Acute Inflammation Flashcards
Inflammation
Allows inflammatory cells, plasma proteins & fluid to exit blood vessels & enter interstitial space
Acute inflammation is the response to
Infection
OR
Tissue Necrosis
Goal is to eliminate pathogen or clear necrotic debris
Acute inflammation is characterized by
Edema Neutrophils Immediate response (peaks within 24 hours) Innate immunity Limited specificity
24 hours after infarction, which inflammatory cells do you see?
Neutrophils
Components of Innate Immunity
Epithelium Mucus Complement System Mast Cells Macrophages Eosinophils, etc
Adaptive Immunity
Lymphocytes
More Specific
Takes Longer
Where is LPS located?
On the outer membrane of gram negative bacteria
Toll-Like Receptors
Present on Macrophages & Dendritic Cells
Recognize PAMPs
Also present on Lymphocytes
Mediate chronic inflammation too
CD14
CD14 = TLR on Macrophage Recognizes LPS Activates NF-κB Activates immune response genes Increases production of multiple immune mediators
NF-κB
Molecular “on” switch for acute inflammation response
Activates immune response genes
Increases production of multiple immune mediators
Arachidonic Acid
Released from Phospholipid Cell Membrane by Phospholipase A2 Undergoes: COX Pathway vs. 5-Lipooxygenase Pathway
Cyclooxygenase Arachidonic Acid Pathway
Produces prostaglandins
PGI2 (Vasodilation, leaky vessels)
PGD2 (Vasodilation, leaky vessels)
PGE2 (Vasodilation, leaky vessels, pain, fever)
Vasodilation occurs at the level of the
Arterioles
Increased vascular permeability occurs at the level of the
Post-capillary venule
5-Lipooxygenase Pathway
Produces Leukotrienes
LTB4 (Attracts & activates PMNs)
LTC4, LTD4, LTE4 (Contract smooth muscle: Vasoconstriction, Bronchospasm, Leaky Capillaries via pericyte contraction)
Which substances attract and activate PMNs?
LTB4
C5a
IL-8
Bacterial Products
LTB4
Attracts & activates PMNs
LTC4
Smooth Muscle Contraction:
Vasoconstriction
Bronchospasm
Leaky Capillaries via Pericyte Contraction → Windows between pericyte-bound endothelial cells
LTD4
Smooth Muscle Contraction:
Vasoconstriction
Bronchospasm
Leaky Capillaries via Pericyte Contraction → Windows between pericyte-bound endothelial cells
LTE4
Smooth Muscle Contraction:
Vasoconstriction
Bronchospasm
Leaky Capillaries via Pericyte Contraction → Windows between pericyte-bound endothelial cells
PGI2
(Vasodilation, leaky vessels)
PGD2
(Vasodilation, leaky vessels)
PGE2
(Vasodilation, leaky vessels, pain, fever)
Mast Cells are Activated By
Tissue Trauma
C3a & C5a
Cross-linking of cell-surface IgE by Ag
Mast Cell Immediate Response
Release of histamine granules (similar effect to prostaglandins):
Vasodilation
Increased vascular permeability
Mast Cell Delayed Response
Production of Arachidonic Acid Metabolites Especially Leukotrienes (2nd phase of mast cell response)
Complement
Pro-inflammatory serum proteins, circulate as inactive precursors
3 Complement Activation Pathways
Classical: C1 binds IgG or IgM, bound to Ag
Alternative: Microbial Products directly activate complement
Mannose-Binding Lectin (MBL): MBL binds mannose on microorganisms, activates complement
Complement Activation (Broad Strokes)
C3 Convertase
C5 Convertase
MAC Formation
C3a
Triggers Mast Cell Degranulation
C3b
Opsonin
Contributes to C5 Convertase
C5a
Triggers Mast Cell Degranulation
Chemotactic Agent for PMNs
C5b
Teams up with C6 - C9 to form MAC
MAC
Membrane Attack Complex
Perforates and Lyses
Hageman Factor
AKA Factor XII
Inactive proinflammatory protein Produced in the liver Activated by exposure to subendothelial collagen or tissue collagen Activated by GN Organisms Activates Coagulation & Fibrinolytic Systems Activates Complement Activates Kinin System Important in DIC & Severe GN Sepsis
High MW Kininogen
Cleaved to Bradykinin
Bradykinin Causes
Vasodilation
Leaky capillaries
Pain
Symphony of Inflammation
Rubor Calor Tumor Dolor Fever
What mediates Rubor & Calor?
Histamine (Most important)
Prostaglandins (PGI2, PGD2, PGE2)
Bradykinin
These lead to vasodilation & increased blood flow through relaxation of arteriolar smooth muscle
What mediates Tumor?
Histamine
Tissue Damage
These lead to leakage of fluid from postcapillary venule into interstitium
What mediates Dolor?
Bradykinin
PGE2
These lead to sensitized nerve endings
What mediates Fever?
Macrophages release IL-1 & TNF → Perivascular COX Activity → PGE2
PGE2 in the hypothalamus raises temperature set point
What is the first phase of Acute Inflammation?
Fluid Phase
Peaks at 12h
What is the second phase of Acute Inflammation?
Neutrophil Phase
Peaks at 24h
What is the third phase of Acute Inflammation?
Macrophage Phase
Peaks at 2 - 3 days
What is contained in storage granules of endothelial cells?
Weibel-Palade Bodies containing:
Von Willebrand Factor
P-Selectin
Histamine induces their release.
Overarching steps of Neutrophil Phase of Acute Inflammation
Margination Rolling Adhesion Transmigration & Chemotaxis Phagocytosis Destruction of Phagocytosed Materials
Neutrophil Phase - Margination
Vasodilation of arterioles slows blood flow in the post-capillary venules.
Heavy particles (normally in the center of the lumen) move to the periphery of the vessel.
Neutrophil Phase - Rolling
Selectins (speed bumps) upregulated on endothelial cells:
P-Selectins (Released from Weibel-Palade bodies, mediated by Histamine)
E-Selectins (Induced by TNF & IL-1)
Sialyl Lewis X binds these selectins
Cells roll along vessel wall
Sialyl Lewis X
Glycoprotein on Leukocytes
Binds to selectins on endothelial cells for leukocyte rolling
Neutrophil Phase - Adhesion
TNF & IL-1 → Upregulation of ICAM & VCAM (Cellular adhesion molecules) on endothelium
C5a & LTB4 → Upregulation of integrins on leukocytes
ICAM/VCAM interaction with Integrins → Adhesion
Neutrophil Phase - Transmigration & Chemotaxis
Leukocytes transmigrate across endothelium of post-capillary venules
Chemotactic Attractants for PMNs: IL-8 C5a LTB4 Bacterial Products
Neutrophil Phase - Phagocytosis
Consumption of pathogens or necrotic tissue
Enhanced by opsonins IgG & C3b
Pseudopods from leukocytes extend to form phagosomes (vesicle)
Phagosomes merge with lysosomes → Phagolysosome
IgG & C3b
Opsonins for phagocytosis
Neutrophil Phase - Oxygen-Dependent Destruction of Phagocytosed Material
Most effective killing
HOCl generated by oxidative burst in phagolysosome
Neutrophil PHase - Oxygen-Independent Destruction of Phagocytosed Material
Less effective killing
Enzymes present in leukocyte secondary granules (Lysozyme, Major Basic Protein)
In which leukocytes can Major Basic Protein be found?
Eosinophils
Marginated Pool of PMNs
Normal PMNs
Hang out like bats on vessel walls of lungs via integrins
Wait for recruitment
Leukocyte Adhesion Deficiency
Autosomal Recessive
Deficit of CD18 subunit of integrins
Clinical Findings (based on lack of marginated pool of PMNs):
Delayed separation of umbilical cord
Increased circulating PMNs
Recurrent bacterial infections (lacking pus formation)
Chediak-Higashi Syndrome
Autosomal Recessive
Protein-Trafficking Deficit
Microtubule railroad tracksdefective, so phagosome can’t be brought to lysosome.
Phagolysosome is not formed.
Clinical Findings:
Increased risk of pyogenic infections
Neutropenia (from impaired mitosis)
Giant granules in leukocytes (exported proteins can’t be trafficked once left the Golgi)
Defective primary hemostasis
Albinism (melanocytes typically form melanin and hand it off to surrounding keratinocytes)
Peripheral neuropathy (can’t traffic proteins from ganglion to nerve ending)
Resolution of Acute Inflammation
PMNs undergo apoptosis
Disappear within 24h after resolution of inflammatory status
Oxidative Burst in Phagolysosome
O2
↓ NADPH Oxidase
Superoxidase Radical
↓SOD
H2O2
↓MPO
HOCl
Chronic Granulomatous Disease
X-Linked Recessive or Autosomal Recessive
NADPH Oxidase Defect
Poor O2-dependent Killing
Leads to infections & granuloma formation w/ Catalase (+) organisms
Nitroblue Tetrazolium Test (NBT Test)
NBT Test
Nitroblue Tetrazolium Test
Screen for Chronic Granulomatous Disease
Turns blue if NADPH Oxidase turns O2 → Superoxidase
Remains colorless if NADPH is defective
Catalase (+) Organisms
Staph Aureus (Classic!) Pseudomonas Cepacia (Now called Burkholderia cepacia) Serratia Marcescens Nocardia Aspergillus Other things less high yield
MPO Deficiency
Most patients asymptomatic
Increased risk for candida infections
Normal NBT Test
H202 never be comes HOCl
Why do Chronic Granulomatous Disease patients have trouble with Catalase (+) Organisms
Most bacteria have an alternative source of H2O2 (with lesser stores), so the host can bypass their NADPH Oxidase defect and still generate HOCl from bacterial H2O2 reserves.
Catalase (+) organisms break down H2O2
In those infections, there is no way for a Chronic Granulomatous Disease patient to make HOCl
Acute Inflammation - Macrophage Phase
Peaks 2 - 3 days after inflammation begins
Monocytes arrive and start calling themselves macrophages
Macrophages phagocytose & destroy material using enzymes in secondary granules (lysozyme)
Not much O2-dependent killing
Macrophages also manage next step of inflammatory process
What is the mechanism for arrival of Monocytes in the Macrophage Phase of Acute Inflammation?
Margination
Rolling
Adhesion
Transmigration
How do Macrophages induce resolution of Acute Inflammation?
IL-10
TGF-β
Anti-inflammatory
How do Macrophages induce the continuation of Acute Inflammation?
IL-8
Calls in new PMNs
Pus = Sign of CONTINUED acute inflammatory response, not CHRONIC.
Who induces the formation of Abscesses?
Macrophages
