Ch 3 Lect: Inflammation and Repair (Dobson) Flashcards
Define:
Inflammation
“Inflammation is a protective response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents”
What are the “5 R’s” of acute inflammation?
- Recognized
- Recruited
- Removed
- Regulated
- Repaired
What are the 5 hallmark signs of acute inflammation?
Rubor (redness)
Calor (heat)
Tumor (swelling)
Dolor (pain)
Loss of function
Features of Acute Inflammation
Onset?
Fast!!!
Minuites or hours
Features of Acute Inflammation
What is the Cellular Infiltrate?
NEUTROPHILS
Features of Acute Inflammation
Feature: Tissue injury, fibrosis?
Usually mild and self-limited
Features of Acute Inflammation
Feature: Local and systemic signs?
Prominent
Features of Chronic Inflammation
Feature: Onset?
Slow!!!
Days
Features of Chronic Inflammation
Feature: Cellular infiltrate?
Monocytes
Macrophages
Lymphocytes
Features of Chronic Inflammation
Feature: Tissue injury/fibrosis?
Otften severe and progressive
Features of Chronic Inflammation
Feature: Local and systemic signs?
Less than acute
Acute inflammation is one of the reactions of the type of host defense known as _______ immunity
Innate
Chronic inflammation is more prominent in the reactions of ________ immunity
Adaptive
What are the primary cells involved in recognition of foreign bodies?
Macrophages
Dendritic cells
Mast cells
What are dendritic cells?
Antigen presenting cells (APCs) that process antigen material and present it on the cell surface to the T Cells of the immune system.
They act as messengers between the innate and the adaptive immune systems.
Gain-of-function mutations in the sensor are the cause of rare diseases known as _______________
Autoinflammatory syndromes
–> Characterized by spontaneous inflammation
What is an effective treatment for autoinflammatory syndromes?
IL-1 antagonists
The inflammasome has been implicated in inflammatory reactions to?
- Urate crystals
- Lipids
- Cholesterol crystals
- Amyloid deposits in alzheimers
What are the three major components of an acute inflammation response?
- Dilation of small vessels leading to an increase in blood flow
- Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation
- Emigration of leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
What is exudate?
High protein and cellular content
What is transudate?
Low protein content, few cells
Inflammatory reactions are initiated, maintained and terminated by ___________
Mediators of inflammation
Table 3-4
Principal mediators of Inflammation
Mediator: Histamine
Source? Action?
Source: Mast cells, basophils, platelets
Action: Vasodilation, increased vascular permeability, endothelial activation
Table 3-4
Principal mediators of Inflammation
Mediator: Prostaglandins
Source? Action?
Source: Mast cells, leukocytes
Action: Vasodilation, pain, fever
Table 3-4
Principal mediators of Inflammation
Mediator: Leukotrienes
Source? Action?
Source: Mast cells, leukocytes
Action: Increased vascular permeability, chemotaxis, leukocyte adhesion and activation
Table 3-4
Principal mediators of Inflammation
Mediator: Cytokines (TNF, IL-1, IL-6)
Source? Action?
Source: Macrophages, endothelial cells, mast cells
Action: Local [endothelial activation]
Systemic [fever, metabolic abnormalities, hypotension (shock)]
Table 3-4
Principal mediators of Inflammation
Mediator: Chemokines
Source? Action?
Source: Leukocytes, activated macrophages
Action: Chemotaxis, leukocyte activation
Table 3-4
Principal mediators of Inflammation
Mediator: Platelet-activating factor
Source? Action?
Source: Leukocytes, mast cells
Action: Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Table 3-4
Principal mediators of Inflammation
Mediator: Complement
Source? Action?
Source: Plasma (produced in liver)
Action: Leukocyte chemotaxis and activation, direct target killing, vasodilation
Table 3-4
Principal mediators of Inflammation
Mediator: Kinins
Source? Action?
Source: Plasma (produced in liver)
Action: Increased vascular permeability, smooth muscle contraction, vasodilation, pain
Process of inflammation more prodominantly occurs in which of the following?
A) Arterioles
B) Venules
C) Lymphatics
A) Arterioles
B) Venules
C) Lymphatics
*Post capillary venules are the primary site where exudation occurs. Very thin layer allow materials to diffuse accross
What does this image reveal?
Lymphangitis
What are the 4 overarching steps of getting a leukocyte to travel from the circulation to the site of infection?
- Margination
- Rolling
- Adhesion to endothelium
- Diapedesis (transmigration)
What are the first two selections to become expressed by TNF and IL-1?
P-selectin
E-selectin
What is the major player involved in diapedesis/transmigration of the leukocyte across the endothelium?
PECAM-1 (CD31)
After the leukocyte has entered the tissue, what does it do to move toward the site of injury?
Utilizes chemotaxis
What is the major exogenous agent for chemotaxis?
N-formylmethionine
What are the major endogenous agents (3) for chemotaxis?
- Cyokines (eg. IL-8)
- Complement (C5a)
- Arachidonic acid (AA), mainly LTB4
What are the functions of integrins?
- Focal attachment
- Trigger signaling cascades
- Influence cell locomotion, proliferation, shape and differentiation
What are the different receptors involved in leukocyte activation?
- GPCRs
- Toll-like receptors
- Cytokine receptor
- Phagocytic receptor
The macrophage mannose receptor is a lectin that binds…
Terminal mannose and fructose residues of glycoproteins and glycolipids.
*These sugars are typically part of molecules found on microbial cell walls
The efficienty of phagocytosis is greatly enhanced when microbes are __________
Oponized
What are the major opsonins?
IgG Antibodies
C3b breakdown product of complement
Mannose-binding lectin
Killing of microbes is accomplished by ______________
Reactive oxygen species (ROS)
Primary granules contain?
Aka?
Large or small?
MPO
Azurophil granules
Large
What is this slide revealing?
Toxic granulation
–> Seen in patients with sepsis
–> Toxic granulations are dark coarse granules found in granulocytes, particularly neutrophils
What is an alternative way that infections are contained?
Use of Neutrophil extracellular traps (NETs)
These NETs prevent the spreading of microbes by trapping them in fibrils
Prostaglandins and leukotrienes are produced from?
Arachidonic acid (AA)
What is the mechanism of aspirin?
Functions to inhibit cyclooxygenase enzyme so that prostaglandins are not produced
What do COX inhibitors inhibit?
Cyclooxygenase
(prostaglandin production)
What are the major cytokines involved in acute inflammation?
TNF
IL-1
IL-6
Chemokines
IL-17
Acute Inflammation
What is the source and action of TNF?
Source: Macrophages (primarily), mast cells, T lymphocytes
Action: Stimulates expression of endothelial adhesion molecules and secretion of other cytokines (systemic effects)
Acute Inflammation
What is the source and action of IL-1?
Source: Macrophages (primarily), endothelial cells and some epithelial cells
Actions: Similar to TNF; endothelial activation (initiation of P and E selectin release) and greater role in fever
Acute Inflammation
What is the source and action of IL-6?
Source: Macrophages, other cells
Actions: Systemic effects (acute phase response)
Acute Inflammation
What is the source and action of Chemokines?
Source: Macrophages, endothelial cells, T lymphocytes, mast cells and others
Actions: Recruitment of leukocytes to sites of inflammation; migration of cells in normal tissues
Acute Inflammation
What is the source and action of IL-17?
Source: T lymphocytes
Action: Recruitment of neutrophils and monocytes
What are the primary cytokines involved in chronic inflammation?
IL-12
IFN-gamma
IL-17
Chronic Inflammation
What is the source and action of IL-12?
Source: ANTIGEN PRESENTING CELLS!!! Dendritic cells, macrophages
Actions: Increased production of IFN-gamma
Chronic Inflammation
What is the source and action of IFN-gamma?
Source: T lympocytes, NK cells
Action: Activation of macrophages
Chronic Inflammation
What is the source and action of IL-17?
Source: T lymphocytes
Actions: Recruitment of neutrophils and monocytes
___ and ___ serve critical roles in leukocyte recruitment by promoting adhesion of leukocytes to endothelium and their migration through vessels
TNF
IL-1
__________________ have been remarkably effective in the treatment of chronic inflammatory diseases; particularly rheumatoid arthritis
TNF antagonists
What do complement proteins
C5a, C3a and C3b
do?
C5a and C3a = Add to the inflammatory response
C3b=Phagocytosis, acts as an opsonin
What disease is associated with inhibiting C1 in the complement pathway?
C1 inhibitor blocks the activation of C1 that leads to hereditary angioedema
What is paroxysmal nocturnal hemoglobinuria (PNH) associated with?
Decary accelerating factor (DAF)
What are the principal mediators of:
Vasodilation?
Histamine
Prostaglandins
What are the principal mediators of:
Increased vascular permeability?
Histamine
Serotonin
C3a
C5a
Leukotrienes C4, D4, E4
What are the principal mediators of:
Chemotaxis, leukocyte recruitment and activation?
TNF
IL-1
Chemokines
C3a, C5a
Leukotriene B4
What are the principal mediators of:
Fever?
IL-1
TNF
Prostaglandins
What are the principal mediators of:
Pain?
Prostaglandins
Bradykinin
What are the principal mediators of:
Tissue damage?
Lysosomal enzymes of leukocytes
Reactive oxygen species (ROS)
What are the morphologic patterns of acute inflammation?
- Serous inflammation
- Fibrinous inflammation
- Purulent (suppurative) inflammation/abscess
- Ulcer
Serous inflammation is marked by exudation of ___________ into spaces created by cell injury or into body cavities lined by the peritoneum, pleura or pericardium.
This is termed an: ________
Cell-poor fluid
Effusion
When does a fibrinous exudate develop?
When vascular permeability allows large molecules such as fibrin to pass out of the blood
or
There is a local procoagulant stimulus (malignant cells)
Where is fibrinous exudate characteristically found?
Lining body cavities
What is purulent inflammation?
Produces pus; an exudate consisting of neutrophils, the liquefied debris of necrotic cells and edema fluid
What is an ulcer?
A local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing of inflamed necrotic tissue
What is the
Onset, Cellular infiltrate, Tissue injury and local/systemic signs of
Chronic inflammation?
Onset: Slow/days
Cellular infiltrate: Monocytes/macrophages and lymphocytes
Tissue injury: Often severe and progressive
Local/systemic signs: less than acute
Monocytes have MANY names based on where they are:
State the name based on the location:
Circulating in blood =
In tissue=
Liver macrophages=
Spleen/lymph node=
CNS=
Lungs=
Skin=
Circulating in blood = Monocytes
In tissue= Macrophages
Liver macrophages= Kupffer cells
Spleen/lymph node= Sinus histiocytes
CNS= Microglial cells
Lungs= Alveolar macrophages
Skin= Langerhans cells
Identify the labeled cells
Classically activated Macrophage (M1)
What are the activated by?
What are they inhibited by?
What are the downstream events upon activation?
Activated: Microbes, IFN-gamma
Inhibited: IL-13, IL-4
Downstream: Inflammation, phagocytosis
Alternatively activated Macrophage (M2)
What are the activated by?
What are they inhibited by?
What are the downstream events upon activation?
Active: IL-13, IL-4
Inhibited: Microbes, IFN-gamma
Downstream: Tissue repair, fibrosis, Anti-inflammatory effects
Eosinophils
Eosinophils have granules that contain _____________
Major basic protein
What is this and what are the components?
Necrotizing granuloma
Name examples of diseases with granulmatous inflammation:
- Tuberculosis
- Leprosy
- Syphilis
- Cat-scratch disease
- Sarcoidosis
- Crohn disease
What are acute-phase reactants?
“Plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred-fold as a part of the response to inflammatory stimuli”
What are 4 examples of acute-phase reactants?
- C reactive protein (CRP)
- Fibrinogen
- Serum amyloid associated protein (SAA)
- Hepcidin
What is the most abundant cell type in the blood?
Neutrophils
(40-70%) of blood composition
What is the least abundant cell type in the blood?
Basophils
(0-1%)
What does a left-shift refer to?
A left shift is related to an accelerated release of cells from the bone marrow post mitotic reserve pool and is therefore associated with a rise in the number of more immature neutrophils in the blood = left shift
_____________ is the process of new blood vessel development from existing vessels. It is critical in healing at sites of injury.
Angiogenesis
What is the major player in the deposition of connective tissue?
TGF-beta
Which method of “intention” allows for the best healing?
First intention
