Lecture 2 Outline: Inflammation Flashcards
1
Q
Theories of Cellular Aging
A
- 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
2
Q
Mechanisms of Cell Injury
A
- deficit injury
- infections injury
- immune reactions
- genetic factors
- physical injury
- toxic injury
3
Q
Deficit Injury
A
- 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
4
Q
Infectious Injury
A
- 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
5
Q
Immune Reactions
A
- activation of component to fight pathology which may harm the cell in the process-hypersensitivity reaction
- antibody attachment
- complement activation
- activation of inflammatory cells
6
Q
Genetic Factors
A
- 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)
7
Q
Physical Injury
A
- external factors cause bodily change
- thermal: temperature, radiation, electrical
- mechanical: trauma, surgery, physical stress theroy
8
Q
Toxic Injury
A
- 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)
9
Q
Atrophy
A
- cell degradation
- reversible reduction in cell and organ size
- results from disease, insufficient blood flow, denervation, etc
10
Q
Hypertrophy
A
- increase in cell and organ size due to increased workload
- pure examples are heart and striated muscles
11
Q
Hyperplasia
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- cell proliferation
- ex: endometrial thickening or callous formation
12
Q
Metaplasia
A
- change in morphology and function
- ex: smokers pseudostratified columnar epithelium into stratified squamous epithelum
13
Q
Dysplasia
A
- increase in cell numbers with altered cell morphology
- combo of metaplasia and hyperplasia
- can be reversible or preneoplastic
- ex: cancer
14
Q
Overview of Inflammation
A
- 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
15
Q
Acute Inflammation
A
-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
16
Q
5 Cardinal Signs
A
- 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
17
Q
Endothelial Cells
A
- 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
18
Q
Platelets
A
- thrombocytes..cell fragments circulating in blood
- release potent inflammatory mediators (increases vascular permeability
19
Q
Neutrophils and Monocytes/Macrophages
A
- 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
20
Q
Monocytes and Macrophages
A
- 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
21
Q
Eosinophils
A
- 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
22
Q
Basophils
A
- bind IgE which triggers release of histamine
- limited to bloodstream
23
Q
Mast Cells
A
- 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
24
Q
Vascular Alterations in Acute Inflammatory Phase
A
- 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
25
Q
Swelling
A
- arterial end: capillary hydrostatic pressure>colloid osmotic pressure, fluid leaves capillary
- venous blood: capillary hydrostatic pressure
26
Q
Cellular Alterations in Acute Inflammation Phase
A
- delivery of leukocytes (mainly neutrophils) to site of injury results in following
- margination, rolling, adhesion
- transmigration (diapedesis)
- chemotaxis
- activation and phagocytosis
27
Q
Margination, Rolling, and Adhesion
A
- 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
28
Q
Transmigration
A
-leukocytes transmigrate through vessel wall and migrate into tissue spaces
29
Q
Chemotaxis
A
- process of directed cell migration
- once they exit the capillary, they are directed by a gradient of chemoattractants
30
Q
Activation and Phagocytosis
A
- 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
31
Q
Histamine
A
- 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
32
Q
Plasma vs. Cell Derived Mediators
A
- plasma derived all come from liver
- cell derived come from cells
33
Q
Arachidonic Acid (aa) Derivatives
A
-splitting of as from membrane phospholipids via phospholipase which results in two pathways: cyclooxygenase and lipoxygenase
34
Q
Cyclooxygenase: COX 1 and COX 2
A
- 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)
35
Q
Lipoxygenase: Leukotrienes
A
- 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
36
Q
Platelet Aggregating Factor
A
- produced by a variety of cells
- induces platelet aggregation
- activates neutrophils and is potent eosinophil chemoattractant
- causes bronchoconstriction
- increases leukocyte adhesion to endothelium
37
Q
Plasma Proteins
A
- 3 interrelated systems important in inflammatory responses are found within plasma
- complement system
- kinin system
- clotting system
38
Q
Complement System
A
- 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
39
Q
Kinin System
A
- 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
40
Q
Clotting System
A
- 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
41
Q
Cytokines
A
- 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
42
Q
Chemokines
A
- 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
43
Q
Nitric Oxide
A
- 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
44
Q
Oxygen-Derived Free Radicals
A
- 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
45
Q
Phagocytosis
A
- 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)
46
Q
Chronic Inflammation
A
- 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
- 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
47
Q
Tissue Repair: Tissue Regeneration
A
- 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
48
Q
Fibrous Tissue Repair
A
- 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
49
Q
Scar Formation
A
- 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
50
Q
Wound Healing: Primary and Secondary Intention
A
- primary: sutured surgical incision, no tissue loss
- secondary: greater tissue loss, can’t approximate, larger amounts of scar tissue, slower healing
51
Q
Phases of Wound Healing: Inflammatory Phase
A
- 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
52
Q
Phases of Wound Healing: Proliferative Phase
A
- 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
53
Q
Phases of Wound Healing: Remodeling Phase
A
- 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
54
Q
Factors that Affect Wound Healing
A
- malnutrition
- blood flow and oxygen delivery
- impaired inflammatory and immune response
- infection, wound separation, and foreign bodies
- bite wounds
- drug interactions
