Palmer General Pathology Section 2: Inflammation and Repair

Why is inflammation important?

Kills and eliminates microbes

Removes debris

Initiates repair

What are the 2 types of immune cells? What is the difference?

Sentinel cells - Already in tissues (EX: Macrophages, mast cells, dendritic cells)

White Blood Cells/Leukocytes - In circulation and must leave to enter tissues (Lymphocytes, monocytes, neutrophils, eosinophils, and basophils)

Inflammatory Mediators Chemicals are released by what cells?

Immune cells

Where are Mass cells located? What is their function in regards to inflammation?

Location: System wide in connective tissues

Function: Releases histamine. Associated with allergic response

Where are Macrophages cells located? What is their function in regards to inflammation?

Location: Free moving through tissue OR fixed within specific organ

Function: Perform phagocytosis, present antigens to T-cells, and release cytokines (TNF)

Where are Neutrophils cells located? What is their function in regards to inflammation?

Location: Within blood vessels

Function: Perform phagocytosis, MOST ABUNDANT, short lived (< 1 day), response to bacteria

Where are Dendritic cells located? What is their function in regards to inflammation?

Location: In most tissues

Function: Present antigens to T-cells, perform phagocytosis

What is the source of Histamine? What is its function?

Source: Mast cells

Function: Vasodilation, increase vascular permeability (allergies)

What is the source of Cytokines (TNF, Interleukins, etc)? What is its function?

Source: Macrophages and activated lymphocytes

Function: Endothelial activation, stimulate fibroblasts, protein catabolism (muscle atrophy)

What is the source of Leukotrienes? What is its function?

Source: Macrophages, mast cells, neutrophils

Function: Increase vascular permeability, chemotaxis, WBC adhesion

What is the source of Prostaglandins? What is its function?

Source: Macrophages, Mast cells, and endothelial cells

Function: Pain, fever, and vasodilation

A monocyte which leaves the blood stream is now named what?

A Macrophage

What stimulus triggers inflammation?

Injury to normal vascular tissues

What are the 5 cardinal signs of inflammation?

Heat - Due to Vasodilation

Redness - Due to vasodilation

Swelling - Due to increased vascular permeability

Pain - Due to stimulation of chemo-nociceptors

Loss of function

What are the 5 R's of inflammation?

1. recognition of injurious agent

2. recruitment of leukocytes

3. removal of agent

4. regulation of response

5. resolution (repair)

What is acute inflammation?

Rapid onset - Minutes to hours

Short duration

Cardinal signs present - Local and systemic signs. NO FIBROSIS (AKA Scar tissue)

Neutrophils present

What is chronic inflammation?

Slow onset

Longer duration

Few signs, angiogenesis, and fibrosis

Macrophages and lymphocytes present

In what 2 ways does the body recognize a stimulus in Acute Inflammation?

1. Recognition of non-self (pathogens or damaged cells) - PAMPS (in plasma membranes and endosomes)

2. Recognition of damage - DAMPS (Released from dying cells)

What things, when out of place in a cell, indicate damaged or dying cells?

Uric acid, ATP, decreased potassium, DNA

DAMPs stimulate damaged cells to release what? What does this do? What is this a major implication for?

IL-1

Induces inflammation and recruits inflammatory cells to the area

Implication for inflammatory diseases like Rheumatoid arthritis, lupus, etc.

What are the 2 steps in the inflammatory process?

1. Recognition of damage

2. Vascular change

What are the 3 types of vascular change?

1. Vasoconstriction

2. Vasodilation - to increase blood flow (which may make the area red and warm)

3. Increased vessel permeability - which can lead to edema and also increase blood viscosity

What are the 3 mechanisms of increasing vascular permeability?

1. Endothelial contraction - Gaps in postcapillary venules which respond to histamine

2. Endothelial necrosis - Which are leaky until repaired. Seen with burns, severe infections and even radiation

3. Angiogenesis - New vessels are made and have immature (leaky) endothelia. Seen in tissue repair and tumors

Where does vasodilation occur?

In the arterioles

Where does increased permeability occur?

In the venules

What is exudate edema?

Protein rich acute inflammation

What is Transudate edema?

Protein poor inflammation

When does edema occur?

When lymphatic drainage can't keep up. May transport microbes or cellular debris

What is Lymphadenopathy?

Disorder of Lymph Nodes

What is Lymphadenitis?

Inflamed lymph nodes. Increased size and pain

What is Lymphangitis?

Inflamed lymphatic channel. Causes a red streak on the surface of skin

What are the steps for leukocytes exiting vasculature?

1. Margination and rolling - Via selectins

2. Firm adhesion - Via integrins

3. Diapedesis (AKA Transmigration, extravasation, emigration) - Process of WBC squeezing out of the vessel

4. Chemotaxis - WBC travelling external to blood vessel to where it needs to go

What are neutrophils replaced by?

Macrophages and lymphocytes

What is "Leukocyte Activation?"

Stimulated by microbes, necrotic tissues, or foreign bodies

What are the 2 components in Phagocytosis?

1. Opsonization

2. Engulfment and degradation

What is opsonization?

Targeting or labelling a cell for destruction

What are opsonins?

Antibodies (IgG) and Complement proteins which enhance macrophages binding and breakdown

What are symptoms Acute-Phase Reaction of inflammation?

Fever - Via pyrogens, which lead to prostaglandin synthesis, which stimulates the hypothalamus to increase body temp

Elevated plasma proteins - Cytokines stimulate increased C Reactive Protein (CRP), increased fibrinogen, and increased Erythrocyte Sedimentation Rate (ESR)

What are the 2 inflammatory mediators?

Prostaglandins - Pain and fever

Substance P - Pain, neurotransmitter

What is the Normal Leukocyte count?

4500-10,000

What is leukocytosis?

When there are more than 10,000 leukocytes in blood

>Typically 15k-30k

Shift to the left

Depends on the infection:

>Bacterial has increased neutrophil counts

>Viral has increased lymphocyte count

What is a Leukemoid reaction?

Extreme leukocytosis

>Leukocyte count of 40k-100k

>Chronic inflammation

>Mimics leukemia

What is Leukopenia?

low leukocyte count

Under 4000 leukocytes

Seen in: HIV, Chemotherapy, and radiation therapy

What are the 6 patterns of inflammation?

1. Serous - blister

2. Fibrinous - scarring

3. Suppurative - pus, abscess

4. Ulcerative - peptic ulcers, canker sore

5. Pseudomembranous - C-diff

6. Granulomatous

What is serous inflammation?

"Blister"

Serum accumulates in or below epidermis

Seen in burns, viral infections, and autoimmunity

What is Fibrinous inflammation?

Seen in severe injury, which increases vessel permeability.

Fibrin rich exudate (Keep in mind fibrin is used in clotting and scarring)

What is a Suppurative AKA Purulent inflammation?

Pus forming local infection.

What is pus?

Neutrophils, necrotic cells, and edema

What is an abscess?

Pus acucmulation

What is ulcerative inflammation?

Superficial area of necrosis

What is pseudomembranous inflammation?

Formed on a mucosal surface and a membranous film composed mainly of fibrin, pus and necrotic cells

What is granulomatous inflammation?

Pattern of chronic inflammation.

>Build up of macrophages

What are the 3 outcomes of acute inflammation?

Resolution (Regen and repair) - Minimal injuries in cells which can replicate. Tissue returns to normal

Chronic inflammation - Severe injury or low ability to replicate. Failure to remove affecting agent. Frequent scarring

Scarring (Fibrosis) - Tissues can't replicate. Alters function

Unresolved inflammatory reactions can lead to what things?

Persistent infection/injury

Immunosuppression

Hypersensitivity

What are some features of chronic inflammation?

Mononuclear leukocytes, tissue destruction, angiogenesis and fibrosis (Scarring and clotting)

What are the 2 types of macrophage activation? Describe each

Classically active: Microbial, inflammation, and stimulate inflammation

Alternatively activated: Anti-inflammatory, tissue & wound repair, inhibit inflammation

What is lymphocytes role in chronic inflammation?

Sustain chronic inflammation

What is macrophages role in chronic inflammation?

Dominant cell at areas of inflammation

Phagocytosis of microbes and injured cells

Initiate angiogenesis and fibrosis

What are the 2 mechanisms of tissue repair?

Regeneration: Replace damaged cells

Scarring: Deposit fibrotic tissue to severely damaged cells which cannot divide/proliferate

What are labile cells?

Cells which constantly divide such as skin and epithelia

What are stable cells?

Capacity to repair but aren't constantly dividing

What is fibrosis/scarring?

Abnormal/extensive collagen deposition

Occurs following:

>Chronic inflammation

>Death of terminally differentiated cells

In myocardial infarction, what is an "infarct"?

A site which will result in fibrosis

When do scars form?

When tissues can't regenerate due to:

>Severe damage

>Prolonged injury

>Injury to terminally differentiated cells

What are the 4 steps in scar formation?

1. Angiogenesis - Generation of capillaries

2. Fibroblast migration & proliferation - build fibrous tissue

3. Collagen deposition

4. Remodeling

How long does it take for granulation tissue to develop? What does it contain?

3-5 days

Contains fibroblasts, WBC's, capillaries, and connective tissue

Macrophages secrete ________ which then activates ________ .

GF's; Fibroblasts

True or false, scars are always vascular

False, initially they are vascular. Later the become progressively avascular, hence why they get a pale colour

How is connective tissue remodeled?

Continually remodeled by a Balance between ECM synthesis and breakdown

What are Matrix Metalloproteinases (MMP's)? What does it break down? What is it produced by? What is its cofactor?

Breakdown collagen

Produced by: Fibroblasts, macrophages, neutrophils, and epithelial cells

Cofactor: Zinc ions

What are keloids? What descent of people are these more common with?

Scarring beyond boundaries of wound due to excessive granulation tissue and excessive collagen

African people

What factors impair healing?

Infection -> Which prolongs inflammation

Nutritional deficiency -> Specifically vitamin C, which decreased the basement membrane and makes vessels fragile

Glucocorticoids (Steroids) -> Reduce fibroblast activity

Poor perfusion - Reduced arterial supply and reduced venous drainage

Increased age, mechanical pressure, anemia, UV light, etc.

The healing of skin wounds is the combination of? What are the phases?

Epithelial regeneration and fibrosis