Inflammation and healing: repair

Created by mcalderone06 

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What are the 3 potential outcomes when a cell is injured?

1. Adaption
2. Resolution/Repair
3. Death of the organism

Healing of injured cells begins with what and ends with what?

Healing of injured cells begins with inflammation and ends with repair.

What is repair? Damaged tissue may consist of what? Mechanisms of repair involve what?

The process by which damaged or dead tissue is replaced by normal issue.

The damaged tissue may consist of only parenchymal cells or a combination of cells and the connective tissue framework of an organ.

Mechanisms of repair involve:
-- the migration, proliferation and differentiation of cells
AND
--the interaction of cells with the extracellular matrix.

What is regeneration? What serves as scaffolding? Give an example. What happens in terms of repair if regeneration cannot occur?

The reparative process by which injured or dead cells are replaced by replicating cells of the same type.

It is assumed that the connective tissue frame work of the organ is intact and serves as "scaffolding" for the orderly replacement of parenchymal cells.

(Example: mild viral hepatitis).

If regeneration can not occur, fibrosis can occur instead.

What is fibrosis? In what 2 types of defects does it occur?

Replacement by connective tissue -- a reparative process by which a defect in tissue is replaced by fibrous tissue (scar).

The defect in the organ involves either
a. Destruction of the connective tissue framework along with parenchymal cells. (example: lung abscess) or
b. Parenchymal cells which can not regenerate. (example: necrosis of myocardium).

What collagen type is formed in most organs for fibrosis?

Type I

Why might patients with vitamin C or nutrition deficiencies have issues with repair?

They can't form Type I collagen necessary for fibrosis/scarring

Do regeneration and replacement occur together or separately? Why? Give an example

Regeneration and replacement by connective tissue often occur SIMULTANEOUSLY in the repair of a disease organ

Because parenchymal cells and connective tissue have been destroyed.

(example: skin laceration).

Classification of cells is based on what? Growth of cells reflects a balance between what? What are the 3 classes of cells? In which cells do you see the most and least fibrosis?

Their ability to regenerate: all normal cells may be grouped into three categories based on their ability to respond to growth stimulation and to regenerate:

Stimulating and inhibiting chemical signals.

3 classes of cells:
1) Labile cells - least fibrosis
2) Stable cells
3) Permanent cells - most fibrosis

What are "labile cells?" Give an example.

Continuously divide.
Examples: Epithelium of skin and mucous membranes; hematopoietic cells.
NOTE: since regeneration happens very easily, you don't get as much fibrosis unless there is MAJOR damage

What are "stable cells?" Give an example.

Low level of replication but rapidly divide when stimulated.

Example: Parenchymal cells of the liver and kidney; fibroblasts, smooth muscle cells, endothelium.

What are "permanent cells?" Give an example.

Permanent cells: Nondividing

Examples: cardiac muscle, skeletal muscle
Note: since regeneration does not happen, you see a lot of fibrosis in response to injury

What are the 4 components of repair?

1. Angiogenisis- Formation of new blood vessels.
2. Migration and proliferation of fibroblasts.
3. Formation and deposition of extracellularmatrix (by fibroblasts).
4. Maturation and organization of the fibrous tissue elements.

What are the two ways that angiogenesis can occur? Regardless of initiating mechanism, vessel maturation (stabilization) involves what?

1) Mobilization of endothelial precursor cells (EPCs) from the bone marrow and from pre-existing vessels (capillary growth):
--EPCs are mobilized from the bone marrow and may migrate to a site of injury or tumor growth --> differentiate & form a mature network by linking with existing vessels.

2) Angiogenesis from pre-existing vessels: Endothelial cells from these vessels become motile and proliferate to form capillary sprouts

Stabilization involves the recruitment of pericytes and smooth muscle cells to form the periendothelial layer.

Targeted mutations in VEGF result in what?

defectie vasculogenesis and angiogenesis

Where is VEGF produced?

Expressed at low levels in a variety of adult tissues

Expressed at higher levels in a few sites, such as podocytes in the glomerulus and cardiac myocytes

What are the main inducing agents of VEGF?

1) HYPOXIA****
2) TGF-B, PDGF, TGF-a

What are the receptors for VEGF? Where are they found?

VEGF-R1, VEGFR-2
restricted to endothelial cells

What are the functions of VEGF?

1) promotes angiogenesis***
2) Increases vascular permeability** (Ex - scabs are leaky)
3) Stimulates endothelial cell migration
4) Stimulates endothelial cell proliferation
5) Selectively induced hyperplasia of lymphatic vasculature (VEGF-C)
6) Upregulates endothelial expression of plasminogen activator, plasminogen activator inhibitor -1, tissue factor and interstitial collagenase

What is granulation tissue? What does it consist of? How does it appear to the naked eye? When is it present?

Specialized tissue that fills in defects within organs when non-regenerative cells and/or connective tissue framework is destroyed during a disease process.


Granulation tissue consists of proliferating fibroblasts laying down immature connective tissue elements and proliferating (new) blood vessels.

The tissue appears red and edematous to the naked eye.

It is only present during healing or an attempt to heal destroyed tissue.

What is organization? What is its purpose?

Organization is the process of transforming granulation tissue into dense scar.

With time, granulation tissue changes as the connective tissue elements, such as collagen, mature, and blood vessels become less prominent

Purpose: Need to check the initial vascular proliferation that occurs so that healing can take place. Persistent granulation tissue impedes healing.

Look at the ratio of what can tell you what stage of healing you're in?

Look at the ratio of blood vessels to collagen deposition. The more cross-linking of collagen, the greater strength of the scar.

What needs to happen to collagen in order for healing?

Cross-linking -- not just deposition. The more cross-linking of collagen, the greater strength.

Type I collagen is found where? Type IV collagen?

1) bundles of banded fibers with high tensile strength-- found in skin, bone, tendon and other organs
2) amorphous - found in ALL basement membranes

What are the steps in wound repair of a laceration?

a. Injury produces a defect in skin --> incites an inflammatory reaction.
b. Blood clot (fibrin and fibronectin).
c. Epithelium regenerates and migrates to cover the defect.
d. Cells (fibroblasts, myofibroblasts, macrophages) proliferate and migrate into the deflect (filled with clot).
--Macrophages remove debris, such as dead cells, and secrete cytokines.
--Fibroblasts, under chemical mediation, produce extracellular connective tissue matrix.
--Myofibroblasts contact the wound.
e. Simultaneously, capillaries (endothelium) at the edge of the defect proliferate and extend into the defect under the influence of chemical mediation.
f. Over time (weeks to months) the defect filled with granulation tissue becomes remodeled into mature collagen (scar) and parenchymal cells. The wound acquires strength through this process (vitamin C required).

Which cells remove debris and secrete cytokines during healing? Which produce extracellular connective tissue matrix? Which contract the wound?

--Macrophages remove debris, such as dead cells, and secrete cytokines.
--Fibroblasts, under chemical mediation, produce extracellular connective tissue matrix.
--Myofibroblasts contact the wound.

What is required for remodeling of granulation tissue into scar and parenchymal cells?

Vitamin C -- necessary for the wound to acqurie strength

For healing by first intention/primary union, how does the wound appear? Is it contained?

How does the surgeon decrease size of the defect? What is the purpose of these maneuvers?

When are sutures removed?

What types of wound heal this way?

The skin wound is generally clean and seen by a physician within a few hours of the injury & defect is generally limited in the amount destroyed tissue.

cleansing --> debridement --> closure of gap with sutures
This allows for the healing process to proceed rapidly and without complications.

Although weeks to months may pass before the healing process is complete, sutures will usually be removed after 5-10 days, depending on the anatomical site.

Ex. well-repaired lacerations, well reduced bone fractures, healing after flap surgery

Identify this tissue

H&E stain of typical granulation tissue -- note blood vessels

Why might you not sweat over a major scar?

granulation tissue has destroyed underlying matrix, so adenexal structures are destroyed and they don't necessarily repair

Describe the orderly phase of wound healing

Inflammation --> granulation tissue --> wound contraction

Collagen accumulation and remodeling begins to occur at the same time as wound contraction.

What type of wounds heal by secondary intention (2nd union). How does the surgeon perform this technique? How does this compare to primary intention? This same process of healing occurs where else in the body? What happens in secondary intention that doesn't happen in primary intention?

3. When a skin wound is large (extensive destruction) or severely contaminated or infected (patient presents for treatment days after the injury), it is allowed to heal by secondary intention.

Cleansing --> debridement --> allowing of wound to "granulate in" without closing the gap with sutures

Although the process of healing is the same, it takes longer because of the size of the defect.

The same process of healing occurs in an internal organ when there is extensive destruction of tissue.

CONTRACTION of skin by myofibroblasts - trying to act as stitches and bring the edges of the wound together

Name 6 local factors that affect wound healing.

a. Nature of wound: size, configuration.
b. Vascular supply: NEED this for healing to occur
c. Infection
d. Foreign bodies: intensifies inflammation but prevents healing when bacteria is present
e. Ionizing Radiation: decreases vascular supply to tissue

What is the significance of vascular supply with regards to healing?

Inflammation and healing can take place only when there is an adequate blood supply. Devitalized tissue will not heal. Tissue with poor vascularity may heal with difficulty or be more prone to infection (example: abscess, fat).

How does infection affect healing?

The presence of bacteria will continue to incite an inflammatory reaction, preventing or prolonging healing.

How does a foreign substance affect healing?

A foreign substance (splinter, suture, artificial heart valve) will intensify inflammation and prevent healing when bacteria are present.

How does ionizing radiation affect healing?

Radiation decreases the vascular supply to tissue.

What systemic factors that affect healing.

a. Circulation: Poor circulation impairs healing
b. Infection:can overwhelm the immune system.
c. Nutrition: vital substances necessary for healing may not be available
d. Hormones: steroids impair healing by inhibiting inflammation

How does poor circulation impair healing? Give 2 examples.

impairs the transportation of oxygen, inflammatory cells and chemical mediators to the site of injury

ex. congestive heart failure or severe atherosclerosis

Why might hormones impair healing?

steroids inhibit the inflammatory process, impairing healing (example; steroid medication, Cushing's syndrome).

Give 2 examples of compliations from wound healing.

Defective scar formation: wound dehiscence, incisional hernia.

Excessive scar formation: Hypertrophic scar, keloid.

Identify this image.

Keloid.
Excess collagen deposition in the skin forming a raised scar known as keloid.
Note the thick connective tissue deposition in the dermis.

Summarize pathways of reparative response after acute inflammatory injury.

Stimulus promptly desrtoyed --> no/minimal necrosis --> if excudate resolved then restitution of normal structure, if exudate organized, there will be scarring.

Stimulus not properly destroyed --> NECROSIS of cells:
--if tissue is composed of stable or labile cells & framework intact --> regeneration (ex. lobar pneumonia(. If framework destroyed --> scarring (ex. bacterial abscess)

--If tissue is composed of permanent cells --> SCAR (ex. MI)

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