1
Q
What is inflammation?
A
Definition: A complex reaction of vascularized tissue to infection or cell injury that involves extravascular accumulation of plasma proteins and leukocytes. Although inflammation serves a protective function in controlling infections and promoting tissue repair, it can also cause tissue damage and disease.
2
Q
What are the four “cardinal” signs of inflammation?
A
- Redness
- Swelling
- Heat
- Pain
3
Q
Is inflammation a good thing or a bad thing?
A
Inflammation is a good thing! It can get out of hand though, if your body can’t fight off the infection - you will have chronic inflammation which can be problematic
4
Q
What is the purpose of inflammation?
A
Purpose
- Remove the pathogen - whatever is offending you
- Remove injured tissue
- Institute wound healing (or scar tissue if the tissue cannot be repaired)
5
Q
What would happen without inflammation?
A
Without inflammation, infections would go unchecked and wound healing would not proceed
6
Q
What is acute inflammation?
A
Acute inflammation
- Accumularion of fluid and neutrophils
- The course of inflammation will be measured in hours or days, but not longer than that
7
Q
What is chronic inflammation?
A
Chronic inflammation
- The offending agent cannot be removed during acute inflammation
- You will find the presence of lymphocytes and macrophages (means you are “eating” things, but you can’t get rid of them)
- The course will be weeks, months or years
8
Q
What is the goal or resolution of inflammation?
A
Resolution
- Removing any of the offending agents and restoring normal tissue architecture
9
Q
What is an abscess?
A
If your body can’t get rid of the infection, you will form an abscess
- “Walled off” collection of pus
- Pus - neutrophils and necrotic debris
- This occurs when the body cannot rid itself of the inciting agent
10
Q
What is scarring?
A
Scarring
- Tissue is irreversibly injured in spite of the elimination of the offending agent
11
Q
When would chronic inflammation occur?
A
When acute inflammation is unable to remove the offending agent
12
Q
What is the process of acute inflammation?
A
Acute inflammation
- Mast cells are released upon injury, pathogen introduction, C5a exposure, heat or cold
- Mast cells will then produce inflmmatory mediators, such as granules of histamine or prostaglandins
13
Q
What are biogenic/vasoactive amines? What do they do?
A
14
Q
What is the effect of vasodilation?
A
Vasodilation
- Occurs by NO
Increased blood flow causes the heat and redness characteristics of inflammation
15
Q
What does the lipid mediator of inflammation do?
A
Causes the pain
- Also a cardinal sign of inflammation
- Lipid mediators bind to receptors on smooth muscles, also act as vasodilators
- This is what causes the pain
16
Q
What can be done to prevent the pain associated with inflammation?
A
NSAIDS (e.g. aspirin)
17
Q
Are lipid mediators of inflammation part of a rapid or delayed response?
A
Rapid response
- You know this because you know pain with inflammation starts right away… That is how your body tells you that something is wrong so you can respond accordingly and protect the injured area
18
Q
what does an injury do to the tissue?
A
Injury → Microbes are introduced
- Triggered activation of complement cascade
- Degranulated the mast cell
- Release histamine, prostaglandin
- Exposes the basement membrane
- Activates Hageman factor (Factor XII)
19
Q
What leads to the cardinal signs of inflammation - pain and edema?
A
KININOGEN which leads to BRADYKININ → pain and edema
20
Q
What cotributes to vasodilation?
A
- Prostaglandins
- Nitric oxide
- Histamine
21
Q
What contributes to the increased vascular permeability?
A
Histamine and bradykinin
22
Q
What contributes to the fever?
A
Prostaglandins
23
Q
What contributes to the pain?
A
Prostaglandins and bradykinin
24
Q
Prostaglandins do a lot of things in the inflammatory response. What are they?
A
Prostaglandins
- Vasodilation
- Fever
- Pain
25
What is the role of histamine, TNF and IL-1 in acute inflammation?
Upregulate adhesion molecules for leukocytes on the endothelium
26
What is the role of C3a and C5a in acute inflammation?
Stimulate chemotaxis toward the site of inflammation
27
What are the first cells to arrive at the site of infection?
Neutrophils
* The first line of defense against bacteria/yeast pathogens
* Within 6-24 hours, neutrophils get phagocytic cells to the tissue
* Neutrophils are able to detect changes on the endothelium when infection is present
* They don't live very long (approx. 24 hours) before undergoing apoptosis
28
What is neutrophil rolling?
Neutrophil rolling
* As neutrophils are circulating, they are "rolled" or "tethered" to the endothelium at the site of infection due to the factors present during infection
* **P-selectin** will bind to the neutrophil's **P-selectin glycolipid-1 (PSGL-1)**
* The interaction between the two has a fairly low affinity, but it still causes the neutrophil to slow down so that it can be tethered to the infection site
29
After neutrophil rolling (slow down, tether to site), neutrophil binding occurs. What is the process?
30
After the neutrophil has completely stopped moving, it must undergo neutrophil extravasation... What does this mean?
Neutrophil extravasation
* The neutrophil _squeezes between the endothelial cells_ and penetrates the _basement membrane_ using surface expressed _MMPs_
* In this step, both the endothelial cells of the tissue and the neutrophil express **PECAM-1**
31
How induces PMNs to migrate toward the site of inflammation?
Chemotaxic substances
* Chemokines bind proteoglycans to form a solid matrix gradient
* PMNs phagocytose extracellular bacteria to prevent spread
* PMN’s release toxic substances that damage host tissue and increase inflammation.
32
This is long, but a really good review of everything we just went through...
Summary
33
What are PMNs?
Also called **granulocytes** - they are a category of **white blood cells** characterized by the presence of granules in their cytoplasm.
* Also called **_p_**oly**_m_**orpho**_n_**uclear leukocytes (PMN) because of the varying shapes of the nucleus, which is usually lobed into three segments
* The term _polymorphonuclear leukocyte_ often refers specifically to _neutrophil granulocytes_, the most abundant of the granulocytes
34
When do PMNs (neutrophil granulocytes) predominate?
In the early inflammatory response - they are later replaced by macrophages
35
What are two of the "problem resolving" skills that macrophages have at the site of infection?
Macrophages
* Anti-microbial activity (M1)
* Anti-inflammatory/pro-resolvign activity
36
We know that monocytes are activated to become macrophages at the site of infection, but what induces this?
Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-gamma
* Recall that IFN-gamma or Interferon gamma is a dimerized soluble **cytokine**
37
How long after the start of inflammation will monocytes and macrophages become the predominant cell type?
24-48 hours
38
What is the job of macrophages?
Macrophages ingest cellular debris such as dead or damaged tissue cells and dead PMN’s (granulocyte neutrophils) to aid in restoring normal tissue architecture.
39
Macrophages secrete **transforming growth factor-beta.** What does this do?
**Transforming growth factor-beta**
* Initiates the wound healing process by inducing the _migration of fibroblasts_ to the site and their subsequent proliferation
* Stimulates the _secretion of collagen_ (scar tissue)
40
In chronic inflammation, what is the timing of tissue destruction and healing?
This is tricky... _Inflammation_, _tissue destruction_ and _healing_ are all happening *simultaneously*.
41
What conditions predispose individuals to chronic inflammation (3)?
1. Persistent infections
* *Myobacterium tuberculosis*
* *Treponema pallidum*
* Some fungal pathogens
2. Chronic exposure to toxic angents
* Silicosis ("miner's lung" - inhaling dust)
3. Autoimmune disease
* Rheumatoid arthritis
* Lupus
42
There are three "hallmarks" of chronic inflammation. What are they?
## Footnote
***Hint**: they match up with the three processes that are taking place during chronic inflammation: inflammation, destruction, healing*
1. Infiltration of _macrophages_ and _lymphocytes_ **(inflammation)**
2. _Tissue destruction_ mediated by macrophage enzymes such as **(****destruction)**
* Elastase
* Collagenase
* Phosphatases
* Lipases
3. Attempts at _healing_ are still proceeding **(healing)**
* Antiogenesis
* Fibrosis
43
What is the systemic effect of inflammation?
Sepsis
44
What is sepsis? What symptoms will be observed?
Sepsis
* When a pathogen gains entrance into the bloodstream
* This can occur during a severe local injury where inflammatory mediators may be released into the bloodstream
Symptoms
* Fever
* Neutrophilia
* Acute phase response
* Shock
45
Why is a fever both a good thing and a bad thing?
Fever
* May enhance the immune system function
* Can also cause septic shock - can be lethal
46
We've been talking about TNF, IL-1 and IL-6 a lot today... What are they?
They are all **cytokines**
* Cytokines work in the process of **inflammation**
**TNF**
* Tumor necrosis factors (or the TNF family) refer to a group of **cytokines** that can _cause cell death_ (apoptosis)
**IL-1**
* The Interleukin 1 family (IL-1 family) is a group of 11 **cytokines**, which plays a central role in the _regulation of immune and inflammatory responses_ to infections or sterile insults
**IL-6**
* Interleukin 6 (IL-6) is an interleukin that acts as both a _pro-inflammatory_ **cytokine** and an _anti-inflammatory_ myokine
47
In a little more detail, what are the advantages of a fever?
Fever
* The immune system functions more effectively at higher-than-normal body temperatures
* Host cells are someone protected from the deterious effects of the TNF-alpha (tumor necrosis factor-alpha) at elevated temperatures
* Pathogens grow poorly at elevated temperatures
48
What do cyclooxygenases do? What is an example of one of them?
Cyclooxygenase
* Blocks prostaglandin E2 synthesis
* Therefore reduces the fever
* Example: aspirin
49
What is neutrophilia?
Neutrophilia
* A state of _increased neutrophils in the peripheral blood_
* This commonly accompanies _acute inflammation_
* It means that there is an accelerated rate of release of _PMNs_ (granular neutrophils) from the bone marrow due to high signals from _IL-1_ and _TNF_
* Also, sustained release by macrophages and T lymphocyte-derived release of granulocyte colony stimulating factor
50
What is the acute phase response?
Acute phase response
* This occur during systemic inflammation (sepsis) as a result of _macrophage-derived interleukin-6 acting on hepatocytes_ to synthesize and release the _acute phase proteins_
* Acute phase proteins such as _C-reactive protein (CRP)_ act as opsonins that facilitate _phagocytosis_ and clearance of pathogens
51
What is the consequence of an increased level of acute phase proteins?
Consequences
* An elevation in the erythrocyte sedimentation rate (ESR)
* Mostly, this just means that an increase in ESR indicates acute inflammation
* CPR can also indicate acute inflammation because it is released into the blood stream as well
52
So, what two things can be tested for in the blood and indicate a state of acute inflammation?
1. Increased C-reactive protein (CPR) - released from the liver
2. increased erythrocyte sedimentation rate (ESR) - due to increased CPR
53
What is the effect of severely high levels of TNF in the bloodstream during sepsis or severe injury?
Shock
54
What happens during a state of shock in the body? There are three main things.
Shock
* Systemic vasodilation with increased vascular permeability leads to a blood volume loss → hypotension
* Systemic activation of the coagulation system (DIC) leads to multi-system organ failure and serious bleeding
* Can cut off blood supply to organs
* Death may result
