Pathogen 3.1 Cells and Inflammation (Student) PDF

Objectives 1. Analyze the essential components of a typical cell and their functions. 2. Analyze how the functions of cells are coordinated and integrated. 3. Interpret the roles of growth factors on cellular activity. 4. Inventory the characteristics of stem cells and their roles in re...

Objectives 1. Analyze the essential components of a typical cell and their functions. 2. Analyze how the functions of cells are coordinated and integrated. 3. Interpret the roles of growth factors on cellular activity. 4. Inventory the characteristics of stem cells and their roles in regenerative medicine. 5. Illustrate reversible and irreversible cell injury, including cytoplasmic and nuclear changes. 6. Analyze the most important causes of cell injury. 7. Contrast four types of cell adaptations. 8. Distinguish between metaplasia and dysplasia. 9. Discuss cellular aging. 10. Compare two forms of cell death: necrosis and apoptosis. Objectives 11. Compare various forms of necrosis and give appropriate examples of each. 12. Analyze the cellular and events of inflammation. 13. Distinguish between the different the vascular changes in acute inflammation. 14. Debate the following terms pertaining to leukocytes involved in an inflammatory response: margination, diapedesis, emigration, exudation, chemotaxis, phagocytosis, and microbicidal substances. 15. Analyze the function of proteins of the complement system, cytokines, and the clotting system in inflammation. 16. Compare and Contrast possible outcomes of acute and chronic inflammation. 17. Demonstrate a granuloma and analyze how it is formed. 18. Analyze the following pathologic terms: serous inflammation, fibrinous inflammation, purulent inflammation, abscess, ulcer, wound, scar, and keloid. 19. Debate the typical local and systemic symptoms of inflammation. 20. Analyze the pathogenesis of fever. The cell as a Unit of Health and Disease (IO:1, 2) Essential Components of Animal Cell Nucleus – DNA storage, transcription and synthesis, mRNA processing Ribosomes – translation Mitochondria – energy production; apoptosis * Oxidative phosphorylation Cytochrome C ER – rough and smooth Rough folds and processes proteins Smooth produces lipids Golgi – modifies proteins for transportation Lysosomes – digestive enzymes for macromolecules Protein, polysaccharides, lipids, nucleic acids Proteosomes – also degrade proteins Peroxisomes – oxidative enzymes for long chain fatty acid metabolism Cytoskeleton – cell shape, polarity (orientation), organization and movement of organelles, cell motility Plasma membrane – regulated movement of solutes, cell-to-cell interaction Lysosomes / Proteasomes Contain 40 different hydrolases – tear stuff apart! Formed in 3 ways Through pinocytosis or receptor mediated endocytosis Phagocytosis – microorganisms are engulfed to form phagosome Autophagy – large proteins and organelles are surrounded by ER membrane and “fed” to the lysosome Proteasomes Denatured or misfolded proteins are tagged with “ubiquitin” then disassembled here  Plasma Membrane Permeable: Very small particles, non-polar particles Water, O2, CO2, ethanol, steroids, vit D Impermeable: Polar particles, large particles Proteins, glucose, ions Ways to get through Passive transport Channels (fast), carriers (slow) Receptor mediated Active Pumps ATPase Endocytosis Caveolae mediated - “little cave” Receptor mediated – clathrin; LDL and transferrin Phagocytosis Endosome → +/- lysosome formation ER / Golgi Synthesis of transmembrane proteins and lipids Rough ER Chaperone molecules ensure protein is properly folded Excess accumulation of misfolded proteins → unfolded protein response → apoptosis Smooth ER Synthesize steroids (gonads and adrenals) Catabolize lipid-soluble molecules (liver) Store calcium (muscle “sarcoplasmic reticulum”) Golgi apparatus Packaging to organelles or plasma membrane N-linked oligosaccharide added to proteins in ER are modified Mitochondria Oxidative phosphorylation Cell death / apoptosis Mitochondria Oxidative phosphorylation Cell death / apoptosis Receptors Extracellular and intracellular receptors Thing that “lands” on a receptor is a ligand This can either initiate a second messenger system to start intracellular functions Or it can interact directly with DNA and affect transcription A few receptor Types Kinase activity Kinase is a molecule that phosphorylates other moiety to initiate cellular activity Receptor tyrosine kinases (RTKs) Insulin, epidermal growth factor G-protein coupled receptors Ligand binds and associates with intracellular guanosine triphosphate binding protein, effects cAMP down stream Steroids Enter the cell and cause receptor to change confirmation, enter nucleus, and initiate transcription factors Transcription Factors DNA-binding domains permit specific binding to short DNA sequences Sometimes transcription factors bind in the promotor region Sometimes they bind to long-range regulatory elements called “enhancers” which – though far away – “loop back” to interact with the genes they regulate “Elements” are pieces of DNA Growth Factors (IO:3) Promote entry of cells into the cell cycle Promote replication Enhance biosynthesis of cellular components Nucleic acids, proteins, lipids, carbohydrates Done to provide the machinery necessary to create daughter cells Prevent apoptosis Growth Factors Stem Cells (IO:4) Totipotent stem cells Give rise to all types of differentiated tissues Adult stem cells Only have capacity to replace damaged cells of the same type Regenerative medicine Use stem cells to heal patients Difficulty lies in implanting cells in patients that remain located at site of damage Cell Injury Causes of Cell Injury (IO:6) Hypoxia/Ischemia Cell function disrupted → damage cell Infection TB/fungus, bacteria, everything else → damage cell Inflammatory response and leukocytes → damage cell Autoimmune disease Your own body → damage cell Toxins Toxins → damage cell More on this later Misc. Immunologic reaction, physical agents, genetic abnormality, nutritional imbalance, aging Toxic Cell Injury Toxins Direct-acting: combine with critical molecular component or cellular organelle, disrupting its function i.e. mercury Latent toxins: these are converted from benign to reactive metabolites which act on target cells Reactive Oxygen Species (ROS): free radicals that are highly reactive and react with cellular components, destroying them Reversible Cell Injury (IO:5) “Still time to fix it” Intracellular swelling Mitochondria and ER Plasma membrane blebbing Clumping of chromatin in nucleus Myelin figures – actually phospholipids that are bits of damaged plasma membrane Cell injury: When Badness Happens Cell injury: When Badness Happens Irreversible Signs (IO:5) Inability to restore mitochondrial function Loss of structure and function of plasma membrane Loss of DNA and chromatin structural integrity Cell injury: When Badness Happens Apoptosis vs. Necrosis Overview (IO: 10) Apoptosis Controlled or programmed cell death Embriogenesis irreversible injury that is recognized in time to control cell demise Features of controlled cell death Organized disassembly Membrane bound → no inflammation One cell or a small group Apoptosis vs. Necrosis Overview (IO: 10) Necrosis Unprogrammed, violent death Swelling → eventual lysis of the cell → inflammation Usually wide-spread – many cells or entire organ Adapting to Cellular Injury IO: 07 Adapting to cellular injury (IO:7) Types of adaptation Hypertrophy Hyperplasia Atrophy Metaplasia Adapting to cellular stress (IO:7) Adaptation in summary: Hypertrophy – increased cell size Hyperplasia – increased cell number Atrophy – decreased cell size Metaplasia – change in adult cell type Hypertrophy (IO:7) Available to all types of cells – in the case of muscle, response to increased demands Can become pathologic, as in the case of heart muscle Hyperplasia (IO:7) Again, increased cell number Can be physiologic, as in 1) the proliferation of glandular epithelium of female breast at puberty and pregnancy and 2) when residual tissue returns after part of an organ is lost Can be pathologic as well, if the growth mechanisms lose their control i.e. cancer Hyperplasia alone is not enough to cause cancer Atrophy (IO:7) Causes include decreased workload, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, aging Metaplasia (IO:7) Change in cell type Smokers' bronchi → Barret’s esophagus → Metaplasia vs. Dysplasia (IO:8) Dysplasia refers to disorderly proliferation of cells Uniformity Polarity/orientation Dysplasia does not indicate cancer, though it is on the pathway to becoming cancerous Necrosis IO:11 Necrosis Type: Coagulative Ischemia/Infarct (Usually occurs in places with stores of glucose) Drop in ATP production Na/K pumps fail Cell swells → pale and firm gross appearance Glycogen supply allows for anerobic metabolism Lactate is produced pH falls Proteins are denatured! Late stage → membrane bound organelles burst Lysosomes spill their contents Lysis of cellular architecture does not occur Cell ruptures Ca enters the cell Macrophages and neutrophils flood in Inflammation ensues Necrosis Type: Liquefactive CNS infarct/ Pyogenic Infxn CNS is highly active tissue and glucose/glycogen poor Thus, no anerobic metabolism pH does not fall ATP pumps still fail and cell swells Organelles rupture Lysosomes spill their contents Enzymes are all active! You get cellular soup! *In pyogenic infection – neutrophils / bacteria emit lytic enzymes On microscopy – soupy vacuoles give “moth eaten” appearance Necrosis Type: Caseous TB (maaaaybe fungus) “Walling off” of infected area by macrophages Called granuloma They attempt to destroy everything inside their perimeter Pink patches surrounded by blue nuclei of macrophages Necrosis type: Fat Necrosis Enzymatic or traumatic Adipose tissue contains triglycerides which are dismantled by pancreatic enzymes Calcium binds Salt + lipids = soap “saponification” White spots are noted on gross evaluation and upon microscopy Necrosis Types: Fibrinoid Hypersensitivity rxn Occurs in blood vessels Sequestered RBC’s surrounded by fibrous material Key signs of Necrosis Increased eosinophilia Nuclear changes Pyknosis: nuclear shrinking and increased basophilia – DNA is dark, shrunken mass Karyorrhexis: nucleus starts to fragment Karyolysis: nucleus breaks apart totally and DNA is broken down by DNase  Fate of cells in coagulative necrosis Cell does not digest itself completely Leukocytes are recruited Cells are digested by their lysosomal enzymes Debris is removed by phagocytosis mediated by infiltrating neutrophils and macrophages Dry gangrene Fate of Liquefactive Necrosis Dead cells are completely digested, leaving creamy yellow liquid eventually to be removed by phagocytes Also the cause of “wet” gangrene Fate of Caseous Necrosis Tissue architecture is obliterated, and cellular outlines cannot be discerned Macrophages and other inflammatory cells predominate Nodular inflammatory lesions persists “Granuloma” Fate of Fat Necrosis Usually, pancreatitis Enzymes released from acinar cells liquify fat cells in the peritoneum Lipases split triglyceride esters that combine with Calcium “saponification” Fate of Fibrinoid Necrosis Immune reactions in which complexes of antigens and antibodies are deposited in vessel walls Bright, pink amorphous appearance Polyarteritis nodosa A word on biomarkers in necrosis Often cellular damage can be located by tests with specificity for the affected organ This occurs after intracellular proteins are released following cell lysis Cardiac muscle: enzyme creatine kinase, contractile protein troponin Hepatic duct epithelium: alkaline phosphatase Hepatocytes: transaminases Apoptosis IO: 10 Apoptosis Controlled dismantling of the cell “Edible” Fragments of apoptotic cells break off – hence the name “apoptosis” which means falling away This is done in a controlled manner, without the intracellular contents spilling out Therefore, there is not much inflammation caused Apoptosis: 2 categories 1. Physiologic apoptosis When cells need to die as a part of normal embryonic development In the immune system, when lymphocytes recognize self-antigens and must be purged 2. Pathologic apoptosis When the cell is damaged severely and irreversibly and must be “taken out” This could be due to severe damage or the emergence of cancer Apoptosis: 2 pathways Intrinsic The cause of most physiologic and pathologic apoptosis, involving the mitochondria in initiating apoptosis sequence The Death Receptor pathway Cells express antigens on their surface that trigger apoptosis Both lead to the initiation of “CASPACES” Proteins Initiator – caspases 8,9 → Effector – caspase 3 → → → Intrinsic pathway Mitochondria contain “cytochrome C” which is contained inside its lipid bilayer If this gets out – CASPACES are initiated → What keeps cytochrome C inside the cell? It’s actually the cell’s default to release it! It depends on a constant signal from outside the cell, saying “don’t self destruct” Bax There is a “door” on mitochondria created by Bax bak homodimer Bak that ushers cytochrome C out of the cell Cytochrome C Unless the cell stops this sequence... Intrinsic pathway So how do we stop it! BCL-2 is a protein that’s created to bind with Bax forming a heterodimer, keeping the “door” from coming together and letting out cytochrome C What keeps the door separated? Growth factors at the surface of the cell – saying “don’t die!” Intrinsic pathway But, when it’s time to... The BAD protein is produced which binds to BCL-2 and allows the Bax bak door to come together and let out cytochrome c → CASPACES 8,9 → 3 →  Intrinsic pathway Got it, what gets this all started? Three key things 1. Planned death as a part of embryonic development 2. Failure to receive external signals from outside the cell that prevent destruction 3. P53 tumor suppressor activity P53 tumor suppressor gene creates P53 protein which can do 3 things 1. Low concentrations of P53 initiate DNA repair mechanisms 2. Medium concentrations of P53 arrest cellular reproduction 3. High concentrations of P53 induces the production of BAD → BCL2 → bax/bak → lets out Cytochrome C → initiates CASPACES 8,9 → 3 → Intrinsic pathway Ok... But what gets P53 started??? Increased concentrations of misfolded proteins in the Endoplasmic reticulum Why would this occur? What is your guess? Intrinsic / Extrinsic Pathway Extrinsic Pathway A cell that has been designated for apoptosis presents an antigen that is recognized by the immune system as marking the cell for self destruction This is called a “death receptor” Two main types addressed in the book: TNF-alpha, and Fas Fas ligand When these receptors are expressed on the surface of the cell, they initiate a sequence of the CASPASE cascade 8,9 → 3 → This is a process that is mostly limited to the death of self-reactive T cells in the thymus Intrinsic / Extrinsic Pathway Review of Apoptosis Intrinsic pathway (Most common) 1. Programed death as a part of embryonic development 2. Loss of growth factors at cell membrane Inhibition of BCL2 through BAD protein pairing→ Bax/Bak dimer → Cyt C → CASPASE 8,9 → CASPASE 3 → 3. Genetic mutation leading to DNA damage or bad protein product A little bit of P53 → DNA repair mechanisms A moderate amount of P53 → DNA repair + arrest cell cycle A lot of P53 → BAD binds to BCL2 → Bax/Bak dimerize → Cyt C leaves mitochondria → CASPASES 8,9 → CASPASE 3 → Extrinsic pathway Self-reactive T cell presents antigen to death receptor (TNF-alpha, Fas Fas) → CASPASE cascade → CASPASE 3 → Pathways leading to cell demise (summary) Causes of Inflammation IO: 12 Causes of inflammation Infections Bacterial, viral, fungal, parasitic Microbial toxins as well Tissue necrosis Foreign bodies Immune reactions - hypersensitivity Causes of inflammation Infections Bacterial, viral, fungal, parasitic Microbial toxins as well Tissue necrosis Foreign bodies Immune reactions - hypersensitivity Two Big Things Happen 1. You get more fluid to the area 2. Your body’s cells “go to war” Two Big Things Happen 1. You get more fluid to the area → vascular changes 2. Your body’s cells “go to war” → cell and protein mediated destruction External Manifestations are as follows: Rubor - redness Calor - heat Tumor - swelling Dolor – painful How does recognition of insult occur? Inflammation: Recognition IO: 12 Recognition Microbes and necrotic cells are recognized by 1. Foreign invaders from outside of the cell → primarily antigen presenting cells 2. Internal stimuli within the cell → signal cellular distress 3. Circulating proteins that indicate that damage has occurred What are the stages of recognition and inflammation? Inflammation: Stages Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Inflammation: Recognition Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Inflammation: Recognition Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Recognition: 1) Foreign Invaders Phagocytes, dendritic cells (both designed to capture foreign invaders) express receptors that detect the presence of infectious foreign invaders When these receptors are activated, they trigger the secretion of specific proteins 1. Cytokines that produce inflammation 2. Anti-viral cytokines (interferons) 3. Cytokines and membrane proteins that activate lymphocytes Recognition: 2) Internal Cellular sensors of Cell Damage Inside the cytosol – there are signals that things have gone awry within the cell Uric acid build up – product of DNA breakdown ATP – in reduced amounts of this signals damaged mitochondria Reduced intracellular K+ indicates loss of ions because of damaged cell membrane DNA – when found in the cytoplasm indicates damaged nucleus These are called “DAMPs” (damage- associated molecular patterns) These activate a multiprotein cytosolic complex called the inflammasome It recruits leukocytes and induces inflammation Recognition: 3) Circulating proteins Compliment system Reacts against microbes and produces mediators of inflammation Lysis of infectious organisms Activation of further inflammatory cells Opsonization of targeted agents Inflammation: Vascular Changes IO:13  Inflammation and Blood Flow Two big steps 1) Increases blood flow (vasodilation) 2) Makes vessels more permeable (permeability) This leads to the escape of fluid proteins and blood cells from the vascular system into the interstitial tissues or body cavities Exudate: has high protein concentration and contains cellular debris Transudate by contrast has low protein content, little cellular material, low specific gravity Result of osmotic pressure or hydrostatic imbalance across vessels with normal permeability Changes in vessels: Vasodilation 1. Vasodilation is induced mostly by histamine released by mast cells– acts on vascular smooth muscle One of the earlies manifestations of acute inflammation Increased flood flow 2. Vasodilation is followed by increased permeability and exudative fluid 3. This leads eventually to exudate build up in the extravascular tissues 4. At this point, blood flow slows... 5. Vessels become engorged with slow moving red cells 6. What we see up on gross inspection is erythema  Changes in vessels: Permeability Inflammatory rxn: physiologic Think of it as “vascular leakage” Release of histamine (bradykinin, leukotrienes) Retraction of endothelial cells → Opening of inter-endothelial spaces Endothelial injury: damage Results from tissue damage like microbe infestation, burns, etc. Leads to cell necrosis and detachment which is sometimes made worse by the attachment of neutrophils Continues until the vessels are thrombosed or repaired  Changes in vessels: Permeability Inflammatory rxn: physiologic Think of it as “vascular leakage” Release of histamine, bradykinin, leukotrienes Retraction of endothelial cells → Opening of inter-endothelial spaces Endothelial injury: damage Results from tissue damage like microbe infestation, burns, etc. Leads to cell necrosis and detachment which is sometimes made worse by the attachment of neutrophils Continues until the vessels are thrombosed or repaired Lymph Involvement Lymphatic vessels become involved, as they are set up to drain away extravascular fluid and its contents Its tissues may become secondarily inflamed – lymphangitis, leading sometimes to inflammation and enlargement of the nodes – lymphadenopathy Inflammation: Stages Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Inflammation: Vascular Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Inflammation: Vascular Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue What does this look like, so far We’ve seen increased blood and fluid to the area → Tumor, rubor, calor We’ve seen increased bradykinin, leukotriene, histamine → dolor Inflammation: Recruitment IO:13 Leukocyte involvement (IO:14) 1) Adhesion and margination Usually, leukocytes are moving to quickly through vessels to attach to the walls and move through them – with reduced blood flow, this is possible In addition, endothelial cells are activated by cytokines that help the leukocytes to adhere to the cell walls Selectins and integrins are molecules that help in this process at the micro level 2) Migration diapedesis Move through the cell wall – transmigration 3) Chemotaxis Chemoattractants actually move the leukocytes to the battle site Bacterial products Cytokines Complement system Lipoxygenase of arachidonic acid – leukotriene Inflammation: Recruitment Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Inflammation: Recruitment Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and complement plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Leukocyte Involvement: Cell Types Leukocytes that are recruited to sites of inflammation perform the key function of eliminating the offending agents. Most important ones are the ones capable of phagocytosis Neutrophils : rapid, transient response Macrophages : slower, but more prolonged response Macrophages also produce substances that aid in tissue repair Responsibility: Ingest or destroy bacteria and other microbes, as well as necrotic tissue and other substances Collateral damage: increased potency of these leukocytes, may induce prolonged inflammation and collateral host tissue damage Macrophages vs. Neutrophils Macrophages last longer and are slower to arrive, eventually support collagen formation, which adds to the changes of chronic inflammation Neutrophils come faster and live longer, do more destruction at the site of acute inflammation – sometimes with negative effect Leukocytes as a whole can do more harm than good in some disease TB, hepatitis, both with prolonged host response does more damage than the microbe How? Granule enzymes and anti-microbial proteins may be released into the extracellular environment. The mechanisms that function to eliminate microbes and dead cells (the physiologic role of inflammation) also are capable of damaging normal tissues (the pathologic consequences of inflammation) Macrophages vs. Neutrophils Neutrophils 6-24 hours Macrophages 24-48 hours Three outcomes of acute inflammation (IO:16) Complete resolution ☺ Healing by connective tissue replacement (scarring or fibrosis) Chronic Inflammation Acute vs Chronic Inflammation (IO:16) Acute Occurs in minutes to hours and lasts from hours to days Marked by exudation of fluid and plasma proteins – causing edema Marked by the emigration of leukocytes, mostly neutrophils (PMNs) and macrophages to a lesser degree Chronic Longer duration Associated with more tissue destruction Presence of macrophages Proliferation of blood vessels Fibrosis Chronic Inflammation (IO:16) Response to prolonged duration (weeks to months) in which inflammation, tissue injury, and attempts at repair coexist in varying combinations Inflammation: Destruction, Termination, Repair IO: 13 Inflammation: Remainder Recognition of threat Response of vascular tissues to insult Recruitment of leukocytes and plasma proteins Destruction of offending substance Termination of sequence Repair of damaged tissue Inflammation: Destruction, Termination, Repair From this point, the body’s inflammatory response will either destroy the source of inflammation, or not If the offending agent is not destroyed, the inflammation may become chronic If it is, then repair mechanisms and tissue healing can take place Inflammation Recap IO: 13  Recap: Overview of Inflammation ▪ = histamine ▪ = complement proteins Quick Recap Inflammation is a beneficial host response to foreign invaders Main parts are vascular reaction and cellular response Steps of inflammation: R’s Recognition, recruitment of leukocytes, removal of the agent, regulation of the response, resolution and repair Causes Infection, tissue necrosis, FB, trauma, immune response (see prior list) Macrophages, and dendritic cells, leukocytes all express receptors that sense the presence of microbes and necrotic cells Circulating proteins recognize microbes in the blood Outcome of acute inflammation is either elimination of offending agent followed by decline of inflammation, or chronic inflammation Mediators of Inflammation IO: 15 Mediators of Inflammation Mediators of inflammation are multifunctional with numerous effects, including: Vasodilation Vasoconstriction Altered vascular permeability Activation of inflammatory cells Chemotaxis Cytotoxicity Degradation of tissue Pain Fever Mediators of Inflammation Two types: cellular and plasma- derived Major cells that release mediators are macrophages, dendritic cells, mast cells Plasma-derived mediators are the compliment proteins Mediators of Inflammation Mediators of inflammation belong to two classes: Cell-derived – produced locally by cells at site of inflammation - may be preformed and stored in granules of platelets and leukocytes, and rapidly secreted upon cellular activation (e.g., histamine) - Synthesized de novo in response to stimulus (e.g., prostaglandins and cytokines) Plasma-derived – circulate in plasma in inactive form and must be transformed by activator (e.g., bradykinin and complement factors) Mediators of Inflammation Mediators: Vasoactive Amines Histamine and serotonin Histamine comes from mast cells Released in response to physical injury, binding of antibodies to mast cells Causes dilation of arterioles and increases permeability of venules Receptors for histamine are H1 receptors which are key for treatment of acute allergic response Serotonin is a vasoactive mediator in platelets and some neuroendocrine cells, in GI tract in particular – importance in inflammation is still vague Mediators: Arachidonic Acid Metabolites Two terms to know: Prostaglandins and leukotrienes Prostaglandins Produced by mast cells, macrophages, endothelial cells Involved in vascular and systemic reactions of inflammation Generated by two different cyclooxygenases called COX-1 and COX-2 Produced in response to inflammation Also contribute to homeostasis in the kidneys – affecting afferent tubule Are protective of the GI tract Of these, COX-2 is involved in inflammatory response but is not in many other tissues normally Leukotrienes Produced in mast cells Involved in vascular and smooth muscle reactions and leukocyte recruitment Key for vasodilation Clinical Correlation The use of prostaglandins has two major side effects: Peptic ulcer Acute and chronic kidney disease Mediators: Cytokines (IO:15) Two in particular are key for systemic response: Tumor necrosis factor and interleukin-I Critical in recruiting leukocytes and promoting adhesion to endothelium 1. Endothelial activation Initiated by increased expression of endothelial adhesion molecules (selectins and integrins) 2. Activation of leukocytes 3. Systemic acute-phase response Fever and SIRS response Mediators: Chemokines (IO:15) cytokines that act as chemo attractants for leukocytes Clinical Correlation Chronic Inflammatory Disease This is suppressed with Agents that block TNF – major cytokine of leukocyte recruitment are successful therapies for this Infliximab (Remicade) Adalimumab (Humira) Etanercept (Enbrel) Mediators: Compliment System (IO:15) Complement System Plasma proteins that work with (complement) the immune system and also participate in the inflammatory response Synthesized in liver; flow freely in the blood Defend the body against infectious microbes Mark microbes for destruction by phagocytes Directly kill microbes by creating membrane-attack complexes (MACs) - Large, cylindrical multiproteins that embed in the invading microbes plasma membrane, creating pores and bursting the microbe Mediators: Others Platelet-activating factor Involved in platelet aggregation + inflammation Kinins Vasoactive peptides: in particular, bradykinin Created by the enzyme kallikrein Increases vascular permeability and causes pain  Mediators: Suppression Lipoxins These suppress inflammation by inhibiting leukocyte recruitment Pharmacologic interventions Cyclooxygenase inhibitors (Cox inhibitors) NSAIDS – COX 2 of particular interest Lipoxygenase Inhibitors Prevent chemotaxis and bronchospasm Corticosteroids Reduce transcription of genes encoding COX-2, phospholipase, proinflammatory cytokines Leukotriene receptor antagonists Prevent actions of leukotrienes – Montelukast Treat asthma and allergy Mediators Recap: For your reference Morphologic Patterns of Acute Inflammation IO:16 Serous Inflammation (IO:18) Exudation of cell poor fluid (“watery”) into spaces: Created by injury to surface epithelium Fluid accumulates in body cavities lined by peritoneum, pleura, or pericardium Blister separated from dermis Fibrinous Inflammation (IO:18) Develops when Vascular leaks are large Local procoagulant stimulus Occurs when there is more severe inflammation Fibrinogen passes through the vessels Deposits of fibrin on pericardium A hallmark of chronic inflammation! Purulent (Suppurative inflammation) (IO:18) Large amounts of purulent exudate (pus) Neutrophils, liquified debris of necrotic cells, edema Bronchopneumonia (a) bacterial abscesses in the lung (b) pus as described above Ulcers Local defect of excavation, of the surface of an organ or tissue that is produced by the sloughing of inflamed necrotic tissue MC in Mouth/GI tract or skin/sub q tissue Chronic Duodenal Ulcer Granulomatous Inflammation (IO:17) Special Case Systemic Inflammation IO: 13, 19, 20 Effects of Inflammation (IO:19) Cardinal signs (local effects) of inflammation Heat (calor), redness (rubor), swelling (tumor), pain (dolor), and loss of function (functio laesa) Systemic Effect (acute phase response) Fever Elevated Temp: 1-4° C above basal (37° C) Pyrogens: prostaglandins produced in the vascular and peri vascular glands of the hypothalamus Exogenous pyrogens: bacterial products stimulate leukocytes to release cytokines (primarily IL-1 and TNF) that increase the enzymes (cyclooxygenase) that convert AA to prostaglandins Acute-phase proteins (synthesized by hepatocytes in the liver secondary to stimulation from cytokines) C-reactive protein increase in inflammation or Fibrinogen: binds to red cells (rouleaux) erythrocyte sedimentation rate Serum Amyloid A Leukocytosis-secondary to rapid release of leukocytes from bone marrow Usually 15,000-20,000 cells/ml, but may far exceed these levels in leukemoid reactions (40,000-100,000 cells/ml). If ↑↑↑, then work up for leukemia indicated Left shift: increase in immature number of neutrophils Other terms: Neutrophilia (bacterial), lymphocytosis (viral), eosinophilia (allergic) Leukopenia-can be caused by certain infections (typhoid fever, some viral infections, rickettsia, and certain protozoa) Effects of Inflammation (IO:19) Other Effects ↓ SWEATING (SECONDARY ↑ HR ↓ BP TO SHUNTING TO DEEP RIGORS VASCULAR BEDS TO PREVENT HEAT LOSS CHILLS ANOREXIA SOMNOLENCE MALAISE Effects of Inflammation (IO:19) Septic Shock Fever Pathogenesis (IO:20) Treatment NSAIDS, turn down prostaglandins Tylenol: UNCLEAR! Tissue Repair IO: 18 Tissue Repair 2 Mechanisms Regeneration or Scar Regeneration vs. Scar Regeneration Regrow the tissue Scar Deposit CT Different tissues consist of continuously dividing Repair occurs by deposition of connective tissue cells (epithelia, hematopoietic tissues), and scar formation if the injured tissue is not The regenerative capacity of a tissue depends on capable of regeneration or if the structural the proliferative potential of its constituent cells. framework is damaged and cannot support regeneration. Cell proliferation is controlled by the cell cycle and is stimulated by growth factors and The main steps in repair by scarring are clot interactions of cells with the extracellular matrix. formation, inflammation, angiogenesis and formation of granulation tissue, migration and Regeneration of the liver is a classic example of proliferation of fibroblasts, collagen synthesis, and repair by regeneration. It is triggered by cytokines connective tissue remodeling. and growth factors produced in response to loss of liver mass and inflammation. In different Macrophages are critical for orchestrating the situations, regeneration may occur by proliferation repair process of surviving hepatocytes or repopulation from progenitor cells. Factors that Inhibit Tissue Repair Tissue repair may be impaired by a variety of factors that reduce the quality or adequacy of the reparative process. Factors that interfere with healing may be extrinsic (e.g., infection) or intrinsic to the injured tissue, and systemic or local: Infection Diabetes Nutritional status Glucocorticoids (steroids) Mechanical factors Poor perfusion Foreign bodies The type and extent of tissue injury Location of the injury and the character of the tissue Cutaneous Wound Healing (IO:18) The main phases of cutaneous wound healing are inflammation, formation of granulation tissue, and ECM remodeling. Cutaneous wounds can heal by primary union (first intention) or secondary union (secondary intention); secondary healing involves more extensive scarring and wound contraction. Wound healing can be altered by many conditions, particularly infection and diabetes; the type, volume, and location of the injury are important factors that influence the healing process. Excessive production of ECM can cause keloids in the skin. Persistent stimulation of collagen synthesis in chronic inflammatory diseases leads to tissue fibrosis, often with extensive loss of the tissue and functional impairment. Cellular Aging IO:9 Cellular Aging Accumulations of errors in DNA ROS (reactive oxygen species), Mutations Decreased cellular replication Cells have a limited capacity for this Intracellular Accumulations Build up of various substances Steatosis- triglycerides Cholesterol Proteins Glycogen Pigments Exogenous: carbon Endogenous: lipofuscin, melanin, hemosiderin Fatty Liver Changes Alcohol abuse, diabetes with obesity, NASH (non-alcoholic steatohepatitis) Atherosclerosis / cholesterol Exogenous carbon Anthracosis Coal miner’s lung Lipofuscin Yellow-brown pigment Fre-radical peroxidation of membrane lipids “Wear and tear pigment” Calcification Aortic valve Thank You! Nussbaum, R. L., McInnes, R. R., Williard, H. F., Thompson, J. S., & Thompson, M. W. (2007). Genetics in medicine. Estados Unidos: Saunders.