/c they got a bacterial infection after the coagulative necrosis. Ex. guy got stabbed (coagulative necrosis) and made a tourniquet and left it on and then it got infected and 2 liquefaction results. how to tell the difference example Person has a stroke Stroke #1 Stroke #2 Evidence of a cyst/cyst formation = a survivable stroke. No evidence of a cyst or coagulation = a non-survivable stroke The tissue undergoes liquefaction and scar tissue repairs it (gliosis) Caseous Necrosis Comes from the word casein Mycrobacterium tuberculosis, leprisae, palladium all these bacteria have a waxy coat made from the protein casein (what makes cheese). We dont have the enzyme to break down casein and at the site of infection you will have a waxy build up from the presence of these bacteria and it looks like cheese! The lesion can be unlocalized or localized. If our immune system can localize the TB and prevent it from being infectious why are there so many cases of unlocalized, infectious TB? Malnutrition, poverty and HIV. Immunocompromised people.

Localized TB
Non-spreading because a Ghon complex is created and this is as far as it goes in a normal healthy person. This is the immune systems way of controlling it its permanent but it keeps it in one place. It leads to a granuloma. 1 TB 2 non-infective, non-spreading non-infective, active but localized to lungs

Unlocalized TB
Spreading systematically to body and brain. 3/military TB infective & spreading

Apoptosis Apoptosis, or Programmed Cell Death, Refers to a Cellular Suicide Mechanism Apoptosis is a prearranged pathway of cell death triggered by a variety of extracellular and intracellular signals. It is part of the balance between the life and death of cells and determines that a cell dies when it is no longer useful or when it may be harmful to the larger organism. It is also a self-defense mechanism, cells that are infected with pathogens or in which genomic alterations have occurred are destroyed. In this context, many pathogens have evolved mechanisms to inactivate key components of the apoptotic signaling cascades. Apoptosis detects and destroys cells that harbor dangerous mutations, thereby maintaining genetic consistency and preventing the development of cancer. By contrast, as in the case of infectious agents, successful clones of tumor cells often devise mechanisms to circumvent apoptosis. The Morphology of Apoptosis Apoptotic cells are recognized by nuclear fragmentation and pyknosis, generally against a background of viable cells. Importantly, individual cells or small groups of cells undergo apoptosis, whereas necrosis characteristically involves larger geographic areas of cell death. Ultrastructural features of apoptotic cells include nuclear condensation and segregation of cytoplasmic blebs of the plasma membrane-bound cellular fragments, fragmentation organelles into distinct regions membrane which often lack nuclei. Cells that have undergone necrotic cell death tend to elicit strong inflammatory responses. Inflammation, however, is not generally seen in the vicinity of apoptotic cells. Mononuclear phagocytes may contain cellular debris from apoptotic cells, but recruitment of neutrophils or lymphocytes is uncommon. In view of the numerous developmental, physiologic and protective functions of apoptosis, the lack of inflammation is clearly beneficial to the organism.

Intracellular Accumulations Intracellular Storage Is Retention of Materials within the Cell. The substance that accumulates may be normal or abnormal, endogenous or exogenous, harmful or innocuous. Nutrients Stored for later use. Fat Glycogen Vitamins Minerals Mallory Body Hyaline protein cytoplasmic inclusion (structural protein aggregation) found in hepatocytes most commonly of patients suffering from chronic alcoholism. Mallory = glassy, smooth look.) Abnormal proteins may be toxic Degraded phospholipids which result from turnover of endogenous membranes, are stored in lysosomes and may be recycled. Overload of normal body constituents Injures a variety of cells. Iron Copper Cholesterol Substances that cannot be metabolized accumulate in cells. These include: 1. Endogenous substrates are not further processed because a key enzyme is missing (hereditary storage diseases) 2. Insoluble endogenous pigments (e.g., lipofuscin and melanin) 3. Aggregates of normal or abnormal proteins 4. Exogenous particulates, such as inhaled silica and carbon or injected tattoo pigments.

Abnormal proteins may be toxic when they are retained within a cell instead of broken down into aa.

Example #1
Normal protein Chaperone binds and it has a normal fxn Mildly abnormal protein Ubiquitin binds and it is degraded Severaly abnormal protein Ubiquitin cant bind, its not degraded and its toxic to the cell

Example #2
Lipofuschin a piece of the membrane thats dysfunctional is normally degraded but in this case the lysosome is missing an enzyme and the lipids will just build up. You can stain for the pieces that are ganging around

Example #3
Black lung carbon pigment builds up and causes the color but its not what kills you and isnt toxic its the silica inhaled that is carcinogenic and causes lung cancer.

Example #4
Hereditary hemochromatosis Fe builds up in your liver! Steatosis When fat accumulates in the liver it is called a fatty liver or steatosis. It is lighter because its yellow and its bigger (hepatomegaly). Causes Of Fat Accumulation In The Liver Chronic Alcoholism Viral Infections Hep A, B and C. B and C are chronic, A is acute. Chronic Liver Stress Progression Key R = reversible, IR = irreversible Chronic liver stress steatosis (R) hepatitis (rev) cirrhosis (IR & progressive) Cirrhosis Causes jaundice and its seen most easily in the sclera o the eye = ICTERUS. Almost impossible to separate jaundice from liver failure. Yellow b/c the liver cant process bilirubin. KERNICTERUS = bilirubin accumulation in the brain only occurs in neonates & is lethal. Its only in babies b/c theres no blood brain barrier. UV lights on babies isomerizes bilirubin to a soluble form that can be pas sed. Jaundice babies that are at risk for kernicterus are put under bili lights.

icterus
Bilirubin Build Up In Sclera

kernicterus
CNS

2 Types of Cirrhosis = Excess Scar Tissue Micronodular Macronodular Small nodules of scar t. surrounding hepatocytes, seen in Large nodules of scar t. surrounding hepatocytes, seen in hep B and alcoholism C. Bilirubin Break Down You can witness the break down of bilirubin to hemoglobin in a bruise. Injurt to small BV release RBC and the hemoglobin is broken down by macrophages. The highlighted color is the color of that pigment. Hemoglobin heme globin biliverdin & Fe non-protein portion - O2 and Fe binding component of hemoglobin-highly insoluble Protein portion broken down into aa 10

bilirubin (and brown) Cellular Aging Summary Hypothesis of Aging After the reproductive period, evolution loses interest in an individual and abandons the organism to events against which nature confers no protection. The doctrine of antagonistic pleiotropy posits the existence of genes that are beneficial during development and the reproductive period but exert baleful influences later in life. Cell culture insert explant to bottom of petri dish coated with ECM protein by thrombin and fibrinogen remove cells from the monolayer and grow it in a new dish over and over = PASSAGE. There is a terminal point where the passage no longer works and normally you just inoculate the cells with a virus to initiate them again so they can undergo passage again but there was a guy named hayflick who discovered hayflicks principle that basically says: the longer the life span of the species the longer they will be able to undergo passage he proved this by taking fibroblasts from many different species and passage-ing them until their terminal point and then graphing them and thats what he found! Phenylketonuria a human disease caused by a mutation in a single gene that codes for the enzyme, phenylalanine hydroxylase. Tyrosine is needed for general protein synthesis, and it is also a precursor for several neurotransmitters (e.g., dopamine, norepinephrine), the hormone thyroxine, and the pigment melanin. Thus, mutations in any one of the genes that affect tyrosine synthesis or metabolism may affect multiple body systems. The disease is characterized by mental retardation and reduced hair and skin pigmentation. Finally, the major non-genetic theories postulate that simple accumulation of various cell injuries eventuates in senescence. Current evidence supports the notion that these hypotheses are not mutually contradictory and that all may contribute to aging. According to this concept, although aging is under some measure of genetic control, it is unlikely that a predetermined genetic program for aging exists. It is likely that the combined effects of a number of genes eventually lead to the accumulation of somatic mutations, deficiencies in DNA repair, the accumulation of oxidative damage to macromolecules, and a variety of other defects in cell function, all culminating in the progressive failure of homeostatic mechanisms characteristic of aging. As Maimonides said, The same forces that operate in the birth and temporal existence of man also operate in his destruction and death. Hutchinson-Gilford Progeria Syndrome ("Progeria", or "HGPS") is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children. Its name is derived from the Greek and means "prematurely old." While there are different forms of Progeria, the classic type is Hutchinson-Gilford Progeria Syndrome, which was named after the doctors who first described it in England; in 1886 by Dr. Jonathan Hutchinson and in 1897 by Dr. Hastings Gilford. HGPS is caused by a mutation in the gene called LMNA (pronounced, lamin - a). The LMNA gene produces the Lamin A protein, which is the structural scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective Lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in Progeria.

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