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
