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HMB202H1S Lecture Notes Unit 1: Introduction to Health and Disease What is Health? -

Balance of human bodily functions All-encompassing includes mental and social wellbeing, but fundamentally about homeostasis

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When we are referring to a disease we mention an “end stage”

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“End stage” - a point during a disease when the disease is irreversible. It is a complete Natural pathological process e.g. fertilization. Normal physiology. We are interested in how our body respond to the disease.

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Etiology is what is causing the diseases this can be a bacterium or virus. As the disease develops it is more likely to become irreversible.

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Neoplasia is a control issue; it Is not a growth/rate phenomenon. Neoplastic cells cannot be controlled. 

Cell returns to normal is the best outcome and what we are geared towards but it does not always happen.

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If you get pneumonia you may have lung scaring that is an adaptation. The body reacts to itself to deal with a disease, also called acute inflammation (part of innate immunity)

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If response is unsuccessful it may result in cell death. If a chemical causes a mutation 96-hour window to be repaired for the DNA.

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Irreversible damage will always lead to cell death also called necrosis which is a pattern of tissue death.

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If we affect different biochemical processes, we can see the affect of this. E.g. if we lower oxygen we will reduce the amount of ATP production in the body.

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Cellular: o Degenerative:  Reversible cell injury  Irreversible cell injury –cell death; necrosis –series of morphological changes that ensue following cell death.  Coagulative necrosis: dead tissue appears firm; structures are recognizable (faint)  Colliquative (liquefaction) necrosis: dead tissue appears semi-liquid; no structures are recognizable.  Caseous necrosis: dead tissue resembles a soft, friable, whitish-grey clump; cream cheese. o Proliferative or Growth Response:  Hyperplasia –  in cell number.  Metaplasia–one type of differentiated tissue is replaced by another.  Dysplasia –alteration in size, shape & organization of mature cells.  Anaplasia–extreme form of arrested or altered differentiation (cancer) (seen mainly in malignant neoplasms)  Neoplasia–new growth –two categories –benign and malignant.

Irreversible injury always leads to cell death. Reversible cell injury the cell can return to normal, it can adapt. Hypoxia – low oxygen Low oxygen > low ATP production > which affects transport. Sodium usually moves out and potassium in but due to lack of ATP it’s the reverse and have influx of sodium and water. Causes organelles to swell – hydropic degeneration.

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The Liver:  Largest gland in the body (~1500g). Located in the upper right hand quadrant of the abdominal cavity, just inferior to the diaphragm. Subdivided into 4 lobes: right, left, quadrate and caudate –first two comprises the bulk of the liver. Liver has both endocrine (hormones) and exocrine (bile) function and is a major center for drug detoxification. We see a hexagon shape when we magnify it. The liver takes blood does its processes and sends it back It has a dual blood supply. Has two pipes coming in and one exiting. Portal system comes from the digestive system in the spleen. It’s a vein (low in oxygen/high nutrients) Hepatic artery – delivers O2 enriched blood to the lobule. As blood goes through goes out of central vein into vena cava. Capillaries allow blood to flow through to the central vein. Can divide the liver into 3 zones. Zone 1 – the outer region; Zone 2 – The mid region; Zone 3 – around the central vein. Zone 1 gets all the nutrients & O2 from the small intestine. Zone 2 is an intermediate. Zone 3 gets least amount of O2 and food. If O2 supply is low Zone 3 suffers the most.

Humans livers have very little connective tissue elements compared to a pig. Very thin and very little amount.

Respiratory System: 

Composed of lungs and a sequence of airways leading to an external environment, functions in providing oxygen and eliminating carbon dioxide from the cells of the body. o Subdivided into two major segments:

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Conducting portion –situated both outside and inside the lungs to convey air form the external environment to the lungs.  Respiratory portion –located strictly within the lungs, functions in the actual exchange of oxygen for carbon dioxide. Alveolus is where gas exchange takes place. Without it there is no gas exchange. Four basic properties of a respiratory organ: o Large vascular surface area (e.g. capillary bed) o Thin membrane surface –for gas exchange, this surface must be kept moist at all times. o Method for renewing the gas media within the lung environment (e.g in humans –diaphragm action. Fish –must keep swimming). o Freely circulating blood (e.g. arteries, veins, sinusoids). Mammalian lungs  a pair of sacs and a duct system. In Humans: Paired intrathorasic organs Divided into lobes: o Three lobes on the right (r. upper, r. middle and r. lower lobe) o Two lobes on the left (L. upper, L. lower lobe). o Lobes are further subdivided into ~ 10 bronchopulmonary segments –important for defining the location of lesions. Separated by a connective tissue. Bronchiole lack cartilage. Respiration begins in the alveoli. Lipid Accumulation – cell death Liquefaction necrosis, tissue debris, cannot recognize the cell; they are dead. In the liver, Fibroblast lay down regenerative nodules where they create scar tissue and try to recirculate O 2 and blood.

Defined as the reaction of vascularized tissue to local injury. Two major subtypes and Repair: o o o

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Acute inflam–involves changes that occur within minutes of Injury and persist for several hours or days. Chronic inflam–is more variable than acute and includes several forms of tissue reactions over a long period of time. Injury stim due to persistence or repetitious (TB) elicits an immune response. Repair –damage tissue is repaired by regeneration or by replacement of the damage parenchyma & stroma by fibrous tissue (e.g. scar)

Exudation - exiting of fluid to area of injury.

Fluid from capillaries is released called suppurative exudate or pus. AI is occurring which is the innate or generic response. Exudation rxn taking place Neutrophils, WBC are the first on the scene

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Cellular exudate, fliud exudate occurs and is engorged with neutrophils.

Adaptive immune system will start up cells take sample and deploy if this does not occur we will see CI occur. This takes some time to occur.

Less cell activity and less cell fluid. Macrophage eats everything in it way such as the debris. Fluid is reabsorbed by two mechanisms; the lymphatic system and macrophages. This system takes up all the fluid to reduce swelling. Goes to lymph nodes > venous system > heart and then out.

Unit 2: Microbiology Bacteria are unicellular, they lack a nucleus. They reproduce by binary fission. Most bacteria are:  0.20 to 2.0 um in diameter  2 to 8 um (microns) in length. Morphology = cell shape – In bacterial world there are three basic shapes. Major cell morphologies Coccus (pl. cocci): spherical or ovoid (Strepto/Staphylo) Rod: cylindrical shape (bacillus) Spirilla: spiral shape – fold in on itself. Many variations on basic morphological types; Pleomorphic bacteria can assume several shapes.

5 Some bacteria have hypha and stalks – the stalk is mainly for nutrient gathering. Halo capsular layer - Those with added on features are more pathogenic

Staphylococcus aureus – sphere shape, usually found on skin but some strains can become virulent. Bacillus anthracis (anthrax) – Rod shape Campylobacter jejuni - Causes salmonella. Causes gastroenteritis. Bacterium that lives in chicken and chicken that is undercooked will give us food poisoning. Helicobacter pylori – causes peptic ulcer, can live in pH range of 2-3. It is a pleomorphic bacterium

Cytoplasmic membrane: thin structure that surrounds the cell  6–8 nm thick  Vital barrier that separates cytoplasm from environment  Highly selective permeable barrier; enables concentration of specific metabolites and excretion of waste products Composition of Membranes:  General structure is phospholipid bilayer  Contain both hydrophobic and hydrophilic components  Can exist in many different chemical forms as a result of variation in the groups attached to the glycerol backbone  Fatty acids point inward to form hydrophobic environment; hydrophilic portions remain exposed to external environment or the cytoplasm The major functions of the cytoplasmic membrane 1. Permeability Barrier – Prevents leakage and functions as a gateway for transport of nutrients into and out of the cell 2. Protein Anchor – Site of many proteins involved in transport bioenergetics, and chemotaxis 3. Energy Conservation – Site of generation and the use of the proton motive force Mitochondria was a primitive bacterium. Archaea is a prokaryote. We evolved from the merging of bacteria and archaea.

6 Peptidoglycan:  Rigid layer that provides strength to cell wall – acts like steel beam.  Polysaccharide composed of – 2 major types of sugars o N-acetylglucosamine and N-acetylmuramic acid  Amino acids  Lysine or diaminopimelic acid (DAP) – mandatory for the integrity of the cell wall Bacterial Cell wall:  Semi-rigid structure gives cell its shape  Protects cell from rupture due to osmotic stress  Composed of peptidoglycan (PG): repeating units of n-acetylglucosamine (NAG) & n-acetylmuramicacid (NAM) linked by peptide bridges  Peptide composition and thickness varies among species The sugar will always be muramic acid. The cell wall contains of these cable coiled around that go around again and again the cell wall.

Peptidoglycan is made up of layers of the first chain We use L Stereoisomer Bacterium Use D stereoisomer Covalent bonds give constant stability Alternating sugars – multiple layers 2 major linkages: - Glyosidic gives backbone - Peptide -> sugar will always be muramic acid Only difference between gram positive and gram negative. Lysozymes break down ß (1,4) glycolic bonds

Bacterium come in two types:  Gram positive – thick layer of peptidoglycan  Gram negative – thin layer of peptidoglycan

Gram-Positive Cell Walls:  Can contain up to 90% peptidoglycan

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Very thin ( sebum ≠ bacteria, fungi o tears, saliva, nasal, perspiration > lysozyme ≠ bacteria – anti-bacterial enzyme that cleaves ß (1,4) glyosidic bonds o stomach > hydrochloric acid, enzymes ≠ many ingested pathogens Barriers: 2nd & 3rd Line Defense:  When barriers breached, the Innate immune system kicks in! very generic rxns will take place. This triggers:  Adaptive Immune System – takes time to start  Lymphoid Organs first though! We want to delay the entry of a bacterium in our body Lymphoid System: - A large system that requires a lot of energy  Responsible for the immunological defense of the body: o Self/non‐self recognition. Makes sure our body does not react to us. Differ between us and invaders o Protection from foreign invader (antigens). o Handled by B‐cells, T‐cells (T4, T8 cells) and antigen presenting cells (dendritic cells/macrophages) initiate and participate in the immune response.  Component organs: lymph node, thymus and the spleen and diffuse lymphoid tissue.  Lymphatic tissue, names by region: wherever there is an entry/exit point there is a lymph hotspot, external to body o Mucosa associated lymphoid tissue (MALT):  Gut associated lymphatic tissue (GALT)  Peyer’s patch Same type of cells  Bronchus associated lymphatic tissue (BALT)  Similar to Peyer’s patch, but located in the walls of the bronchus.  Appendix, tonsils, anal region.  Aggregate in small intestine to form lymph nodules.  Lymphatic organs: o Lymph node o Spleen and thymus  Primary (central) Lymphoid Organ o Development and maturation of lymphocytes - immunocompetent cells o Thymus, fetal liver, pre‐ &post‐natal bone marrow  Secondary (peripheral) Lymphatic organs: o Provide the proper environment for immunocompetent cells to react, their work area! o Lymph node, spleen, diffuse lymphoid tissue and post‐natal bone marrow

The main function:  To drain up tissue fluid

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Deals with antigen – through lymph nodes It filters lymph It is pertained to secondary lymph nodes.

Lymphocytes close to epithelial cells, lymph nodes are made up of aggregation of B cells The Tonsil: - Diffuse lymphatic tissue - Round spots are secondary lymph nodule activated by an antigen, travels to lymph nodules and it proliferates - Primary lymph nodule means that it hasn’t been activated/stimulated yet. Mainly find B cells in the cortex. When mentioning lymph nodes, we mention a third layer Para cortex region also called Thymus dependent zone. Mainly T cells. Medullary region blood flows through but no filtration occurs only lymph filtration. There are macrophages that are lining the lymphatic vessel and they deal with the filtration. Spleen:  White pulp – mixture of T&B cells  Red Pulp – all other cells  Filtration occurs in the sinusoids. And deals with antigens Thymus:  A highly compartmentalized organ  Lobules cordon off one area from another  Has something of a blood brain barrier. Called thymus blood barrier.  Located in the superior mediastinum and extending over the greater vessels of the heart.  Encapsulated organ with two lobes, Wt 40g.  Originates early in the embryo and continues to grow until puberty. After the first few years it does begin to atrophy and becomes infiltrated with adipocytes.  During development of the embryo, T‐cells migrate to the thymus to become immunologically competent.  remove thymus in early development causes irreversible damage to the bodies immune system (impairment of function).  2 major components: o Parenchyma o Stroma  Encapsulated connective tissue and sends septa (trabeculae) into the lobes, subdividing them into incomplete lobules. Made up of collagen and is compartmentalizing the organ. Thymus Cortex:  Dense population of lymphocytes (stains darker) compared to the medulla region of the thymus. Mainly T ‐cells  extensive proliferation and become immunocompetent.  Contains macrophages and epithelial reticular cells (ERC: 3 types in cortex, and 3 types in the medulla).  ERC function include barrier formation (occluding junctions) and some types help “educate” T‐cells. Thymus Cortex ERCs  Type I ERC: o Separates the capsule and septa from the cortex. o Surrounds the vascular elements of the cortex. o Forms the blood ‐ thymus barrier. o Isolates (via occluding junctions) the thymus cortex from the rest of the body. o Polymorphous nuclei and a well defined nucleolus.  Type II ERC: o Located in the mid cortex.

12 Have long wide processes that form de cortex into small T‐cell compartments. Type III ERC: o Deep in the cortex near the medulla – c o Long wide processes similar to type I – Type II and III play a role in the “education” of developing T‐cells. Macrophage produce both. Thymus is very compartmentalized organ. This antigen. T‐cells (competent, but naïve) enter the medull around the body. o

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ther which further subdivides the s.

MHC I and II molecules to g in contact with any foreign o secondary lymphatic organs

Thymus Summary  Types II and III ERCs educate T‐cells by testing their ability to recognize self‐MHC molecules and self‐epitopes.  T‐cells not able to recognize self ‐MHC molecules and self‐epitopes are destroyed.  Highly, highly compartmentalized Innate Immunity:  Secondary system of host defense  Always present  Immediate defense  Responses are generic  Short lived immunity Types of Cells Involved  Mast Cells – recognize a pathogen and release histamines – involved with vasodilation. o release bioactive chemicals  Neutrophils (PMNs) – 1st on the scene o signals other cells, eats & digests pathogens  Macrophages – second on the scene o stimulates other immune cells & eats & digests pathogens & cellular debris. o It takes the microbe and presents itself on its surface o And start the adaptive response  via the Compliment System  Fibroblasts come in laying down collagen and starts the repair process and create granulation tissue to provide food and O2

Pathogen Associated Molecular Patterns: Pattern Recognition Receptors – Found on WBC.

13 PAMPs Include:  LPS  Flagellin  Lipoteichoic acids  Peptidoglycan  ds/ss vRNA; Bact DNA  Repeating structural units

Inflammation:  Defined as the reaction of vascularized tissue to local injury.  Two major subtypes and Repair: o Acute inflam – involves changes that occur within minutes of injury and persist for several hours or days. o Chronic inflam – is more variable than acute and includes several forms of tissue reactions over a long period of time. Injury stim due to persistence or repetitious (TB)  elicits an immune response. o Repair – damage tissue is repaired by regeneration or by replacement of the damage parenchyma & stroma by fibrous tissue (e.g. scar) Acute Inflammation:  Involves changes that occur within minutes of injury and persist for several hours or days.  A self‐limiting process, whose goal is for the total or partial elimination of the injury with the restoration and/or replacement of the damaged tissue within days of the injury.  The vascular response to injury is a reactionary process that sets up the “delivery system” of inflammation  In order for an infection to occur a pathogen must bind to a cell

Repair and Healing:  One of the primary functions of inflammation process is to heal wounded tissue.  Healing may occur as a result of resolution or repair.  Resolution involves the return of injured tissue to normal structure and function. Occurs when the injury was not extensive and the parenchyma are capable of regenerating. The alternative is fibrous repair Fibrous Repair: Sequence of Events  Cut in skin, bleeding, formation of clot (fibrin-fibronectin gel or matrix).  Acute inflammation develops: o Rapid accumulation of Neutrophil followed by macrophages. o Macrophages responsible for wound debridement –removal of any RBCs, fibrin and cellular debris making room for capillary buds and fibroblast. o Capillary budding from endothelial cells from pre-existing capil project out and form capillary loops, eventually forming arterioles and venules. o Fibroblast enter and remodel the fibrin-fibronectin matrix into scar tissue. o new arterioles and venules, replacement of skin if needed.  Granulation – process by which the initial blood clot was converted into fibrous connective tissue o Clot was replaced by granulation tissue –characterized by the proliferation of new small blood vessels and fibroblasts. o Derived from its pink, soft granular appearance on the surface of wounds. Adaptive Immunity:  Tertiary source of host defense  Called into action – cell mediated and humoral immunity  Takes time to mount defense  Responses are antigen specific  Remembers specific pathogens Antigens & Antibodies

14  Antigen: o foreign body; epitope – region that reacts with an antibody, TCR, SIGs  Antibodies o immunoglobulin (Ig)  mark antigens for elimination  TCR – T‐cell receptor; SIG – surface immunoglobins or membrane ‐bound antibodies. Types of Immunoglobulins:  IgM - stops infection by toxins & viruses  IgG - protects newborns  IgA - defense of mucosal surfaces  IgE - allergy  IgD - triggers B lymphocytes Immunological Specificity & Memory:  recognition of specific invader MHC (HLA) Types of Cells Involved:  Macrophages o engulfs foreign bodies  Helper T o boost immune response  Cytotoxic o eliminates infected or tumor cells  B...