Inflammation Handout PDF

Inflammation  Learning Objectives Describe the general features and mechanisms of inflammation Describe the role of the principal mediators in inflammation Describe in detail vascular and cellular events associated with inflammation Distinguish between acute and chronic infla...

Inflammation  Learning Objectives Describe the general features and mechanisms of inflammation Describe the role of the principal mediators in inflammation Describe in detail vascular and cellular events associated with inflammation Distinguish between acute and chronic inflammation  “inflammatio” (latin) action of… …setting ablaze, kindling, setting on fire Light a fire Hallmarks of acute inflammation Described by Aulus Cornelius Celsus >2,000 years ago ©Trinidad Montero-Melendez  Inflammation: Friend or Foe? Inflammation = protective response to eliminate cause of injury and necrotic cells or tissues resulting from the original insult Inflammation destroys, neutralizes harmful agents and initiates healing Infection is not synonymous with inflammation Inflammatory reaction and subsequent repair can cause considerable harm Components of the inflammatory reaction capable of also injuring healthy tissue  Chemical agent Pathogenic Physical agent Tissue microorganism Injury Synthesis & Release of Mediators of Inflammation Capillary ↑ ↑ Capillary Attraction of Systemic dilation permeability leukocytes response Increased Extravasation Migration to Fever, blood flow of fluid site of injury Leukocytosis Redness, Heat, Swelling, Edema, Pain, Loss of Function Major Players in Inflammation Chemical Mediators of Inflammation May be produced locally by cells at the site of Inflammation… …or may be circulating in plasma as inactive precursors that are activated at site of inflammation Most mediators induce effect by binding to specific receptors on target cells (except ROS and some proteases) Mediators are prime targets for anti- inflammatory drugs Mediator Source Principal Action Histamine Mast cells, basophiles Vasodilation, increased vascular permeability, endothelial activation Serotonin Platelets Vasodilation, increased vascular permeability https://courses.lumenlearning.com/microbiology/chapter/inflammation-and-fever/ Histamine stored as preformed molecules in mast cells. Serotonin in platelets. Both vasoactive amines among the first mediators to be released in acute inflammatory reactions Mediator Source Principal Action Prostaglandins Mast cells, Vasodilation, pain, fever leukocytes Leukotrienes Mast cells, Increased vascular permeability, chemotaxis, leukocytes leukocyte adhesion / activation Arachidonic acid derivatives Steroidal anti-inflammatory NSAIDs drugs (cortisol) (aspirin, indomethacin)  Mediator Source Principal Action Platelet- Leukocytes, Vasodilation, increased vascular permeability, activating endothelial leukocyte adhesion, chemotaxis, degranulation, factor (PAF) cells oxidative burst Membrane phospholipid derivative (like prostaglandins and leukotrienes) Characterized by very broad spectrum of inflammatory effects Up to 1000x more potent than histamine in inducing vasodilation and increasing vascular permeability May also cause vasoconstriction and bronchoconstriction Mediator Source Principal Action Reactive Oxygen Leukocytes Killing of microbes Species (ROS) (neutrophils, Macrophages) Microbes, immune complexes, cytokines activate leukocytes to produce and release ROS ROS within lysosomes destroy phagocytosed microbes Low ROS increase cytokine (later) production and release thereby amplifying inflammatory response Low ROS increase adhesion molecule (later) expression High ROS causes tissue injury Mediator Source Principal Action Nitric oxide Endothelium Vascular smooth muscle relaxation, macrophages killing of microbes Smooth muscle relaxation & vasodilation Reduced leukocyte adhesion Reduced platelet adhesion / aggregation Killing microbes Mediator Source Principal Action Cytokines Macrophages, lymphocytes, Local endothelial activation (adhesion endothelial cells, mast cells molecules), chemotaxis, leukocyte activation, systemic effects Cytokines = Polypeptides or small proteins secreted by cells for interaction and communication between cells (signaling proteins) “Cytokine” = General name “Lymphokines” = Cytokines made by lymphocytes “Monokines” = Cytokines made by monocytes “Chemokines” = Cytokines with chemotactic activities “Interleukin” = Cytokine made by one leukocyte acting on other leukocytes “Interferons” = Cytokines released in response to presence of pathogens “Tumor Necrosis Factors” = Cytokines involved in systemic inflammation  Cytokines Autocrine, paracrine and endocrine signaling Cell communicates with itself Cell talks to a neighbor Cell sends message via blood circulation to a distant cell nl.dreamstime.com Cytokine Network  Produced after inflammatory stimuli Continuously produced  The Inflammosome (discovered 2002) The inflammasome is a cytosolic multiprotein complex responsible for the activation of inflammatory responses. The inflammasome promotes the maturation and secretion of pro-inflammatory cytokines (IL 1 and IL 18). Toxins Active ILs Activate inflammosome Pro-ILs Inflammosome  Antigen processing cells T-Helper cells Regulatory T cells Pro-inflammatory Anti-inflammatory cytokines cytokines Additional… …about cytokines Different cells can secrete the same cytokine A single cytokine can act on different cells (pleiotropy) Same functions can be stimulated by different cytokines (redundancy) One cytokine can stimulate target cells to make additional cytokines (cascade) Plasma Protein-derived Mediators of Inflammation Mediator Source Principal Action Complement Plasma (liver) Increase vascular permeability, vasodilation, proteins opsonization, leukocyte activation, degranulation of mast cells (histamine release) Kinins Plasma (liver) Increase vascular permeability, vasodilation, pain Proteases Plasma (liver) Endothelial activation, leukocyte recruitment Circulating proteins of three Interrelated systems are involved in the inflammatory response 1) Complement system 2) Kinin cascade 3) Coagulation system Figure enlarged next slide  Hageman Factor in contact with basement membrane (ECM), collagen, activated platelets Clotting cascade Kinin cascade ↑Vascular permeability Pain Complement cascade C3a, C5a: ↑Vascular Permeability, Leukocyte Recruitment & activation  Acute inflammation = Rapid response to injury designed to deliver leukocytes & plasma proteins to site of injury Mediators of inflammation activate the two major components of inflammation: Vascular reaction Cellular response Vasodilation: Increased vessel Emigration of leukocytes caliber & increased blood flow (neutrophils) from Increased vascular permeability: circulation and Structural changes permitting fluid & accumulation at plasma proteins to leave circulation the site of injury “3rd component”: Leukocyte activation at site of injury Normal capillary bed Inflamed capillary bed  Increased Vascular Permeability (DETAILS) Non-inflammatory conditions During inflammation, an exudate is formed because vascular permeability increases as result of increased interendothelial gaps  “Exudate” = Protein-rich fluid which leaks from blood vessel into (interstitial matrix) due to increased vascular permeability Edema: Excess of watery Fluid collecting in the cavities or tissues of the body Protein (albumin!) leakage from blood vessel Increase of osmotic pressure in interstitium More fluid “sucked out” out of blood vessel “Stasis” = Increase of blood viscosity  Major mechanism for increased vascular permeability: Endothelial cell contraction produces intercellular gaps Immediate transient response Occurs rapidly after binding of mediators to receptors Mediators: Histamine, bradykinin, leukotrienes Short-lived (15-30 minutes) Slower, prolonged retraction of endothelial cells Results from changes in cytoskeleton Induced by cytokines: TNF, IL-1 Takes 4-6 hours to develop, lasts for > 24 hours  Margination Free-flowing leukocytes exit the central blood stream and interact with endothelial cells by close mechanical contact. 3 factors accelerate contact between leukocytes and endothelial cells 1) Laminar flow:As blood flows from capillaries to post-capillary venues, circulating cells swept by laminar flow against the vessel wall Laminar Flow: Liquid flow is smooth, occurs in parallel layers. Flow is greatest at the center and diminishes towards the periphery: Bullet shaped https://astarmathsandphysics.com/a-level-physics-notes/fluid-dynamics/2752-laminar-andulence.html velocity profile 2) Relative speed: The smaller RBC move faster then larger white cells. As a result, leukocytes are pushed out of the fast flowing axial center column 3) Stasis: Slows down movement of all cells Cellular events: Leukocyte recruitment and activation (DETAILS) Integrin activation & Adhesion Rolling Diapedesis Chemotaxis  Endothelial and Leukocyte Adhesion Molecules Integrins: Transmembrane glycoproteins expressed on leukocytes Interact with ligands expressed on endothelial cells Selectins: Receptors expressed on leukocytes and endothelium Contain extracellular domain that bind sugars Integrins www.selexys.com/about.asp Potential drugs: Antibodies against Selectins. Reduce inflammatory response Selectins  Summary Leukocyte Recruitment to sites of inflammation (from Robbins Basic Pathology, 8th ed., page37) Leukocytes are recruited from blood into the extracellular tissue, where infectious pathogens or damaged tissues may be located. They migrate to site of infection and are activated to perform their function Recruitment is multi-step process consisting of loose attachment to and rolling on endothelium, firm attachment to endothelium and migration through inter-endothelial space Various cytokines promote expression of selectins and integrin ligands on endothelium (TNF, IL-1), increase avidity of integrins for their ligands (chemokines), and promote directional migration of leukocytes (also chemokines), many chemokines produced by tissue macrophages Leukocytes at site of “damage” become activated Phagocytosis of particles Production of “killer substances”: Lysosomal enzymes, reactive O and N species Production of mediators to further amplify inflammatory response Phagocytosis of microbes by activated leukocytes  Leucocyte-induced tissue injury Leukocytes not selective ROS, RNS and enzymes not confined to leukocytes Pathology of inflammatory response >> Pathology of invader Inflammatory response in autoimmune diseases Inflammatory response against “harmless” allergens Clinical examples of leukocyte-induced injury: Inflammatory disorders Acute respiratory distress syndrome Acute transplant rejection Asthma Acute Glomerulonephritis Septic shock Vasculitis Arthritis Asthma Chronic Atherosclerosis Chronic transplant rejection Pulmonary fibrosis  Chronic Inflammation Short term, days Vascular changes Acute inflammation Edema Neutrophiles (the “chief” phagocytic leukocytes) Weeks, months, years Tissue destruction Chronic inflammation Repair involves angiogenesis and fibrosis Macrophages  Role of macrophages in chronic inflammation “Recruited” from circulating monocytes Activated by non- immunologic stimuli......and/or by immune system Products of activated macrophage cause tissue injury...... and fibrosis Acute & Chronic Inflammation: SUMMARY Fibrosis  Fibrosis “Fibrosis” = Development of fibrous connective tissue (largely collagen) as a reparative response to injury or damage. “Fibrosis” = Connective tissue deposition that occurs as part of normal healing or to the excess tissue deposition that occurs as a pathological process. “Fibrosis” = Excessive scarring, which exceeds the normal wound healing response to injury in many tissues From: Ralf Weiskirchen et al. “Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications” Molecular Aspects of Medicine, 30 June 2018  Systemic effects of inflammation Acute Phase Response “Somnolence” = “Sleepiness" State of strong desire for sleep “Anorexia” = Eating disorder, excessive weight loss “DIC”: Disseminated intravascular coagulation, blood clots form throughout the body, blocking small blood vessels  Acute Phase Proteins (APPs) Large group (ca.30) of biochemically and functionally unrelated proteins Plasma concentrations increase or decrease in response to tissue injury, acute infections, burns, or chronic inflammation. Opsonization (Marking of pathogens for phagocytosis) Complement activation Support of coagulation …and many other cytokines  C-reactive protein (CRP) Protein pentamer, whose blood levels rise in response to inflammation Secreted by liver in response to IL6 secretion by macrophages and T cells Binds to lysophosphatidylcholine on dying cells and bacteria to activate complement system via C1q REPAIR  Learning Objectives Describe the underlying features of wound healing and tissue repair  Tissue Repair Example: Liver lobule Complete replacement of damaged components: REGENERATION or RESOLUTION Non-damaged matrix (Basement Membrane) If complete restitution not possible: HEALING with SCAR FORMATION  Tissue repair depends on: 1. Cell proliferation (Proliferative capacity of cells and tissues) 2. Extracellular growth factors 3. Extracellular matrix (ECM) 1. Cell proliferation - Proliferative capacity of tissues a) Continuously dividing tissues (“labile tissues”) Cells continuously lost and replaced Hematopoietic cells in bone marrow Epithelia in GI tract b) Stable Tissues Cells are quiescent (G0), minimal replicative activity Capable of proliferation in response to injury Liver, pancreas c) Permanent tissues Cells terminally differentiated, nonproliferatic Neurons and cardiac muscle cells 2. Extracellular Growth Factors The most representative functions of the main growth factors http://www.sawc.net/article/clinical-utility-growth-factors-and-platelet-rich-plasma-tissue-regeneration-review-18318  Three patterns of extracellular growth factor signaling Autocrine Signaling Paracrine Signaling Endocrine Signaling General MOA of Extracellular Growth Factors 3. Extracellular Matrix & Tissue Repair ECM = dynamic, constantly remodeling macromolecular complex, synthesized locally, assembles into a network that surrounds cells. ECM = significant proportion of any tissue Sequesters water Mechanical stability of soft tissue ECM Substrate for cell adhesion Scaffolding for tissue renewal Reservoir for growth factors ECM regulates the proliferation, movement and differentiation of the cells living within it. Synthesis and degradation of ECM accompanies wound healing.  Two basic forms of ECM Basement Membrane Interstitial Matrix Highly organized matrix around endothelial cells Between cells in connective tissue Plate-like “chicken wire mesh” 3-dimensional amorphous gel  Cutaneous Wound Healing (Example for Tissue Repair) Depending on degree of damage of ECM: “Healing by First Intention” “Healing by Second Intention” Uninfected surgical incision Larger wound Extensive cell and tissue loss More intense inflammatory reaction Death of only few epithelial and connective tissue cells Abundant development of Granulation tissue (see next slide) Epithelial regeneration Wound contraction and accumulation predominates over fibrosis of ECM and scar formation Granulation tissue Perfused fibrous connective tissue that replaces fibrin clot Grows from base of wound Composed mainly of inflammatory cells and fibroblasts Active angiogenesis: New blood vessels Initial restructuring of tissue = temporary barrier against hostile environment www.scienceboard.net