Inflammation PDF

Introduction to Inflammatory Cells and Mediators Kimiko Suzue, M.D., Ph.D. [email protected] RWCLC 1.069 Learning Objectives: 1. Discuss steps and cardinal signs of inflammation. 2. Describe the cellular and vascular events of acute inflammatory cells, including the chemical mediat...

Introduction to Inflammatory Cells and Mediators Kimiko Suzue, M.D., Ph.D. [email protected] RWCLC 1.069 Learning Objectives: 1. Discuss steps and cardinal signs of inflammation. 2. Describe the cellular and vascular events of acute inflammatory cells, including the chemical mediators which are involved. 3. Classify types of extracellular fluids associated with injury and describe pathologic conditions in which these can be found. Pathology learning objectives for the week 1. Discuss causes of cell injury 2. Discuss acute and chronic inflammatory cells and mediators (it precedes/correlates with the type of tissue repair which subsequently occurs) 3. Discuss diseases with mutations affecting inflammatory cells/mediators 4. Describe morphologic patterns of acute and chronic inflammation 5. Describe the process of cell and tissue regeneration 6. Discuss the extracellular matrix components involved in regeneration and repair 7. Describe the process of repair by connective tissue deposition Overview of Inflammation • Protective host response involving host cells, blood vessels, proteins • Intended to eliminate initial cause of injury and necrotic cells/tissues • Initiates repair process • Can injure normal tissues What is Inflammation? An integrated and tightly controlled set of events associated with the body’s response to: • Injury (trauma, tissue damage/necrosis) • Infection (bacterial, fungal, viral) • Insult (chemical, radiation, thermal, foreign body, environmental substances) • Itself (autoimmunity to self antigens) Sequence of Events in Inflammatory reaction Reaction to: Injury, Infection, Insult, Itself Recruitment of leukocytes (Acute Inflammation) Removal of inciting agent Regulation of response by mediators Resolution and repair of damaged tissues If injury persists: Chronic inflammation Steps of Inflammatory response 5 R’s • Recognition of injurious agent -Cell receptors (Toll-like receptors, Fc receptors, complement receptors) • Recruitment of leukocytes • Removal of agent • Regulation (control) of response • Resolution (repair) of damaged tissue If injury persists: Chronic inflammation Cardinal Signs of Inflammation External manifestations of vascular change and leukocyte recruitment/activation: • Calor (heat) • Rubor (redness) • Tumor (swelling) • Dolor (pain) • Functio laesa (loss of function) Cardinal Signs of Inflammation • Calor (heat) • Rubor (redness) • Tumor (swelling) • Dolor (pain) Acute vs. Chronic Inflammation Acute Inflammation • Immediate response (minutes to days) • Limited specificity • Neutrophils, macrophages • Fluid and plasma exudation Chronic Inflammation • Delayed response (days to years) • More specificity • Lymphocytes, plasma cells, macrophages • Vascular proliferation and scarring Acute inflammatory response is part of Innate Immunity Components Neutrophils, macrophages, monocytes, dendritic cells, mast cells, natural killer (NK) cells, complement, physical epithelial barriers, secreted enzymes Diversity Limited; molecules encoded by inherited (germline) genes Response to Nonspecific-ie. for molecules shared by pathogens microbes; Occurs rapidly; No memory response Summary Mechanisms are in place even before an infection; enable rapid responses to invading microbes Chronic inflammatory response is part of Adaptive Immunity T lymphocytes, B lymphocytes, Immunoglobulins (Antibodies) Very large; receptor genes formed by somatic recombination of V(D)J gene segments during lymphocyte development Highly specific, refined over time; Develops over longer periods, memory response is faster and more robust Develops as a response to infection and adapts to infection; Recognizes a large number of antigens Robbins Pathology Acute inflammatory response Chronic inflammatory response Mediators of Acute Inflammatory Response • Neutrophils • Endothelial cells • Mast cells • Eosinophils • Platelets • Histamine • Cytokines • Arachidonic acid metabolites • Complement Neutrophils • Mature neutrophils emerge from bone marrow (Can circulate for 6-8 h in blood) • Aka polymorphonuclear cells, PMNs, polys, segs • Central to acute inflammation • Can phagocytose microorganisms and tissue debris • Can produce reactive oxygen species • Multilobed nucleus • Cytoplasm with granules Leukocyte alkaline phosphatase, collagenase, lysozyme, lactoferrin, proteinases, acid phosphatase, myeloperoxidase, -glucuronide Neutrophils • Express selectins and integrins for binding to other cells and to migrate out into interstitium • Express receptors which recognize: - Fc portion of IgG and IgM - C5a, C3b and iC3b (complement) - Arachidonic acid metabolites (LTB4) - Cytokines • Undergo oxidative burst, degranulation and form neutrophil extracellular traps • Neutrophil chemotactic factors: C5a, IL-8, LTB4, kallikrein, platelet-activating factor Oxidative Burst O2 ---------NADPH oxidase-------------- O2  - superoxide O2  - ---------SOD-------------- H2O2 (hydrogen peroxide) H2O2 ---------MPO-------------HOCl  (Hypochlorous radical, bleach) HOCl is a powerful antimicrobial agent Neutrophil extracellular traps Platelets Platelets • Formed from megakaryocytes in bone marrow • Bits of cytoplasm (no nucleus) • Contain inflammatory mediators as dense granules and alpha granules • Promote clot formation Which of the following do you see? • Neutrophils • Endothelial cells • Mast cells • Eosinophils • Platelets Eosinophils • Defend against parasitic infections; produces major basic protein (MBP) a helminthotoxin • Associated with allergic reactions; produces histamine • Acute and chronic inflammatory reactions; some eosinophils are normally present in peripheral tissues (mucosal lining of respiratory, gastrointestinal and genitourinary tracts) • Cytoplasmic granules with lysosomal enzymes, cytokines and major basic protein (toxic to parasites) Mast Cells/Basophils Courtesy of Hsieh Chi-Feng Mast Cells • Normally not found in circulation but are found in tissues adjacent to vessels and widely distributed throughout connective tissue (ie. lung, GI mucosal surfaces, skin) • Recognize microbial products (innate immunity)and also has receptors for IgE antibody • Contains preformed histamine granules (arteriolar vasodilation and increased vascular permeability of postcapillary venules) • Activated by: • Trauma • Cross-linking of cell-surface IgE receptors • C3a and C5a complement proteins Mast Cells • Immediate response: Release of preformed histamine granules (Soon after its release, can be inactivated by histaminase) • Delayed response (second phase of mast cell acute inflammatory response): Synthesis and secretion of lipid mediators (arachidonic acid metabolites: prostaglandins and leukotrienes) and cytokines Basophils have many structural and functional similarities to mast cells. But not usually in tissues and are <1% of circulating white blood cells Abbas, Lichtman, Pillai Endothelial cells Endothelial cells • Monolayer of cells lining blood vessels • Regulates vascular contraction and relaxation • Regulates platelet aggregation (Nonactivated platelets do not bind to normal endothelium) • Can express upregulated levels of adhesion molecules (ICAM and VCAM) which can anchor activated neutrophils Endothelial cells Arachidonic acid Released from phospholipid cell membrane by phospholipases AA metabolites called eicosanoids (derived from 20-carbon fatty acids) 2 main pathways: - Cyclooxygenase produces prostaglandins - 5-Lipoxygenase produces leukotrienes Cyclooxygenase pathway WIDE PGI2, PGD2, PGE2: Vasodilation and increased vascular permeability PGE2: FEVER Mediates pain TXA2: Vasoconstriction, platelet aggregation 5-Lipoxygenase LTB4: Neutrophil chemotaxis and activation LTC4, LTD4, LTE4: Smooth muscle contraction (increases bronchial tonebronchospasm, increases vascular permeability) LXA4, LXB4: Inhibition of neutrophil recruitment Complement made in iver, circulate in blood • Serum proteins which “complement”/help host defense and inflammation • Complement proteins C1 to C9 circulate as inactive precursors • Critical step: formation of C3 convertase which cleaves and activates C3 • C3 cleavage occurs in 3 pathways 1-Alternative pathway 2-Classical pathway 3-Lectin pathway Complement GM makes classic cars • Classical pathway: C1 complement component binds IgG or IgM bound to antigen • Alternative pathway: Microbial cell wall components (i.e. endotoxin) directly activates complement • Lectin pathway: Plasma lectin binds to mannose residues on microbes Complement • All 3 pathways lead to formation of C3 convertase, mediates C3 C3a & C3b • Then produces C5 convertase, mediates C5C5a & C5b • C3a & C5a Chemotaxis; Recruits & Activates leukocytes; Induce mast cells to degranulate histamine released vasodilation, increased vascular permeability • C3b = opsonin, augments phagocytosis • C5b complexes with C6-C9 Formation of MAC Complement Acute Inflammation • Immediate response (minutes to days) • Limited specificity • Neutrophils • Fluid and plasma exudation Mediators of Acute Inflammatory Response • Neutrophils • Endothelial cells • Mast cells • Eosinophils • Platelets • Arachidonic acid metabolites • Complement • Histamine • Cytokines Vascular & Cellular Reactions of Acute Inflammation Vascular changes: -Vasodilation -Increased vascular permeability Cellular events: -Neutrophil emigration -Cellular recruitment -Activation of neutrophils neutrophil emigration happeneds on venous side Vascular Reactions of Acute Inflammation Vasodilation: - Locally increased blood flow due to arteriolar smooth muscle relaxation - Prostaglandins, histamine, bradykinin - Erythema (rubor) and Warmth (calor) Vascular Reactions of Acute Inflammation Increased vascular permeability: - Movement of protein-rich fluid into extra-vascular space - Endothelial contraction (histamine) - Endothelial disruption (tissue damage) - Swelling (tumor) Vascular Permeability & Fluid Leakage Effusions • Greater than normal volume of fluid within the pericardial, abdominal, or pulmonary cavity • Classified as transudate or exudate particularly when found in pleural or peritoneal cavity • Differentiation based primarily on the protein concentration although other additional tests to be considered are often preformed Transudates • Fluids of non-inflammatory origin with low protein concentration • Increased volume caused by alterations in hydrodynamic factors as: – Increased venous pressure (heart failure, hepatic cirrhosis with portal hypertension) – Hypoproteinemia (nephrotic syndrome, protein losing enteropathy) – Lymphatic blockage Exudates • Fluids of inflammatory origin characterized by – Increased protein concentration – Frequently contain inflammatory cells (turbid) – Glucose concentration decreased • Causes: – Malignancy – Infection – Pancreatitis Collection of Effusions • From chest or abdomen bedside procedures – Through chest wall: “thoracentesis”; pleural fluid – Through abdominal wall: “paracentesis”; ascitic fluid • Into pericardium usually ultrasound-guided – “pericardiocentesis”, pericardial fluid Paracentesis Thoracentesis neutrophils Acute Inflammation • Immediate response (minutes to days) • Limited specificity • Neutrophils • Fluid and plasma exudation Mediators of Acute Inflammatory Response • Neutrophils • Endothelial cells • Mast cells • Eosinophils • Platelets • Arachidonic acid metabolites • Complement • Histamine • Cytokines A 65 year old female presents with a 3 month history of fatigue and shortness of breath. She has general lymphadenopathy, hepatosplenomegaly and a right pleural effusion. A thoracentesis was performed. Pleural fluid culture: No bacterial/fungal growth Pleural fluid LDH=190 U/L (ref range <122 U/L) Serum LDH=210 U/L (ref range 120-250 U/L) Cytology: Abundant lymphocytes Transudate or Exudate? Introduction to Inflammatory Cells and Mediators Kimiko Suzue, M.D., Ph.D. [email protected] RWCLC 1.069 Learning Objectives: 1. Discuss steps and cardinal signs of inflammation. 2. Describe the cellular and vascular events of acute inflammatory cells, including the chemical mediators which are involved. 3. Classify types of extracellular fluids associated with injury and describe pathologic conditions in which these can be found.