Acute and Chronic Inflammation Flashcards
Causes of Inflammation
1) **Infectious Organisms
2) Anything that results in significant
Damage to Cells or Tissue Necrosis:
_Physical and Chemical Agents
_Trauma
_Foreign Body
3) **Hypersensitivity Autoimmune Diseases
4) **Neoplasia
Types of Inflammation
1) Acute:
_**Minutes - Days
_Predominantly *Neutrophil Response and *Fluid Protein Exudates
2) Chronic:
_**Weeks - Years
_Mainly *Lymphocytes and *Macrophages merging to Tissue Destruction and/or Repair
3) Granulomatous:
_Weeks - Years
_Special Type of *Chronic Inflammation with Transformed Macrophages called
*Epithelioid Histiocytes
4) Repair:
_**Days - Years
_Resolution of Inflammation to the Previous Tissue State or Formation of **Scar
2 Types of Edema
Transudate: _*Clear Fluid _An ultrafiltrate of *Plasma, _*Low Protein Content _*Low Specific Gravity, *Less than 1020 (*Hydrodynamic) _Seen with Increased Hydrostatic Pressure or Leaky Vessels.
Exudate: _*Cloudy Fluid _*High Protein Content _*High Specific Gravity, *Greater than 1020 (*Inflammatory) _Seen in *Inflammation Due to *Increased Permeability, with leakage of fluid, proteins, and Blood cells from the vessels.
Forms of Edema
Edema:
_Excess Fluid @ Interstitial Tissue
_Can be Exudate or Transudate
Effusion:
_Equivalent to Edema, but @ Body Cavity
_Serous Effusion: Has Transudate Fluid
_Serosanguinous Effusion: Has Blood-Tinged Fluid
Fibrinous Exudate:
_Contains Large Amounts of Circulating Fibrinogen,
which Transforms into Solid Fibrin.
Pus or Suppurative Inflammation:
_Purulent Exudate with Many Neutrophils and Dead Cells.
Lab Signs of Inflammation
1) Leukocytosis:
_Increased Leukocytes (WBCs) @ Blood
_Measured by CBC
_Observed on a Peripheral Blood Smear
=> Increased WBC with Differential: **Acute: (1) Increased **Neutrophils (3-Lobe Nuclei) (2) Increased **Bands _A higher percentage of immature PMNs forms **Bands = **Left Shift
Chronic and some forms of Viral inflammation:
_Lymphocytosis predominates
Parasitic Infections:
_Eosinophilia predominates.
(2-Lobe Nuclei with Red Granules)
2) Increased Acute Phase Reactants (CRP):
_Proteins that are Increased in Serum with Onset of Inflammation
3) Increased Sedimentation Rate:
_Non-specific indicator of inflammation
(Sed rate is also increased by things other than inflammation)
4) Markers of Inflammation:
_Including Enzymes that leak from Damaged Cells
(Tissue Destruction and Leakage of Intracellular Contents into the Blood):
(1) *Creatinine Kinase (CK) from *Muscle
(2) *Transaminases, e.g. *ALT or *AST from *Liver
(3) *Amylase and *Lipase from *Pancreas
(4) *LDH from *Many *Sources
Vascular Events of Acute Inflammation
1) **Vasodilation:
_Dilation of Arterioles
_Resulting in Increased Flow to Capillaries,
_Redness, and Heat
Several Mediators, Most Notably:
_Histamine: from Mast cells
_Nitric Oxide (NO): from Vascular Smooth Muscle
2) **Increased Permeability of Microvasculature:
_Mostly Venules
_Quickly follows Vasodilation
(Similar mediators).
_*Endothelial cells *Contract, Resulting in:
(1) Exudation of Fluid and Protein
(2) **Edema
(3) **Stasis or **Vascular Congestion: Slow Blood Flow
3) **Vascular Stasis:
= *Blood cells Slow Down in the vessels
_Due to Vasodilation and Exudation of Fluid
_This allows *Chemical Mediators to Accumulate and Act on the Cells here,
_**Activating *More *Leukocytes and *Endothelial cells
_Most pronounced @ Venules
Vascular Events:
Increased Permeability of Microvasculature
- Intercellular Gaps:
1) *Immediate Transient Response:
_Occurs when Endothelial cells Contract, Widening the Intercellular Gaps in
@ Small Venules.
_Mediators act *Rapidly and Last only *15-30 Minutes.
_Main Mediators:
- Histamine and
- Nitric Oxide
_Other Mediators:
- Bradykinin,
- Leukotrienes,
- Neuropeptide Substance P
2) *Delayed Sustained Response:
_Occurs with Mild Sublethal Injury, typically in late sunburn but also with X-ray or UV radiation or after exposure to certain Bacterial Toxins.
_Caused by *Contraction of Endothelial cells and Mild Endothelial cell Damage
_Leakage *Begins Late, Taking *2-12 Hours, and Lasting several Hours to Days.
_Mediators Include: IL-1, TNF, IFN-gamma, Hypoxia \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
*Direct Endothelial Cell Injury and Necrosis:
1) *Immediate Sustained Response:
_Seen with Severe Injury, such as Severe Burns or Direct Microbial Attack of Endothelial cells.
2) *Immediate Leakage:
_Continues for Several Hours to Days until there is Thrombosis and Repair.
_Affects @ Venules and Capillaries.
_______________
*Direct Endothelial Cell Injury and Necrosis Induced BY Leukocytes:
_Inflammation Results in PMN (Neutrophil) Adhesion to Vessels
_PMNs then Degranulate and may cause Local injury to Vascular Endothelium.
_@ Lungs
(Alveolar Capillary Leak
with Pulmonary Edema)
_@ Kidneys
(Glomerular Injury and
Renal Failure)
_______________
**Transcytosis:
= Increased Transport of Fluids and Proteins Through Endothelial Cell Channels (near intercellular junctions)
_Mediators, e.g. VEGF, Promote Vascular Leakage by Increasing the Number and Size of these Channels.
Leukocyte Migration
Neutrophils Respond Non-Specifically to Injurious Stimuli,
_Producing their Effects on All Cells in the Immediate Vicinity.
_Response it Most Prominent within the First Day of Inflammation
1) Neutrophils traveling in the Blood are Attracted to the inflammation area.
2) They Approach the vessel wall During Stasis,
_Stick Weakly to Endothelium,
_and Roll Over until
_they Adhere Firmly and stop rolling over.
Mediators of Adhesion:
1) **TNF, **IL-1, and **Chemokines:
_Produced by Macrophages, Mast cells, and Endothelial cells
_in *Response to Microbes
2) **TNF and **IL-1 Activate Endothelial Cells to produce
* *E-Selectins, Integrin ligands ICAM-1 and VCAM-1, and L-Selectin ligands.
3) Selectins **Bind Weakly to Lectins,
_Resulting in Loose Adhesions
_and Rolling Over
4) Histamine and Thrombin Up-Regulate P-Selectins to Mediate Platelet Adhesion.
5) IL-1 further Increases ICAM-1 and VCAM-1 Expression on Endothelial cells.
6) C5a Increases Affinity of Integrins on Neutrophils,
_Resulting in Firm Adhesion
7) **Diapedesis:
= Migration through Endothelium
_Occurs through Vascular Gaps Between Endothelial cells
_Mediated by ICAM-1 and PECAM-1 (CD31)
8) Leukocytes Release Collagenases to Transverse the Basal Membrane
9) They Attach to Extracellular Matrix (ECM) via Integrins and CD44.
Endothelial and Leukocyte Adhesion Molecules
Endothelial: P-Selectin Leukocyte: Sialyl-Lewis X-modified proteins Major Role: _Rolling (Neutrophils, Monocytes, T cells)
Endothelial: E-Selectin Leukocyte: Sialyl-Lewis X-modified proteins Major Role: _Rolling and Adhesion (Neutrophils, Monocytes, T cells)
Endothelial: GlyCam-1, CD 34
Leukocyte: L-Selectin
Major Role: Rolling
(Neutrophils and Monocytes)
Endothelial: ICAM-1
Leukocyte: LFA-1 Integrin
Major Role: Adhesion, Arrest, Transmigration
(Neutrophils, Monocytes, Lymphocytes)
Endothelial: VCAM-1
Leukocyte: VLA-4 Integrin
Major Role: Adhesion
(Eosinophils, Monocytes, Lymphocytes)
Chemotaxis
= **Chemical Mediators Draw Leukocytes into the Area of Injury
_Via a Chemical Gradient
(Chemical Trail)
(This is once the Leukocytes have left the circulation and arrived in the tissues)
This makes the Inflammatory Process **More Localized
Mediators of Chemotaxis:
1) Exogenous:
_Bacterial products
2) Endogenous:
_Complement, Mainly **C5a
_Leukotriene, Mainly *B4
_Cytokines, Mainly *IL-8
The Chemotactic agents Bind to Leukocyte Cell Membrane Receptors,
_Resulting in Phosphorylation, Transduction, and Release of Cytoplasmic Calcium.
This Results in:
1) Motion via Actin/Myosin Contraction
2) Activation of Arachidonic Acid Metabolic Pathways
3) Modulation of Adhesion Molecules
4) Phagocytosis
5) Degranulation
Leukocyte Attachment to Stimuli
Neutrophils Attach to Offending Agent via Receptors for Microbial Products,
e.g. *Toll-like Receptors and *Opsonins Coating these agents:
(1) **Complement (C3b): Generated by Immune or Non-immune Complement Activation
(2) **Collectins: = Lectins in the Plasma that Bind to Microbial Wall
(3) **Immunoglobulin (IgG-Fc)
Leukocyte Activation
- *Surface Receptors Signaling Activation:
1) Increase *Cytoplasmic Calcium
2) Activate Enzymes, e.g. **Protein Kinase C and **Phospholipase A2
Which then induce Functional Responses:
1) *Arachidonic Metabolites via *Phospholipase A2
2) *Degranulation and *Secretion of *Lysosomal Enzymes,
and Activation of Oxidative Burst
3) *Secretion of *Cytokines,
and Modulation of Leukocyte Adhesion Molecules
Phagocytosis and Degranulation
Phagocytosis: Mainly by Neutrophils and Macrophages
Degranulation of Neutrophils Releases Proteolytic Enzymes from Granules into Phagolysosomes where the agent is Degraded.
**Phagocytes Express Receptors for Cytokines,
such as *IFN-gamma *Produced by *NK cells upon Microbial contact,
_Which *Potentiate Phagocytosis.
Killing
3 Ways of Degradation and Killing of Agents:
1) **Reactive Oxygen Species:
_Myeloperoxidase Reacts with Hydrogen Peroxide to Form a Highly Reactive Oxidant, Hypochlorous Free Radicals
2) **Enzymes: Neutrophil Granules (Lysosomes) contain several Enzymes that *Punch Holes in Bacterial Membranes.
3) *Acid Hydrolases:
_Digest Cellular Debris in the Phagolysosomes.
Defects in Leukocyte Function
Adhesion:
_Defective *Beta2 Integrins
=> Recurrent Infections
=> and Impaired Wound Healing
Phagocytosis:
_Defects in *Membrane Associated Protein,
which is involved in Membrane Docking and Fusion
=> Results in Defective Fusion of Lysozymes into Phagosomes
=> As seen in **Chediak Higashi Syndrome
Microbicidal Activity:
_Defects in *NADPH Oxidase
=> Result in **Chronic Granulomatous Disease
Morphology of Acute Inflammation
Dilated Small Blood Vessels or *Congestion with Slow Blood Flow aka *Stasis.
**Neutrophils and Extracellular Fluid (Edema)
**Serous Inflammation:
_Dominated by *Thin Fluid *Derived From *Plasma
_or Secreted by Mesothelial Cells from Peritoneum, Pleura, or Pericardium,
which is called **Effusion
**Fibrinous Inflammation:
_Occurs with Higher Increases in Vascular Permeability
_Resulting in Leakage of **Fibrin into Extravascular Spaces,
_which is called **Fibrinous Exudate and is Typical of Body Cavities:
Pleura or Pericardium
Inflammation and Tissue Injury
As part of Normal Host Defense Reactions against microbes, Adjacent Tissues suffer **“Collateral Damage”
- Some Inflammatory Mediators may Produce Tissue Damage:
(1) Ruptured Degranulated Neutrophils *Release Lysosomal *Enzymes and *ROS into *Extracellular Spaces
(2) Lysosomal Enzymes include
- *Elastases,
- *Collagenases,
- *Cathepsin,
- *Proteases
(3) Exocytosis of *Arachidonic Acid Metabolites
Inflammation and Tissue Injury
Disorders
(Red Frame)
Acute Disorders:
1) Acute Respiratory Distress Syndrome
_Neutrophils
2) Acute Transplant Rejection:
_Lymphocytes
_Antibodies and Complement
3) Asthma:
_Eosinophils
_IgE Antibodies
4) Glomerulonephritis:
_Neutrophils, Monocytes
_Antibodies and Complement
5) Septic Shock:
_Cytokines
6) Lung Abscess:
_Neutrophils (and Bacteria)
Chronic Disorders:
1) Arthritis:
_Lymphocytes, Macrophages
_Antibodies?
2) Asthma:
_Eosinophils
_IgE Antibodies
3) Atherosclerosis:
_Macrophages
_Lymphocytes?
4) Chronic Transplant Rejection:
_Lymphocytes
_Cytokines
5) Pulmonary Fibrosis:
_Macrophages
_Fibroblasts
Termination of Response
Host Defense is very powerful and must be tightly controlled to avoid collateral damage.
*Chemical Mediators:
_Produced in Rapid Bursts
_Often **Short-Lived
*Neutrophils also have *Short Life.
There are Multiple **Stop Signs:
1) **Switch of **Leukotrienes to Anti-Inflammatory **Lipoxins
2) Release by Macrophages of *Anti-Inflammatory *Cytokines, such as **TGF-Beta and **IL-10
3) Release of Anti-Inflammatory Lipid-Derived Mediators, such as **Resolvins and **Protectins
4) **Cholinergic Reflexes that Inhibit Macrophages/TNF
Cell Derived Chemical Mediators
Red Frame
1) Histamine:
Source:
_Mast cells,
_Basophils,
_Platelets
Actions:
_Vasodilation,
_Increased Vascular Permeability,
_Endothelial Activation
_____________
2) Serotonin:
Source:
_Platelets
Actions:
_Vasodilation,
_Increased Vascular Permeability
_____________
3) Platelet-Activating Factor:
Source:
_Leukocytes,
_Mast cells
Actions: _Vasodilation, _Increased Vascular Permeability, _Leukocyte Adhesion, _Chemotaxis, _Degranulation, _Oxidative Burst
_____________
4) Prostaglandins:
Source:
_Mast cells,
_Leukocytes
Actions:
_Vasodilation,
_Pain, Fever
_____________
5) Leukotrienes:
Source:
_Mast cells,
_Leukocytes
Actions: _Increased Vascular Permeability, _Chemotaxis, _Leukocyte Adhesion, and _Leukocyte Activation
_____________
6) Reactive Oxygen Species:
Source:
_Leukocytes
Actions:
_Killing of Microbes,
_Tissue Damage
_____________
7) Nitric Oxide:
Source:
_Endothelium,
_Macrophages
Actions:
_Vascular Smooth Muscle Relaxation,
_Killing of Microbes
_____________
8) Cytokines (TNF, IL-1_:
Source:
_Macrophages,
_Endothelial cells,
_Mast cells
Actions:
_Local Endothelial Activation (Expression of Adhesion Molecules),
_Fever/Pain/Anorexia/Hypotension,
_Decreased Vascular Resistance (Shock)
_____________
9) Chemokines:
Source:
_Leukocytes,
_Activated Macrophages
Actions:
_Chemotaxis,
_Leukocyte Activation
Preformed Mediators
Stored Preformed Molecules are among the First Released Mediators.
1) **Histamine:
_Stored in *Mast Cells, *Basophils, and *Platelets
Actions:
_Powerful Vasodilator
_Also Increases Vascular Permeability via Gaps Between Endothelial Cells
2) **Serotonin:
_Stored in *Platelets
_Released During Platelet Aggregation
Action: *Vasodilator
Arachidonic Acid Pathway
1) Cell Membrane Phospholipids are Converted by Phospholipases to Arachidonic Acid
_Cyclooxygenase Pathway:
2) Cyclooxygenase (COX) Converts Arachidonic Acid to Prostaglandin
3) Prostaglandin is Converted to Either
_Prostacyclin
_Thromboxane
_PGD or PGE
_Lipoxygenase Pathway:
2) Lipoxygenases Converts Arachidonic Acid to Lipoxins
Arachidonic Acid Pathway
Cyclooxygenase Pathway
Mediated by **COX1 and **COX2
Leads to **Production of Prostaglandins:
(1) **PGD2: Causes *Vasodilation
(2) **PGE2: Causes *Pain and *Fever
(3) **Prostacyclin (PGI2):
_Formed in Vascular Endothelium.
_Causes *Vasodilation.
_Also Inhibits Platelet Aggregation.
(4) **Thromboxane (TXA2):
_Formed in Platelets
_Causes *Vasoconstriction and *Platelet Aggregation
_____________
Cyclooxygenase Inhibitors:
Pathway is *Blocked by *COX1 and *COX2 Inhibitors:
_Non-steroidal anti-inflammatory drugs (NSAIDS): e.g. indomethacin, aspirin, etc.
Newer Cox2 Inhibitors are More Selective.
Cox1 is Constitutively Expressed.
Cox2 is Expressed Only After Inflammatory Stimuli.
Arachidonic Acid Pathway
Lipoxygenase Pathway
Leads to Formation of
5-HydroxyEcosaTetraEnoic Acid (5-HETE), which is a
_Powerful Chemoattractant for Neutrophils
_Precursor of *Leukotriene B4 (LTB4).
Leukotriene B4 (LTB4) Promotes:
(1) *Chemotaxis
(2) Leukocyte *Adhesion to Venule Endothelium
(3) Generation of *ROS
(4) Release of *Lysosomal Enzymes
Cysteinyl-containing Leukotrienes include:
_the Precursor LTA4 and
_the Leukotrienes Derived from LTA4, such as LTC4, LTD4, and LTE4, which Promote:
(1) Chemotaxis
(2) Vasoconstriction
(3) Bronchospasm
(4) Increased Vascular Permeability
**Lipoxins are also made in this pathway, such as LXA4 and LXB4.
Lipoxins are *Produced by Platelets.
They are Derived from LTA4 Produced by Leukocytes.
Lipoxins are *Leukotriene Inhibitors:
(1) *Inhibit Neutrophil Chemotaxis and Adhesion
(2) Stimulate Monocyte Adhesion
(3) Stimulate Vasodilation
(4) Attenuate LTA4 Vasoconstriction
____________
**Lipoxygenase is NOT Blocked by NSAIDs.
Many *New Inhibitors for this enzyme have been developed and are useful in treating Asthma and may:
(1) Block Leukotriene Production, e.g. Zileuton
(2) Block Leukotriene Receptors, e.g. Montelukast
Broad Spectrum Inhibitors, such as **Corticosteroids, **Block the ENTIRE Arachidonic Acid Pathway.
Arachidonic Acid Metabolites
(Eicosanoids)
(All of it is in Red Bold)
Vasodilation:
_PGI2 (Prostacyclin)
_PGE1, PGE2, PGD2
Vasoconstriction:
_Thromboxane A2
_Leukotrienes C4, D4, E4
Increased Vascular Permeability:
_Leukotrienes C4, D4, E4
Chemotaxis, Leukocyte Adhesion:
_Leukotriene B4
_HETE
Platelet Activating Factor (PAF)
Another Phospholipid-Derived Mediator
Stored in *Most Inflammatory Cells.
Stimulates Most Vascular and Cellular Inflammatory Reaction as well as Platelet Aggregation, including:
(1) Vasoconstriction and
(2) Bronchoconstriction
(3) Leukocyte Adhesion,
(4) Chemotaxis,
(5) Degranulation, and
(6) Oxidative Burst
(7) **Boosting of Synthesis of Other Mediators
Reactive Oxygen Species
ROS
The inflammatory process generates many Oxygen-Derived Free Radicals, which May be Released Extracellularly.
Production Depends on **Activation of the NADPH Oxidase System.
Main Free Radicals:
(1) Superoxide Anion (O2)
(2) Hydrogen Peroxide (H2O2)
(3) Hydroxyl Radical (OH), which may Combine with NO to Produce Reactive Nitrogen Species.
(Free Radicals have single, lone electrons, making them very reactive and prone to oxidizing other things.)
Free Radicals Help **Kill Microbes.
Small amounts of ROS **Amplify Inflammation and are Scavenged by Cellular Pathways.
- **Inappropriate Amounts of ROS is Damaging to the Host, Causing:
(1) Endothelial Cell Damage
(2) Damage to other cell types: epithelial, etc.
(3) Inactivation of Anti-Proteases
(Examples: ulcerative colitis, crohn’s disease. Increase risk for colon cancer. H. pylori. Increases risk for gastric cancer.)
Nitric Oxide (NO)
Synthesized in cells containing **Nitric Oxide Synthase (NOS).
- Endothelial Cells contain *eNOS, which Regulates *NO Production.
- Macrophages have Inducible NOS, aka *iNOS, and Produce *Large Amounts of NO and Reactive NO species.
NO Action is Short-Lived, depending on its concentration.
Neurons contain nNOS, which Produces Small Amounts of NO.
*Small Amounts of NO:
_Induce Smooth Muscle Relaxation
_Induce *Vasodilation
_Are *Anti-Thrombogenic to *Platelets
Small amounts produced by Neurons may act as a Neurotransmitter.
*Large Amounts Produced by *Macrophages are *Cytotoxic to *Bacteria and *Host cells.
- Inappropriate NO Release by Macrophages in **Sepsis Causes
(1) **Extensive Vasodilation,
(2) Hypotension, and
(3) ***Septic Shock
(Septic shock can result in cardiac arrest.)
Cytokines
Are Produced Mainly by
**Lymphocytes and **Macrophages
After Stimulation by Pathogens, Toxins, Cell Injury, or Inflammatory Mediators.
Cytokines include: _Lymphokines _Monokines _Chemokines _Colony Stimulating Factor _Interleukins _Growth Factors \_\_\_\_\_\_\_\_\_\_\_\_
*2 Most Important Cytokines:
***Interleukin-1:
Produced by *Activated Macrophages,
and by many other cell types.
**Tumor Necrosis Factor:
_TNF-Alpha: From Macrophages
_TNF-Beta: From *T cells
Both of these cytokines cause:
(1) *Endothelial Cell Activation,
(2) *Induce Acute Phase Responses,
(3) *Stimulate Fibroblasts,
(4) *Stimulate Leukocytes to *Secrete Other Cytokines
Effects of TNF and IL-1
Red Frame
Local Effects:
@ Vascular Endothelium: (Inflammation)
(1) Increase Expression of Leukocyte Adhesion Molecules
(2) Production of IL-1, Chemokines
(3) Increase Procoagulant Activity
(4) Decrease Anticoagulant Activity
____________
@ Leukocytes: (Inflammation)
(1) Leukocyte Activation
(2) Cytokine Production
___________
@ Fibroblasts: (Repair)
(1) Fibroblast Proliferation
(2) Increase Collagen Synthesis
________________
Systemic Effects:
(Systemic Manifestations of Inflammation)
(1) Fever
(2) Leukocytosis
(3) Increase Acute Phase Proteins
(4) Decrease Appetite
(5) Increase Sleep
Cytokines List, Principal Sources, and Their Principal Actions in Inflammation
(Red Frame)
ACUTE Inflammation:
**TNF Source: _Macrophages _Mast cells _T cells
Actions: _Stimulates Expression of Endothelial Adhesion Molecules _Stimulates Secretion of Other Cytokines _Systemic Effects \_\_\_\_\_\_\_\_\_\_\_\_\_\_
**IL-1 Source: _Macrophages _Endothelial cells _Some Epithelial cells
Actions:
_Similar to TNF
_Greater Role in Fever
______________
**IL-6
Source:
_Macrophages
_Other cells
Actions:
_Systemic Effects
(Acute Phase Response)
______________
**Chemokines: Source: _Macrophages _Endothelial cells _T cells _Mast cells _Other cell types
Actions:
_Recruitment of Leukocytes to Sites of Inflammation
_Migration of Cells to Normal Tissues
______________
CHRONIC Inflammation:
**IL-12
Source:
_Dendritic cells
_Macrophages
Actions:
_Increased Production
of IFN-gamma
______________
**IFN-gamma
Source:
_T cells
_NK cells
Actions:
_Activation of Macrophages
(Increased Ability to Kill Microbes and Tumor cells)
______________
**IL-17
Source:
_T cells
Actions:
_Recruitment of Neutrophils and Monocytes
Cytokines Categorized by Action
Cytokines are Categorized by their Actions:
1) **Autocrine:
_Acts @ Same cell where they are produced
2) **Paracrine:
_Acts @ Adjacent cells,
such as During the Activation of Neutrophils and Fibroblasts
3) **Endocrine: _Acts Systemically throughout the Body, such as in the Acute Phase Reactions: (TNF:) -Fever, Fatigue, Decreased Appetite, and Increased WBC count
Cytokines Categorized by Function
Red Frame
(Red Frame)
Cytokines Categorized by Function:
(1) Regulate Lymphocytes:
_IL-2, 4, 10, TGF-Beta
(2) Regulate Innate Immunity:
_TNF-Alpha, IL-1b, IL-6, IFN-gamma, IFN-Beta
(3) Activate Macrophages:
_IFN-gamma, TNF-Alpha, TNF-Beta, IL-5, IL-10, IL-12
(4) Chemokines:
_IL-8 (Leukocytes), Lymphotaxin
(5) Stimulate Hematopoiesis:
_IL-3, IL-7, c-kit, Colony Stimulating Factor (CSF), Stem Cell Factor
Plasma Protein Derived Chemical Mediators
**Bradykinin, **C3a, and **C5a:
_All Increase Vascular Permeability
_C5a Promotes Chemotaxis
**Thrombin:
_Produces FSP, which Increases Vascular Permeability and Chemotaxis
_Thrombin also Promotes Leukocyte Adhesion and Fibrosis
**Activated Hageman Factor:
Activates:
(1) **Kinin System:
Kinins => *Vasodilation
(2) **Clotting System:
Thrombin => *Inflammation
(3) **Fibrinolysis System:
FSP => *Inflammation
(4) **Complement:
Anaphylatoxins => *Chemotaxis
_______________
Principal Sources:
Plasma, Produced in Liver
(For all 3)
Mediator: Complement Products (C5a, C3a, C4a) Actions: _Leukocyte Chemotaxis _Leukocyte Activation _Vasodilation (Mast cell Stimulation)
Mediator: Kinins Actions: _Increased Vascular Permeability _Smooth Muscle Contraction _Vasodilation _Pain
Mediator: Proteases Activated During Coagulation
Actions:
_Endothelial Activation
_Leukocyte Recruitment
Plasma Inflammation Mediator Systems
**Inflammation and Blood Clotting Promote Each Other.
- 4 Plasma Mediator Systems for Inflammation:
(1) Coagulation
(2) Fibrinolysis
(3) Kinin
(4) Complement
_All are *Activated by Coagulation **Factor XII aka **Hageman Factor
Includes many mediators from **Vascular Endothelium and **Circulating Blood.
These systems interact continuously in the course of inflammation to keep the area of Tissue Destruction Localized and to Reduce Hemorrhage from Damaged Blood vessels.
There is a Gradient whereby Inflammatory Stimuli predominate Closer to the injury site, while inflammatory Inhibitors are Increased in the Surrounding Tissues.
Coagulation
Clotting is Divided into 2 Pathways that converge into a *Common Pathway that Culminates in the Formation of Thrombin (Factor IIa), the most critical coagulation factor, which acts at multiple stages.
Prothrombin (Factor II) is converted into Thrombin.
Thrombin converts Fibrinogen (Factor I) into Fibrin (Factor Ia).
Formation of the **Fibrin Clot is the **Result of **Cross-Linking of **Soluble Fibrinogen Monomers into **Insoluble Polymeric Fibrin.
________________
**Intrinsic Clotting Pathway:
_Activated by Hageman Factor (Factor XII), a Plasma Protein Produced by the *Liver.
_PTT Test
_Factor XII is *Activated by *Surface Contact with *Negatively Charged Collagen During the Leak of Plasma Proteins Due to Endothelial Damage.
________________
**Extrinsic Clotting Pathway:
_Activated by Tissue Factor (Factor III / **Thromboplastin)
_PT Test
_Tissue Factor is Released @ Sites of Tissue Injury
_Tissue Factor Activates Factor VII.
Coagulation Diagram
Extrinsic Pathway: (3, 7)
1) Tissue Factor (Factor III) (Thromboplastin) is Released @ Sites of Tissue Injury
2) Tissue Factor (Factor III) (Thromboplastin) Activates Factor VII.
3) Factor VIIa Activates Factor X in the presence of Calcium.
(Common Pathway)
______________
Intrinsic Pathway: (12, 11, 9)
1) Endothelial Damage results in Leakage of Plasma Proteins and Exposure of Negatively Charged Collagen.
2) Hageman Factor (Factor XII) is Activated by the Exposed Negatively Charged Collagen.
3) Factor XIIa Activates Factor XI.
4) Factor XIa Activates Factor IX.
5) Factor IXa, together with Factor VIIIa, Activates Factor X.
(Common Pathway.
_______________
Common Pathway: (10, 2, 5, 1)
1) Factor X is Activated in the presence of Calcium by Factors IXa and VIIIa (Intrinsic) or Factor VIIa.
2) Factor IIa (Thrombin) Activates Factor V.
3) Factor Xa, with Factor Va, Activates Factor II (Prothrombin) in the presence of Calcium.
4) Thrombin (Factor IIa) Activates Fibrinogen (Factor I) to Fibrin (Factor Ia) in the presence of Calcium.
5) Thrombin (Factor IIa) also Activates Factor XIII in the presence of Calcium.
6) Factor XIIIa Cross-Links Fibrin into a Fibrin Clot.
Coagulation Inhibitors
**Endothelial Cells Play a Major Role in Balancing Coagulation.
Endothelial cells Produce *Heparin-like Molecules
_which Activate the Anti-Thrombins
*Antithrombin III:
_Inhibits Thrombin and Activated Factors IXa, Xa, and XIIa
Endothelial cells Produce *Thrombomodulin
_Activates Protein C and Protein S, which inactivate Factors Va and VIIa.
Fibrinolysis
= Destruction of the Fibrin Clot
Clotting and Fibrinolysis are Balanced at the inflammation site by Mediators.
Plasminogen is Activated by:
(1) Factor XII-Dependent Pathway
(2) **Plasminogen Activators, such as **t-PA, which is Produced by *Endothelial cells.
Inactive *Circulating **Plasminogen is Converted to **Plasmin.
**Plasmin then Degrades Fibrin into **Fibrin Split Products, such as the Fibrin-Derived **D-dimers.
_D-dimer Test measures amount of clotting. Excess D-dimer = Excess Clotting
Coagulation and Inflammation
Plasmin
_Splits Fibrinogen to FSP (Fibrinopeptides), which Increase Vascular Permeability and Chemotaxis.
_Plasmin can also Activate Factor XII
Thrombin Increases Leukocyte Adhesion and Fibroblast Proliferation.
Factor Xa Increases Vascular Permeability and Leukocyte Exudation.
Kinin System
Vasoactive Peptides Derived from *Plasma Kininogens (Produced in Liver) by Action of *Kallikreins.
_Liver Produces Prekallikrein, which transforms to Kallikrein upon Contact with Collagen from Denuded Vascular Endothelium.
Kinin and Coagulation Systems are intimately connected.
Factor XIIa converts Plasma Prekallikrein to Kallikrein, which Converts HMW Kininogen to **Bradykinin.
- *Bradykinin has Similar Effects to Histamine:
(1) Causes Arteriolar Dilation
(2) Increases Permeability of Venules
(3) Causes Smooth Muscle Contraction
(4) Causes Pain
Kallikrein is a Potent Activator of Factor XII, which is an Amplification Effect.
Kallikrein aids in Converting C5 to C5a, which is Chemotactic.
Complement System
Classic Pathway:
_Activated by IgG / IgM
_Starts @ C1, then C2 and C4
Alternate Pathway:
_Activated by Bacterial Products (Endotoxin)
_Starts at C3, aka **Properdin
Lectin Pathway:
_Activated by Bacterial Mannose Residues Binding to MBL.
Release of Complement Components Amplifies Inflammation:
1) Activation of **Anaphylatoxins **C3a and **C5a
_by Plasmin and Lysosomal Proteases,
_Causing Increased Vascular Permeability and Vasodilation
2) **C5a is **Chemotactic
_And Activates Cell Membrane Arachidonic Acid Pathway
_Also Increases Leukocyte Adhesion
3) **C3b is an **Opsonin
_Aids in Phagocytosis
4) **Membrane Attack Complex **C5-9
_Lyses Cells
Outcomes of Acute Inflammation
**Complete Resolution:
_Tissue Restored to Normal
**Healing and Fibrosis:
_Tissue is Damaged and is Repaired with Residual Fibrosis
**Abscess Formation:
__Collection of **Pus (= Death PMNs, Necrotic Tissue, Edema) Produced by Pyogenic Organisms (Staphylococci) when they are incompletely eradicated.
_*May Require *Drainage if Becomes **Walled Off (b/c difficult, then, for drugs to reach it)
**Ulceration:
_Necrosis of the Epithelial Lining
**Progression to Chronic Inflammation:
_Irritating agent persists
_Evolution to a Mononuclear Inflammatory Cell Infiltrate
(Lymphocytes and Monocytes)
Chronic Inflammation
= Inflammation of Prolonged Duration, *Weeks - Months,
in which Active **Inflammation, **Tissue Destruction, and **Repair Occur **Simultaneously.
*May Follow Acute Inflammation, but
very *Often it Begins *Insidiously as a *Low Grade *Asymptomatic Host Response.
Causes of Chronic Inflammation
1) **Persistent Infection
_By Microbes, such as Tubercle Bacilli,
_Evoking a Delayed Type Hypersensitivity (DTH) Immune Response
=> May take a **Granulomatous Pattern
2) *Prolonged Exposure to Non-Degradable Toxic Material,
Endogenous or Exogenous.
3) *Autoimmune Diseases
4) *Repeated Unresolved Episodes of Acute Inflammation.
Morphology of Chronic Inflammation
1) **Mononuclear Cell Infiltrate with **Macrophages, **Lymphocytes, and **Plasma cells.
_Some Neutrophils may be present.
2) **Tissue Destruction
_By Persistent Offending Agent and/or Inflammatory Response
3) **Healing with **Connective Tissue, **Angiogenesis, and **Fibrosis
_Replaces Damaged Tissue
4) **Scar Predominates over Tissue Destruction.
(Red Frame)
Chronic Inflammation Lasting for Months may demonstrate Neutrophils, which are characteristic of Acute inflammation.
In some forms of Chronic inflammation, Neutrophils may be Present in Large Numbers for a Long time, such as in Chronic Osteomyelitis.
Macrophages
**Macrophages are the Dominant Cell Players in Chronic Inflammation.
They are “Fixed” in Tissues of the Mononuclear Phagocyte System, aka Reticuloendothelial System:
Bone Marrow, Lymph Nodes, Liver, Spleen.
They are Present in almost All Tissues.
1) *1-2 Days After Inflammation Begins, *Monocytes Migrate to Extravascular Tissues and Differentiate into Macrophages.
2) They can Aggregate in areas of Inflammation from Months to Years.
3) *Macrophages Become Activated by
_ *IFN-gamma Produced by *Lymphocytes and NK cells,
_Bacterial Toxins,
_and other Inflammation *Chemical Mediators
4) Activated Macrophages:
_Enlarged,
_Increase their Lysosomal Enzymes,
_Increase their Ability for Phagocytosis,
_**Secrete Active Products that can **Produce Tissue Injury and Fibrosis,
a **HALLMARK of Chronic Inflammation.
__________________
Acute Inflammation:
_Irritant is Eliminated and Macrophages Disappear.
Chronic Inflammation:
_Irritant Persists
_Macrophages Accumulate:
(1) Monocytes are Recruited from the Circulation by Chemoattractants, such as C5a, PDGF, TGF-Alpha, Collagen, and Fibronectin Breakdown products.
(2) Monocytes are Immobilized by Inhibiting Factor (MIF) and Oxidized Lipids.
____________________
Macrophages Produce a *Large Arsenal of Mediators that Help to *Kill Microbes:
(1) *Some of these Produce *Tissue Injury:
**Reactive Oxygen and **Nitrogen Species, and
Extracellular Matrix **Proteases.
(2) Some are Cytokines Recruiting Additional Inflammatory Cells, such as IL-1 and TNF, which Attract Neutrophils and Cause Fever.
(3) **Others are Growth Factors Implicated in Repair that Induce **Angiogenesis and **Fibrosis.
Lymphocytes
Are Mobilized in Both Humoral and Cellular Immune Responses.
*Play an Important Role in Chronic Inflammation.
**Lymphocytes and **Macrophages interact in a ***Bidirectional Way.
Growth Factors and Cytokines Released by Activated Macrophages, such as **IL-1 and ***TNF, *Recruit More Lymphocytes and Inflammatory Cells.
Macrophages Present Antigen to T cells and Produce Costimulators and Cytokines, such as IL-12, that Stimulate T cells.
T cells Produce Cytokines, such as IFN-gamma, that Activate Macrophages.
Plasma Cells
Are Terminally Differentiated B cells that **Produce Immunoglobulines.
**Increase in Number as the **Inflammatory Process *Persists.
In some Persisting Chronic Inflammations, Macrophages, Lymphocytes, and Plasma cells assume the Appearance of a Lymphoid Organ.
Fibroblasts
**Fibroblasts Produce **Extracellular Matrix, **Including **Collagen and Fibronectin.
Fibroblasts are involved in the Repair process and in Walling Off the areas of Non-Resolving Inflammation.
Fibroblast Proliferation and Collagen Synthesis is Stimulated by Macrophage Products (TGF-Beta) *Leading to **Fibrosis = the **Most Important Complication of Chronic Inflammation.
Mast Cells
Small Numbers of Mast cells are Found in many tissues, Usually Perivascular.
They may participate in Acute or Chronic Inflammation.
They Express Surface IgE Fc Receptors.
_Circulating Basophils may have a similar Role.
Their Granules contain Preformed Mediators, such as Histamine, that are Released Upon IgE-Antigen Binding and Cross-Linking.
Eosinophils
Eosinophils participate in inflammatory reactions Mediated by IgE, including Parasitic Infections.
They contain **Major Basic Protein on their Granules, which is Toxic to Parasites and to Host Epithelia.
Eosinophils are Recruited by **Eotaxin.
Granulomatous Inflammation
= **Distinct Type of Chronic Inflammation
Characterized by Focal Accumulation of Macrophages
= **Granuloma.
Epithelioid Macrophages
_Are *Large Macrophages with *Abundant Pink Cytoplasm
_May Fuse to Become Multinucleated **Giant Cells
Additional Inflammatory cells, including a collar of *Lymphocytes With/Without *Plasma cells.
*Old ones are Frequently *Surrounded by *Fibrosis
_May even *Calcify = Dystrophic Calcification.
IFN-gamma
_Produced by T cells
_Transforms Macrophages into *Epithelioid and *Giant cells.
Granulomas Caused by:
_**Non-Degradable Foreign Material
_Or by **Insoluble Antigens,
such as those in TB Bacilli and in Fungi, which cause Necrotizing Caseating Granulomas.
Macrophages Engulf these Antigens and Present them to T cells.
Giant Cells
2 Types:
Foreign Body Granulomas:
_Reaction to Non-Degradable Particles:
=> Sutures, Silicon implants, Inorganic dusts like talc, etc.
Immune Granulomas:
_Reaction to Insoluble Antigens:
=> Infectious
=> Non-Infections
(1) Infectious Granulomas: _Very Often Contain Langhans Type Giant Cells _Produce Caseous Necrosis _Seen with many microbes, typically => Tuberculosis and Fungi
(2) Non-Infectious Granuloma:
_Prototype is **Sarcoidosis,
a disease caused by an unknown agent that is associated with
*Non-Caseating Granulomas in *Many Tissues.
__________________
Giant Cells may be Located Within the Granuloma or @ its Periphery:
_Foreign Body Type Giant Cells:
Nuclei are Scattered in Cytoplasm
_Langhans Type Giant Cells:
Nuclei are Lined up @ Periphery
_______________
Granulomas eventually Shrink and *Disappear or *Leave a *Small *Calcified *Scar.
Loss of Immunity May Lead to:
_Spread of Infection, or even
_Reactivation After Many Years of Quiescence
(Example: Mycobacteria latent hiding in lysosomes of phagocytes)
