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Inflammation and Repair

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Notes

Show Notes

Slide 1 :

INFLAMMATION & REPAIR Keith J. Kaplan, MD Mayo Clinic

Slide 2 :

Chapters 3 and 4 Will not cover Cell Cycle & Proliferative Potential (Chapter 4) Covered in Neoplasia Lecture (Chapter 8) You need to know first 8 Chapters of Robbins

Slide 3 :

Chapters 2 and 3 You need to know first 9 chapters of Robbins

Slide 4 :

• Egyptian papyrus - 3000 B.C. • Celsus (Roman in 1st century A.D.) Rubor - Tumor - Calor - Dolor redness - swelling - heat - pain • Virchow added functio laesa later History

Slide 5 :

What is inflammation? Inflammation – Protective response intended to eliminate the initial cause of cell injury and the necrotic cells and tissues arising from the injury Inflammation is intimately associated with the repair process which includes parenchymal cell regeneration and scarring

Slide 6 :

Acute - minutes to days Characterized by fluid and protein PMN’s Exudate SG > 1.020 Chronic - weeks to years Lymphocytes and macrophages ACUTE Inf - PMN’s (Polymorphonuclear Cells) CHRONIC Inf - Mononuclear Cells Inflammation EXUDATE

Slide 7 :

Acute inflammation “The immediate and early response to an injurious agent” Chronic inflammation “Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously“

Slide 8 :

Exudate • ? vascular permeability • high protein & cell debris • SG > 1.020 Transudate • normal vascular permeability • hydrostatic pres. ? plasma ultrafiltrate • low protein (mostly albumin) • SG < 1.012 Edema • exudate or transudate ; interstitium or cavity

Slide 9 :

Acute inflammation major components Transient vasoconstriction Vasodilatation Endothelial permeability Extravasation of PMNs

Slide 10 :

Five classic local signs of acute inflammation Heat Redness Swelling Pain Loss of function Calor – vasodilatation Rubor – vasodilatation Tumor – vascular permeability Dolor – mediator release/PMNs Functio laesa – loss of function

Slide 11 :

Vascular changes you need to know this Transient vasoconstriction Vasodilation Exudation of protein rich fluid Blood stasis Margination Emigration/Transmigration

Slide 12 :

Vascular changes Protein exits vessels : ? intravascular osmotic pressure ? intravascular hydrostatic pressure Endothelial gaps at intercellular junctions: * immediate transient response * histamine, bradykinin, leukotrienes, substance P

Slide 13 :

Fig 3-2

Slide 14 :

Vascular permeability Vasodilation – increased blood flow Increased intravascular hydrostatic pressure Transudate - ultrafiltrate blood plasma (contains little protein) Again, this is very transient and just gets the process started. Think acute inflammation, think EXUDATE Exudate - (protein-rich with PMNs) Exudate is the characteristic fluid of acute inflammation Intravascular osmotic pressure decreases Osmotic pressure of interstitial fluid increases Outflow of water and ions - edema

Slide 15 :

Fig 3-3

Slide 16 :

How do endothelial cellsbecome permeable? Endothelial cell contraction Junctional retraction Direct endothelial injury (immediate sustained response) Leukocyte-dependent endothelial injury Increased transcytosis of fluid

Slide 17 :

Direct endothelial injury (immediate sustained response) Endothelial cell necrosis and detachment Result of severe injury or burn Occurs immediately and lasts until vessel repaired

Slide 18 :

Occurs at sites of leukocyte accumulation Due to leukocyte activation which releases proteolytic enzymes and toxic oxygen Leukocyte-dependent endothelial injury

Slide 19 :

Leukocyte Cellular Events Margination and Rolling Adhesion and Transmigration Migration into interstitial tissue

Slide 20 :

SLOWING CONCENTRATION Margination Rolling Adhesion Transmigration

Slide 21 :

Fig 3-6

Slide 22 :

Selectins CAMS Integrins Mucin-like glycoproteins (Sialyl-Lewis X PSL-1 & ESL-1) Weak and transient binding Results in rolling Integrins upregulated and activated for increased affinity to CAMS Results in firm adhesion

Slide 23 :

Margination Normal flow - RBCs and WBCs flow in the center of the vessel A cell poor plasma is flowing adjacent to endothelium As blood flow slows, WBCs collect along the endothelium ? Margination

Slide 24 :

Endothelial Activation The underlying stimulus causes release of mediators which activate the endothelium causing selectins and other mediators to be moved quickly to the surface

Slide 25 :

Selectins Selectins bind selected sugars Selected + Lectins (sugars) = Selectins Some selectins are present on endothelial cells (E-Selectin) Some selectins are present on leukocytes (L-Selectin) Some selectins are present on platelets (P-Selectin) Weak & transient binding Results in rolling

Slide 26 :

Fig 3-9

Slide 27 :

Rolling Selectins transiently bind to receptors PMNs bounce or roll along ? Rolling

Slide 28 :

Slide 29 :

Adhesion Mediated by integrins ICAM-1 and VCAM-1

Slide 30 :

Slide 31 :

Transmigration Mediated/assisted by PECAM-1 & ICAM-1 (Integrins) Diapedesis (cells crawling) Primary in venules Collagenases degrade BM ? Permeability

Slide 32 :

Slide 33 :

Chemotaxis Movement toward the site of injury along a chemical gradient Chemotactic factors include Complement components (20 serum proteins) Arachadonic acid (AA) metabolites Soluble bacterial products Chemokines, cytokines

Slide 34 :

Phagocytosis & Degranulation Phagocytosis (engulf and destroy) Degranulation and the oxidative burst destroy the engulfed particle Recognition & attachment Opsonins coat target and bind to leukocytes Engulfment Killing/degradation O2 dep: Reactive O2 species in lysosomes & EC O2 indep: Bactericidal permeability agents, lysozyme, MBP, lactoferrin

Slide 35 :

Leukocyte-induced tissue injury Lysosomal enzymes are released into the extracellular space during phagocytosis causing cell injury and matrix degradation Activated leukocytes release reactive oxygen species and products of arachidonic acid metabolism which can injure tissue and endothelial cells These events underlie many human diseases (e.g. Rheumatoid arthritis)

Slide 36 :

Table 3-3

Slide 37 :

Leukocyte adhesion deficiency 1 (LAD-1) Recurrent bacterial infections Inflammatory lesions lack neutrophil infiltrate High numbers of neutrophils in the circulation Neutrophils from patients can roll but do not stick ? chain of CD11/CD18 integrin Transfuse patients with normal neutrophils and they can emigrate

Slide 38 :

Mechanism of leukocyte adhesion deficiency 1 (LAD -1) Absence of integrins on neutrophils Mutation in n-terminal region of the integrin ? chain inhibits proper integrin assembly Normal function is restored following transfection of patient cells with cDNA for ? chain

Slide 39 :

Chediak-Higashi Syndrome This syndrome has been on every board test since Noah Defect in chemotaxis and lysosomal degranulation into phagosomes

Slide 40 :

Slide 41 :

Chronic Granulomatous Disease Defect in NADPH oxidase system Marked decrease in ability to kill microorganisms

Slide 42 :

Slide 43 :

Chemical mediators of inflammation Plasma-derived Circulating precursors Have to be activated Cell-derived Sequestered intracellular Synthesized de novo Most mediators bind to receptors on cell surface but some have direct enzymatic or toxic activity Mediators are tightly regulated

Slide 44 :

Fig. 3-14

Slide 45 :

Slide 46 :

Plasma Mediator Systems - Interaction 1. Kinin 2. Clotting 3. Complement 4. Fibrinolytic

Slide 47 :

C5 C5a Plasminogen ? Plasmin C3 C3a Fibrin ? FSPs Prothrombin ? Thrombin Fibrinogen XII Kinin Complement Clotting Fibrinolytic Fibrinopeptides Prekallikrein XIIa Kallikrein High Mol. Wt. Kininogen Bradykinin Plasma Mediator Systems - Interaction

Slide 48 :

Fig. 3-17

Slide 49 :

Kinin cascade Leads to formation of bradykinin Bradykinin causes Increased vascular permeability Arteriolar dilatation Smooth muscle contraction Bradykinin is short lived (kininases) Vascular actions similar to histamine

Slide 50 :

Complement system Role in immunity (C5-9 complex) Membrane Attack Complex (MAC C5-9) Punches a hole in the membrane

Slide 51 :

Complement system Role in inflammation (c3a and c5a) Vascular effects Increase vascular permeability and vasodilation Similar to histamine Activates lipoxygenase pathway of arachidonic acid metabolism (c5a)

Slide 52 :

Complement system Leukocyte activation, adhesion and chemotaxis (c5a) Phagocytosis c3b acts as opsonin and promotes phagocytosis by cells bearing receptors for c3b

Slide 53 :

Inflammatory Mediators from Complement Anaphylatoxins: C3a, C5a, & C4a trigger mast cells to release histamine and cause vasodilatation C5a also activates the lipoxygenase system in PMNs and monocytes ? release of inflammatory mediators Leukocyte activation, adhesion, & chemotaxis: C5a activates leukocytes, promotes leukocyte binding to endothelium via integrins and is chemotactic for PMNs, monos, eos, & basos

Slide 54 :

Inflammatory Mediators from Complement Phagocytosis: C3b and C3bi are opsonins Control: Convertases are destabilized by "decay accelerating factor" (DAF) Inability to express DAF causes paroxysmal nocturnal hemoglobinuria C1 inhibitor (C1INH) deficiency causes hereditary angioneurotic edema

Slide 55 :

Fig 3-16

Slide 56 :

Vasoactive amines Histamine Found in mast cells, basophils and platelets Released in response to stimuli Promotes arteriolar dilation and venular endothelial contraction results in widening of interendothelial cell junctions with increased vascular permeability Serotonin Vasoactive effects similar to histamine Found in platelets Released when platelets aggregate

Slide 57 :

Bradykinin: Potent biomolecule 1. Vasodilatation 2. Increased vascular permeability 3. Contraction of smooth muscle 4. Pain on injection 5. Short life, kininase degrades Factor XII activated by: 1. Plasmin 2. Kallikrein 3. Collagen & basement membrane 4. Activated platelets 5. Co-factor = HMWK Vascular Permeability: - Bradykinin - Fibrionopeptides - Fibrin Split Prod. - Factor Xa - Leukotrienes

Slide 58 :

Arachidonic Acid (AA) Where is it located? AA is a component of cell membrane phospholipids The breakdown of AA into its metabolites produces a variety of biologic effects

Slide 59 :

Arachidonic acid metabolites Metabolites of AA - short-range hormones AA metabolites act locally at site of generation Rapidly decay or are destroyed

Slide 60 :

Arachidonic Acid AA is released from the cell membrane by phospholipases which have themselves been activated by various stimuli and/or inflammatory mediators AA metabolism occurs via two major pathways named for the enzymes that initiate the reactions; lipoxygenase and cyclooxygenase

Slide 61 :

AA metabolites (eicosanoids) Cyclooxygenases synthesize Prostaglandins Thromboxanes Lipoxygenases synthesize Leukotrienes Lipoxins

Slide 62 :

Fig 3-17

Slide 63 :

PGG2 ? PGH2 PGI2 Prostacyclin TXA2 Thromboxane PGD2 ; PGE2 PGF2 Vasodilatation Inhibits Platelet Aggregation Vasoconstriction Promotes Platelet Aggregation Vasodilatation Edema PGI2 TXA2

Slide 64 :

Arachidonic Acid Pathways you need to know this Lipoxygenase 5-HETE Chemotaxis 5-HPETE Leukotriene generation Leukotrienes Vasoconstriciton Bronchospasm Increased vascular permeability Cyclooxygenase Prostaglandins Vasodilatation Increased vascular permeability Prostacyclin Vasodilatation Inhibits platlelet aggregation Thromboxane A2 Vasoconstriction Promotes platlelet aggregation

Slide 65 :

Arachidonic Acid Pathways you need to know this Lipoxygenase 5-HETE, 5-HPETE, Leukotrienes Spasm (Vaso, Broncho) Cyclooxygenase Prostaglandins - EDEMA Prostacyclin vs TXA2 Vasodilatation vs. Vasoconstriction Platelet aggregationInhibits vs. promotes

Slide 66 :

Arachidonic Acid Metabolites Participate in every aspect of acute inflammation Effective Anti-inflammatory agents act on AA pathways Aspirin and Non-Steroidal Anti-inflammatory Drugs (NSAID’s) - Cyclooxygenase path Steroids act, in part, by inhibiting Phospholipase A2

Slide 67 :

Platelet-Activating Factor (PAF) Another phospholipid-derived mediator released by phospholipases Induces aggregation of platelets Causes vasoconstriction and bronchoconstriction 100 to 1,000 times more potent than histamine in inducing vasodilation and vascular permeability Enhances leukocyte adhesion, chemotaxis, degranulation and the oxidative burst It does everything!

Slide 68 :

Slide 69 :

Cytokines Polypeptides that are secreted by cells Act to regulate cell behaviors Autocrine, paracrine or endocrine effects These “biological response modifiers” are being actively investigated for therapeutic use in controlling the inflammatory response.

Slide 70 :

1. Macrophages make IL-1 & TNF-? 2. T-cells make TNF-? (lymphotoxin) 3. Can be autocrine, paracrine, endocrine 4. IL-1, TNF, IL-6 ? acute phase responses, fever, (appetite, slow wave sleep, ? circ. pmn,? ACTH, ? corticosteroids) TNF notable for role in septic shock and maintenance of body mass (cachexia in cancer from ? ? TNF-? ) Lymphocyte function

Slide 71 :

Fig 3-21

Slide 72 :

Selected Inflammatory Cells & Their Chemokines Table 3-5

Slide 73 :

Nitric Oxide NO is a soluble free radical gas Made by nitric oxide synthetase (NOS) in endothelium (eNOS), macrophages (iNOS), and specific neurons in the brain (nNOS) Broad range of functions and effects that are short range Vasodilatation by relaxing smooth muscle. ? platelet aggregation Inhibits mast cells Regulates leukocyte recruitment

Slide 74 :

Outcomes of Acute Inflammation Resolution Fibrosis Abscess formation Progression to chronic inflammation

Slide 75 :

Chronic inflammation Difficult to define Inflammation of prolonged duration in which active inflammation, tissue injury and the healing proceed simultaneously Occurs in: Persistent infections - AFB, fungi, Treponemes Low toxicity Delayed hypersensitivity Granulomatous inflammation Prolonged exposure potentially toxic agents Silica Toxic plasma lipids ? atherosclerosis Autoimmunity - RA, lupus

Slide 76 :

Chronic inflammation is characterized by: Infiltration with mononuclear cells (macrophages, lymphocytes & plasma cells) Tissue destruction Repair involving angiogenesis and fibrosis Macrophage is the prima donna of chronic inflammation

Slide 77 :

Key macrophage events 1. Recruitment from circulation 2. Local Proliferation 3. Immobilization 4. Differentiation (microglia, kupffer, alveolar macrophage, osteoclasts). Macrophage prominent role due the large repertoire of products it can produce when activated Tox. O2 Proteases Collagenases Chemotx factors Coag factors AA metabolites NO PDGF FGF TGF-?

Slide 78 :

Note that the activated macrophage releases products that are similar to those released by PMNs Fig 3-28

Slide 79 :

Antigen Presentation to T cells Lymphocyte Activated Lymphocyte Macrophage Activated macrophage IFN-? IL-1 TNF-? Other inflammatory mediators Fig 3-30

Slide 80 :

Granulomatous Inflammation Aggregations of activated, modified (epitheliod) appearance Granuloma – focal collection of granulomatous inflammation Bacteria Tuberculosis Leprosy Parasites Schistosomiasis Fungi Histoplasmosis Blastomycosis Metal/Dust Berylliosis Silicosis Foreign body Splinter Suture Graft material Sarcoidosis

Slide 81 :

Granuloma

Slide 82 :

Slide 83 :

Repair Regeneration of injured tissue by parenchymal cells of the same type Replacement by connective tissue Starts as early as 24 hours Granulation tissue at 3 - 5 days Four Components: Angiogenesis Migration and proliferation of fibroblasts Deposition of extracellular matrix (ECM) Remodeling (Maturation & organization of fibrous tissue)

Slide 84 :

Proliferative Potential Labile cells - continuously dividing Epidermis, mucosal epithelium, GI tract epithelium etc Stable cells - low level of replication Hepatocytes, renal tubular epithelium, pancreatic acini Permanent cells - never divide Nerve cells, cardiac myocytes, skeletal muscle

Slide 85 :

Components of the processof fibrosis Angiogenesis - New vessels budding from old Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM Scar remodeling, tightly regulated by proteases and protease inhibitors

Slide 86 :

Tissue Remodeling Balance of deposition vs. degradation Zn-dependent matrix metalloproteinases Interstitial collagenases ? type I, II, III collagen Gelatinase ? type IV collagen & fibronectin Stromelysins ? variety of ECM Membrane-bound matrix metalloproteinases (MBMM) Tissue inhibitors of metalloproteinase (TIMP)

Slide 87 :

Fig 4-16Scar remodeling is regulated by metalloproteinases and their inhibitors Tissue inhibitors of metalloproteinase

Slide 88 :

Wound healing Complex but orderly phenomenon number of processes Induction of acute inflammatory response by an initial injury Regeneration of parenchymal cells Migration and proliferation of both parenchymal and connective tissue cells Synthesis of ECM proteins Remodeling of connective tissue and parenchymal components to restore tissue function Remodeling of connective tissue to achieve wound strength

Slide 89 :

Healing by first intention (primary union) Clean, uninfected, surgical incision with sutures: Blood clot forms < 24 hours – PMNs appear 24-48 hrs cut edges of epidermis thicken from basal cell hyperplasia, and epithelium migrates for union 4. By day 3 – PMN’s replaced by macrophages. Granulation tissue invades & collagen at margins.

Slide 90 :

Healing by first intention (primary union) Incision filled with granulation tissue. Maximal neovascularization & collagen bridges gap. Epidermis covers & is mature. 6. One week – After suture removal wound strength only 10% (compared with unwounded skin) 7. Second week – Continued collagen deposition and fibroblast proliferation. PMNs gone. 8. First month – Scar with cellular connective tissue and no inflammatory cells. Regressed vascular channels. 9. Third month – 70-80% of maximum strength.

Slide 91 :

Fig 4-17 Healing by first intention

Slide 92 :

Healing by second intention (seperated) Large tissue defect to fill common denominator Differs from primary union in several ways: More fibrin, more debris ? more intense inflammation More granulation tissue is formed Wound contraction aided by myofibroblasts

Slide 93 :

Fig 4-17Healing by second intention:Larger injury, abscess, infarction.Process is similar butresults in much larger scar and then primary union

Slide 94 :

Slide 95 :

Factors that influence healing Nutrition - vitamin C Metabolic status – diabetes hinders Circulatory status Hormones – steroids/glucocorticoids inhibit Infection Mechanical stress Foreign bodies Size, locations and type of the wound Whether a wound heals by primary or secondary union is determined by the nature of the wound, rather than by the healing process itself

Slide 96 :

Slide 97 :

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