Patho 03 – Acute Inflammation and Acute Phase Reactants 1

INFLAMMATION  Adhesion: firmly adhere via INTEGRINS on endothelial cell surface

Components  ICAM1 and VCAM 1
Vascular reaction/blood vessel reaction: c before d  Transmigration (Diapedesis)
Cellular reaction  Post-capillary venules
Cells in blood stream  Chemokines: act on adherent leukocytes; stimulates cell to
Polymorphonuclear leukocytes/neutrophils: 1st line of defense migrate
Lymphocytes (B cells/T cells): produce cytokines  PECAM-1/CD31 (platelet endothelial cell adhesion molecule-1)
Platelets: hemostasis  Major adhesion molecules that mediate binding events needed to
Eosinophil, Basophil: anaphylactic reactions traverse
Monocytes  Chemotaxis
Endothelial cells  Chemoattractants
Outside BV  Exogenous
Tissue basophils or mast cells  Bacterial products
Fibroblasts: secretion of collagen; healing and repair  Peptidases (w/ N-formylmethionine terminal AA)
st
Macrophage: 1 line of defense; innate immunity  Endogenous
Sequential Steps  Cytokines esp IL-8 (most potent)
 Recognition of injurious agents  LTB4 and arachidonic acid metabolites
 Recruitment of leukocytes  C5a and components of complement
 Removal of agent  Mechanism
 Regulation (control) of response  Chemoattractants bind to GPCR on surface of leukocytes
 Resolution  ↑second messenger, ↑Ca2+ and GTPases, kinases
Cardinal Signs  Induce polymerization of actin (at leading age; myosin is
 Heat (calor) localized at back)
 Redness (rubor)  Leukocytes migrate toward stimulus
 Swelling (tumor)  Post-capillary venules
 Pain (dolor)  Chemokines: act on adherent leukocytes; stimulates cell to
 Loss of function (functio laesa) migrate
 PECAM-1/CD31 (platelet endothelial cell adhesion molecule-1)
ACUTE INFLAMMATION
 Major adhesion molecules that mediate binding events needed to
Components
traverse
 Alterations in vascular caliber
 Structural change in microvasculature 3. Leukocyte Activation
 Emigration of leukocytes  Activation
 Diapedesis  Production of mediators
Stimuli: infection (most common), trauma, physical & chemical agents,  Degranulation, secretion of lysosomal enzymes
tissue necrosis, foreign bodies, immune reactions  Activation of oxidative burst (h2o2, superoxide, hydroxyxl)
Tissue Cells Important: Mast cells & macrophages!  Secretion of cytokines
 Mast cells: activated by oxygenation of IgE molecules  Modulation of leukocyte adhesion molecule
 Macrophages: interleukins and cytokines Steps of Phagocytosis
(1) Recognition and attachment by phagocytic receptors
1. Vascular changes
 Efficiency enhanced through OPSONINS
 Change in vascular flow and caliber
 IgG Abs, C3b, MBL
 Vasodilation (rubor and calor)
 Macrophage mannose receptor
 Induced by histamine (mast cells, basophils platelets),
 Lectin; binds terminal mannose and fucose residues of
prostaglandin, nitric oxide
glycoproteins and glycolipids
 Arteriolar vasodilation  opening of new capillary beds 
 Recognizes microbes (host cells: sialic acid, N-AG)
increased blood flow
 Scavenger receptors
 Increased permeability of microvasculature: out-pour of protein-
 bind and ingest LDL and microbes
rich exudate
(2) Engulfment
 Stasis
 Pseudopods flow around it to form PHAGOSOME which fuses with
 Extravasation  concentrated RBC in blood  inc blood
LYSOSOME = PHAGOLYOSOME
viscosity  SLOWER CIRCULATION
(3) Killing or degradation
 Dilated small vessels packed with RBCs, erythema
 Reactive oxygen species
 Margination of leukocytes along vascular endothelium
 Produced by phagocyte oxidase (NADPH oxidase) in phagolysosome
 Increased vascular permeability (hallmark of acute inflammation)
through oxidation of NADPH, reducing oxygen to superoxide
 Formation of endothelial gaps in post-capillary venules
anion
(immediate transient response)
 Nitric oxide
 Most common mechanism; contraction of endothelial cells
 Damage lipids, proteins, nucleic acids
 Due to histamine, bradykinin, leukotrienes
 Promotes vasodilation
 Direct endothelial injury resulting in necrosis and detachment
 Granule enzymes
(acv)
 Oxygen dependent killing
 Delayed prolonged leakage (mild injury; after 2-12 hrs)
 Respiratory burst
(cv)
 Activation of NADPH oxidase
 Leukocyte-mediated endothelial injury (late response, long)
 Chronic granulomatous disease: defect
(pc,v)
 H2O2-MPO-halide system
 Increased transcytosis involving VEGF
 Most efficient
(v)
 MPO + halide, can convert H2O2 to hypochlorite
 Leakage from new blood vessels (site of angiogenesis)
 Destroys microbes via halogenation or lipid peroxidation
2. Leukocyte Extravasation (Diapedesis)  Oxygen independent
 Margination, Rolling and Adhesion  Bactericidal permeability increasing protein, lysozyme,
 Margination: leukocytes in peripheral position due to decrease of lactoferrin, MBP, defensins
shear stress  Release of leukocyte products and leukocyte-induced tissue injury
 Rolling: leukocytes adhere transiently to endothelium via  Lysosomal enzymes
SELECTINS (in endothelial cell surface; tumbling  Reactive oxygen intermediates
 Selectins are expressed when endothelial cells are activated  Products of arachidonic acid metabolism (PG and LT)
by cytokines
CHEMICAL MEDIATORS OF INFLAMMATION
 Patho 03 – Acute Inflammation and Acute Phase Reactants 2

Components  LTB4: chemotaxis

 Alterations in vascular caliber  LTC4, LTD4, LTE4: vasoconstriction, bronchospasm, inc permeability
 Structural change in microvasculature  Lipoxin A4, B4: vasodilation, inhibit chemotaxis, stimulate monocyte
 Emigration of leukocytes adhesion
 Action is usually short-lived bec of presence of other factors which
Vasoactive Amines
would modulate action of the others
 Histamine
 From mast cells
 Causes arteriolar dilatation
 Increased permeability of venules
 Serotonin
 From platelets and enterochromaffin cells
Plasma Proteins
 Complement System
 Innate and adaptive immunity
 C1 – C12
 Critical step: activation of C3 through
 Classical pathway
 Antigen-antibody (IgG or IgM complex) important in diseases
with immune complex disposition
 Activates C1
 Lectin pathway
 Binds to lectin on surface of cells (mannose-binding
lectin)
 Alternative pathway
 In the presence of bacteria in the bloodstream
 Starts with activation of C3
 Impt clinically: classical and alternative Cytokines and Chemokines
 Complement-derived factors play a role in variety of phenomena in  Cytokines
acute inflammation  TNF & IL-1: most important
 Vascular phenomena: C3a, C5a, C4a  Usually the first one involved
 Anaphylatoxins; involved in anaphylactic reactions
 Leukocyte adhesion, chemotaxis and activation: C5a
 Phagocytosis: C3b
 Opsonin
 Kinin system
 Generates vasoactive peptides from kininogens by the action of
kallikreins
 Activation results in the release of bradykinin
 Increase vascular permeability, contraction of smooth muscle,
vasodilation, pain
 Short-lived
 Clotting System
 Two pathways: intrinsic and extrinsic
 Culminate in activation of thrombin and formation of fibrin
 To wall off offending agent
 Thrombin
 Provides main link between coagulation system and inflammation

 Chemokines
 Chemoattractants
 4 Groups
 C-X-C: act on neutrophils
 Promote neutrophilia & leukocytosis
 C-C: attract monocytes, eosinophils, basophils and lymphocytes
 C: lymphocytes
 CX3C: monocytes & T-cells
Nitric Oxide
 Vasodilator from endothelium
 iNOS: microbicidal (inside WBC)
 eNOS: vasodilation
 TNF & IL-1: most important
Lysosomal Constituents of Leukocytes
Once clotting system is activated, through Factor XII, the kinase system  PMN: specific and azurophilic
is also activated (most impt: bradykinin). Cascade activates other  Both empty into phagocytic vacuoles that form around engulfed
clotting factors, culminating in formation of fibrin. Plasmin also material or the granule contents can be released into the
activates complement cascade extracellular space
 Different granule enzymes serve different functions
Arachidonic Acid Metabolites
 If unchecked, can lead to further tissue inflammation
 Arachidonic acid metabolites: PG, LT and lipoxins
 Regulated by anti-proteases
 Arachidonic acid is a 20-carbon polyunsaturated fatty acid derived
 Alpha1-antitrypsin
from dietary sources or by conversion from essential fatty acid
 Alpha2-macroglobulin
linoleic acid
 Modulate whole inflammatory process
 Normally esterified in membrane phospholipids
 Activation of phospholipases  diff products
 Patho 03 – Acute Inflammation and Acute Phase Reactants 3

Oxygen-derived Free Radicals

 Metabolites that may be released extracellularly from leukocytes
after exposure to chemotactic agents, immune complexes, or a
phagocytic challenge
 Includes:
 Superoxide ion
 H2O2
 Hydroxyl radical
 ROS intermediates
 Implicated in:
 Endothelial cell damage
 Inactivation of anti-proteases
 Injury to other cell types
 Detoxified by antioxidants (e.g. ceruloplasmin, transferrin,
superoxide dismutase, catalase, glutathione peroxidase) also mediates
damaging effects of released enzymes during acute inflammation [Doc RFF]
Neuropeptides
 Substance P and Neurokinin A are produced in the CNS and PNS
 Mediates pain
 Bradykinin: from kinin system
 Substance P: a neuropeptide
OUTCOMES OF ACUTE INFLAMMATION
 Complete resolution/restitution/healing
 Abscess formation (pus)
 Healing by fibrosis and scarring
 If tissue is large
 Progression to chronic inflammation
 If offending agent is still there
Morphologic Patterns
 Serous Inflammation: release of tissue fluid
 Example: blisters with watery-fluid exudation
 Fibrinous: rich in fibrin and cells
 Suppurative or purulent: rich in pus
 Ulcer: no restitution or resolution that will happen if tissue
damage is severe