Lecture 2 Outline: Inflammation

Question 1

Theories of Cellular Aging

Answer 1

• wear and tear: may account for decline in function of cells that cannot regenerate (heart and brain); genetically predetermined process
• free radicals cause DNA damage: most popular and widely tested, based on presence of free radicals causing DNA damage
• telomere aging clock: telomere=protective structure at end of c’some get truncated during cell division; protects the genes on the c’some from being truncated instead and over time they become shorter
• telomerase replenishes the caps and elongates c’somes
• cells eventually enter into senescence (cellular aging) state, this shortening process is associated with aging, cancer, and a higher risk of death

Question 2

Mechanisms of Cell Injury

Answer 2

• deficit injury
• infections injury
• immune reactions
• genetic factors
• physical injury
• toxic injury

Question 3

Deficit Injury

Answer 3

• lack of vital component
• ex: ischemia: blood flow below minimum necessary to maintain homeostasis, usually result of arterial obstruction by a thrombus (clot attached to origin site); this leads to hypoxia or anoxia–>reduction in ATP synthesis–>intracellular accumulation of ions and fluid–>swelling; all this results in inadequate transport of oxygen in the body
• nutritional factors: imbalances in essential nutrients may lead to cell injury or cell death; i.e. deficiency in essential amino acids, protein malnutrition, iron deficiency, vitamin C deficiency, deficit of water, constant temp, or waste disposal

Question 4

Infectious Injury

Answer 4

• invasion by pathologic factors
• bacteria: invade tissues and release exotoxins and endotoxins; cause cell lysis and degradation of ECM
• viruses: usually RNA viruses which disrupt integrity of nucleus and PM resulting in influx of ions and cell swelling–>cell death; often integrate themselves into cellular genome-encodes production of foreign proteins on cell surface recognized as foreign by T-cells and then cell is destroyed
• fungi and parasites

Question 5

Immune Reactions

Answer 5

• activation of component to fight pathology which may harm the cell in the process-hypersensitivity reaction
• antibody attachment
• complement activation
• activation of inflammatory cells

Question 6

Genetic Factors

Answer 6

• cellularly encoded mutations or malformations
• alterations in structure or number of c’somes that induce multiple abnormalities (ex: down syndrome)
• single mutations of genes that cause changes in the amount or functions of proteins (ex: sickle cell anemia)
• multiple gene mutations that interact with environmental factors to cause multifactorial disorders (ex: diabetes type 2)

Question 7

Physical Injury

Answer 7

• external factors cause bodily change
• thermal: temperature, radiation, electrical
• mechanical: trauma, surgery, physical stress theroy

Question 8

Toxic Injury

Answer 8

• either internal or external factors cause poisoning effects
• endogenous factors: metabolic errors, gross malformations, hypersensitivity reactions
• exogenous factors: injury to cells directly-heavy metals that disrupt membrane proteins; lead, carbon monoxide, alcohol; injury to cells after metabolic transformation into toxic agent (acetaminophen)

Question 9

Atrophy

Answer 9

• cell degradation
• reversible reduction in cell and organ size
• results from disease, insufficient blood flow, denervation, etc

Question 10

Hypertrophy

Answer 10

• increase in cell and organ size due to increased workload

- pure examples are heart and striated muscles

Question 11

Hyperplasia

Answer 11

• cell proliferation

- ex: endometrial thickening or callous formation

Question 12

Metaplasia

Answer 12

• change in morphology and function

- ex: smokers pseudostratified columnar epithelium into stratified squamous epithelum

Question 13

Dysplasia

Answer 13

• increase in cell numbers with altered cell morphology
• combo of metaplasia and hyperplasia
• can be reversible or preneoplastic
• ex: cancer

Question 14

Overview of Inflammation

Answer 14

• coordinated rxn of body tissues to cell injury and cell death that involves vascular, humoral, neurologic, and cellular responses: intended to eliminate initial cause of cellular response, inflammatory phase begins once the blood clot forms, it is the second line of defense
• starts with vasodilation and increased capillary permeability–>movement of various cells–>brings different agents to blood stream that have different responses
• function: inactivate injurious agent, break down and remove dead cells, initiate healing of tissue

Question 15

Acute Inflammation

Answer 15

-early reaction of local issues and their BVs to injury: typically occurs before adaptive immunity becomes established, goal is to remove injurious agent and limit extent of injury

Question 16

5 Cardinal Signs

Answer 16

• rubor: redness (caused by arteriolar vasodilation and chemical mediators)
• calor: increased temperature (caused by arteriolar vasodilation and chemical mediators)
• tumor: swelling caused by exudation and leukocyte infiltration and due to increased capillary permeability and escape of plasma proteins
• dolor: pain-increased irritation of nerve endings by physical or chemical factors…may cause reflex guarding
• loss of function

Question 17

Endothelial Cells

Answer 17

• single cell thick epithelial lining of BVs
• produce antiplatelet and antithrombotic agents and vasodilators and vasoconstrictors
• helps with cell adhesion
• helps in repair process through production of growth factors

Question 18

Platelets

Answer 18

• thrombocytes..cell fragments circulating in blood

- release potent inflammatory mediators (increases vascular permeability

Question 19

Neutrophils and Monocytes/Macrophages

Answer 19

• phagocytic leukocytes: evident within hours
• neutrophils are the first type of leukocyte to appear
• have surface receptor involved in activation
• neutrophils: primary phagocyte generates hydrogen peroxide and nitric oxide to destroy debris

Question 20

Monocytes and Macrophages

Answer 20

• monocytes become macrophages when the move from the blood into the tissues
• monocytes are largest of circulating leukocytes
• monocytes released from bone marrow are macrophages
• both produce potent vasoactive mediators (PGs, leukotrienes, PAF, etc)
• engulf larger and greater quantities of foreign material than neutrophils
• aid in signaling process of immunity, help resolve inflammation, and help initiate healing

Question 21

Eosinophils

Answer 21

• produce lipid mediators and cytokines that induce inflammation…associated with immediate hypersensitivity reactions and allergic disorders (true for eosinophils, basophils, and mast cells)
• increased during allergic reactions and parasitic infections

Question 22

Basophils

Answer 22

• bind IgE which triggers release of histamine

- limited to bloodstream

Question 23

Mast Cells

Answer 23

• do not develop until they leave the circulation and lodge into tissue sites
• activation results in release of preformed contents of their granules (histamine, interleukin, cytokines, etc)
• involved in IgE-triggered reactions with helminth infections

Question 24

Vascular Alterations in Acute Inflammatory Phase

Answer 24

• vasoconstriction (briefly)
• rapid vasodilation–>increased capillary blood flow
• increase in vascular permeability–>increased loss of exudate occurs from blood into injured tissue area (where protein goes, fluid follows)–>loss of proteins decreases capillary osmotic pressure and increases interstitial osmotic pressure
• increase in cap pressure–>outflow of fluid
• blood flow stagnates outside BVs and you get a clot (platelet aggregation)
• increased permeability (vascular leakage) results from endothelial gaps due to chemical mediators

Question 25

Swelling

Answer 25

• arterial end: capillary hydrostatic pressure>colloid osmotic pressure, fluid leaves capillary
• venous blood: capillary hydrostatic pressure

Question 26

Cellular Alterations in Acute Inflammation Phase

Answer 26

• delivery of leukocytes (mainly neutrophils) to site of injury results in following
• margination, rolling, adhesion
• transmigration (diapedesis)
• chemotaxis
• activation and phagocytosis

Question 27

Margination, Rolling, and Adhesion

Answer 27

• slow blood flow causes leukocytes to accumulate (margination) and adhere to endothelial cells of BV wall
• leukocytes slow migration with rolling movement and finally adhere tightly along endothelial wall
• adhesion glycoproteins on both leukocytes and endothelial cells cause them to stick together

Question 28

Transmigration

Answer 28

-leukocytes transmigrate through vessel wall and migrate into tissue spaces

Question 29

Chemotaxis

Answer 29

• process of directed cell migration

- once they exit the capillary, they are directed by a gradient of chemoattractants

Question 30

Activation and Phagocytosis

Answer 30

• monocytes, neutrophils, and tissue macrophages activated to engulf and degrade bacteria and cellular debris
• recognition and binding of particles by specific receptors on surface of phagocytic cells
• coating of antigen with antibody or complement is called opsonization (makes more susceptible to phagocytosis)
• endocytosis: surround and enclose particle in phagosome, which then destorys microbe

Question 31

Histamine

Answer 31

• preformed in mast cell and basophil granules: important in early inflammatory response and in immediate IgE mediated hypersensitivity reactions
• causes endothelial contraction (forming gaps) thus increasing permeability and increasing blood fluid loss into interstitial spaces
• short lived (15-30 minutes
• causes vasodilation of arterioles (increased permeability in small venules)
• highest concentration in connective tissues near BVs
• causes bronchoconstriction in lungs–>hard to breathe

Question 32

Plasma vs. Cell Derived Mediators

Answer 32

• plasma derived all come from liver

- cell derived come from cells

Question 33

Arachidonic Acid (aa) Derivatives

Answer 33

-splitting of as from membrane phospholipids via phospholipase which results in two pathways: cyclooxygenase and lipoxygenase

Question 34

Cyclooxygenase: COX 1 and COX 2

Answer 34

• produce prostaglandins (PG): induce inflammation, fever, PGD2, PGE2, PGF2, variety of actions on vascular tone and permeability and can cause pain
• produce prostacyclin: PGI2; found predominantly in endothelial cells, potent inhibitor of platelet aggregation and vasodilator
• produce thromboxane: TXA2; found in platelets and other cells and is potent platelet aggregator and vasoconstrictor
• drugs like corticosteroids, NSAIDS and aspirin have anti-inflammatory properties because they inhibit the COX pathway of aa (so you don’t get the pain, decreased inflammation; also stops platelets from coagulating which increases blood flow)

Question 35

Lipoxygenase: Leukotrienes

Answer 35

• B4 is potent chemotactic agent
• C4, D4, E4 are potent vasoconstrictors; act as potent mediators of increased vascular permeability on venules only: “slow reacting substance of anaphylaxis” SRS-A cause slow and sustained constriction of bronchioles
• effects similar to histamine: up to 1000x more potent as histamine in producing increased vascular permeability
• migration of leukocytes to areas of inflammation

Question 36

Platelet Aggregating Factor

Answer 36

• produced by a variety of cells
• induces platelet aggregation
• activates neutrophils and is potent eosinophil chemoattractant
• causes bronchoconstriction
• increases leukocyte adhesion to endothelium

Question 37

Plasma Proteins

Answer 37

• 3 interrelated systems important in inflammatory responses are found within plasma
• complement system
• kinin system
• clotting system

Question 38

Complement System

Answer 38

• through series of enzymatic rxns plasma proteins fragments are formed, get potent inflammatory mediators
• functions in innate and adaptive immunity
• acts as defense mech against microbial agents
• chemical activation by microorganisms or antigen-antibody complexes leads to products that: (4 events)
• vasodilates capillaries: C3a and C5a-cause histamine release from mast cells (degranulation)…referred to as anaphylatoxins
• act as chemotactic agent for phagocytes
• coat (opsonization) surfaces of microbes to make more susceptible to phagocytosis
• form MAC (membrane attack complex)…lysis of target organisms
• C3 and C5 are most important inflammatory mediators

Question 39

Kinin System

Answer 39

• triggered by contact activation of Hageman factor–>bradykinin–>pain and vasodilation
• generates vasoactive peptides from plasma proteins called kinogens by action of specific proteases called kallikreins
• release of vasoactive bradykinin which: increases vascular permeability, contracts smooth muscle, produces pain, stimulates release of histamine (mast cells), activate aa cascade

Question 40

Clotting System

Answer 40

• plasma proteins come in contact with foreign materials, generate Hageman Factor (clotting factor XII produced in liver)–>prothrombin–>thrombin–>fibrinogen–>fibrin which forms a clot
• localizing effect: 1. fibrin meshwork stops blood but contains exudate, microorganisms and other foreign materials (containing phagocytes) 2. prevents spread of infection
• conversion of fibrinogen to fibrin: by action of thrombin, fibrin binds to protease-activated receptor, endothelial cells and smooth muscle cells

Question 41

Cytokines

Answer 41

• proteins produced primarily by macrophages and lymphocytes
• two major cytokines from activated macrophages that mediate inflammation: interleukin-1 and tumor necrosis factor
• local actions: stimulates leukocyte adhesion to endothelium, activates fibroblasts, chondrocytes, osteoclasts, stimulates inflammatory mediators
• systemic actions: induces fever, increases metabolism, causes hypotension

Question 42

Chemokines

Answer 42

• chemotactic cytokines
• act as chemoattractants
• high concentration at sites of injury and infection
• two types: inflammatory (recruit leukocytes during an inflammatory response-only present during inflammatory response) and homing: constitutively (always) expressed

Question 43

Nitric Oxide

Answer 43

• produced by variety of cells
• many roles in inflammation
• reduces platelet aggregation and adhesion
• vasodilator
• regulates leukocyte recruitment
• blocking of NO increases leukocyte adhesion (delivery of NO decreases number of leukocytes)
• reduces cellular phase of inflammation
• impaired production by endothelial cells may lead to inflammatory changes that occur with atherosclerosis
• mediator against infection

Question 44

Oxygen-Derived Free Radicals

Answer 44

• may be released extracellularly from leukocytes during phagocytic process
• the superoxide radical (H2O2) and hydroxyl radical (OH-) can combine with NO to form other intermediates and increase inflammatory process

Question 45

Phagocytosis

Answer 45

• opsonization of foreign particles with proteins
• binding of proteins with leukocytes
• invagination of leukocyte d/t calcium influx and subsequent changes of cytoskeletal proteins
• complete encapsulation called phagosome
• digestion of phagosome or death of both cells (pus or purulence)

Question 46

Chronic Inflammation

Answer 46

• develops if underlying cause is not addressed or if repeated episodes of acute inflammation occur in same tissue
• hallmarks are: 1. nonspecific chronic inflammation-accumulation of specific leukocytes instead of neutrophils at injury site (lead to proliferation of fibroblasts with subsequent scar tissue
• 2. granulomatous inflammation: distinct form of chronic inflammation; granuloma-lesion with macrophages surrounded by lymphocytes, dense connective tissue membrane usually encapsulates the lesion
• can contribute to healing but usually not the full return of function d/t loss of parenchymal cells and then scar formation

Question 47

Tissue Repair: Tissue Regeneration

Answer 47

• organs and tissues are composed of 2 types of structures: parenchymal (cells that are not specialized)-functioning cells of an organ or body part or stromal-supporting connective tissues
• body cells divide into 3 types: labile-divide continuously throughout life (epithelial cells), stable-normally stop dividing when growth ceases, divide with appropriate stimulus (hepatocytes, smooth muscle tissue, vascular endothelial cells, and kidney cells), and permanent-cannot divide, replaced with scar tissue

Question 48

Fibrous Tissue Repair

Answer 48

• occurs by replacement with connective tissue: generation of granulation tissue and formation of scar tissue
• granulation tissue: involves growth of newly form capillaries, fibrogenesis, and involution (decrease in size) to formation of scar tissue
• ECM components: fibronectin, hyaluronic acid, proteoglycans, and collagen
• fibronectin and hyaluronic acid first to be deposited in healing wound
• proteoglycans appear later to help stabilize and aid in hydration of tissue
• collagen synthesis contributes to subsequent formation of scar tissue

Question 49

Scar Formation

Answer 49

• process occurs in 2 phase: 1. emigration and proliferation of fibroblasts into injury site and 2. deposition of ECM by these cells
• with healing number of fibroblasts and new BVs decrease with increased synthesis and deposition of collagen
• ultimately granulation tissue scaffolding evolves into a scar: composed of inactive fibroblasts, dense collagen fibers, fragments of elastic tissue, and other ECM components

Question 50

Wound Healing: Primary and Secondary Intention

Answer 50

• primary: sutured surgical incision, no tissue loss

- secondary: greater tissue loss, can’t approximate, larger amounts of scar tissue, slower healing

Question 51

Phases of Wound Healing: Inflammatory Phase

Answer 51

• vascular and cellular phases
• after 24 hours macrophages enter: phagocytosis and release of growth factors to stimulate epithelial growth
• with large defect in deeper tissue, neutrophils and macrophages are needed to facilitate wound closure: a wound may heal in absence of neutrophils, but cannot heal in absence of macrophages

Question 52

Phases of Wound Healing: Proliferative Phase

Answer 52

• begins within 2-3 days of injury and may last as long as 3 weeks
• building new tissue: fibroblast
• as early as 24-48 hours after injury: fibroblasts and vascular endothelial cells form granulation tissue, fragile tissue that bleeds easily
• epithelialization: migration, proliferation, differentiation of epithelial cells at wound edges to form new surface layer; epithelial cell migration requires moist surface and is impeded by dry, necrotic wound surface; collagen synthesis reaches a peak within 5-7 days and may continue for weeks

Question 53

Phases of Wound Healing: Remodeling Phase

Answer 53

• begins ~3 weeks after injury: can continue for 6 months or longer
• architecture of scar reorients to increase tensile strength: most wounds do not regain full tensile strength after healing (~70-80% after 3 months)
• contraction of scar tissue over joints tends to limit movement and cause deformities: stretched scar tissue fails to return to original length d/t loss of elasticity
• keloid: abnormality in healing…tumor like mass caused by excess production of scar tissue, overabundant deposition of Type III collagen

Question 54

Factors that Affect Wound Healing

Answer 54

• malnutrition
• blood flow and oxygen delivery
• impaired inflammatory and immune response
• infection, wound separation, and foreign bodies
• bite wounds
• drug interactions