Tissue Injury & Repair 2: Wound Healing Flashcards
What is extracellular matrix?
Network surrounding cells…very dynamic.
Synthesized by mesenchymal cells.
It includes the Interstitial matrix and Basement Membrane.
What are mesenchymal cells?
Anything that is not epithelial such as muscle, blood, lymphatics, collagen, CT, fibroblasts.
Collagen is usually type II fibers.
What is the connective tissue layer of the skin? Does connective tissue regenerate?
The underlying dermis from the epithelium is the CT.
CT does not regenerate therefore will form scar tissue (fibroblasts). Anything below the epidermis WILL NOT regenerate.
What is the purpose of the ECM?
- Provides mechanical support for tissues.
- Substrate for cell growth and formation of tissue micro environments.
- Scaffold for tissue renewal.
- Regulates cell proliferation and differentiation.
- Stores regulatory molecules (growth factors) used for cell growth and proliferation.
What is the interstitial Matrix?
a. k.a interstitium
- Synthesized by mesenchymal cells (fibroblasts)
- Collagens: fibrous proteins (type I, II, III= fibrillar)
- Composed of water hydrated gels (proteoglycans and hyaluronan)
- Adhesive glycoproteins (fibronectin)
What type of Collagen do tendons in adults contain?
predominately Type 1 collaged fibers. Tenocytes (tendon fibroblasts) –> Long nuclei
What is the Basement Membrane?
- sheet like depositions of ECM in which epithelial cells rest on.
- Beneath epithelium or endothelium
- Synthesized by epithelium and the underlying mesenchymal cells
- Type IV collagen (nonfibrillar = lamina densa) and laminin
- Can also be a site of pathology e.g. laminitis
Comment on the BM of the Equine Hoof…
The equine hoof is a specialized epidermis that produces lamellae to increase the surface area of the hoof since all of the animals weight rests on it.
It is made up of Primary and Secondary Epidermal Lamellae and has Primary and Secondary Dermal layers. In between the two layers sits the basement membrane.
The weight of the animal hangs off of the basement membrane.
What is laminitis?
Although the term laminitis would indicate inflammation of the lamellae, it is not just that.
Laminitis is a name for a ‘SET OF CLINICAL SIGNS’ not a disease.
The dorsal surface of P3 (distal phalynx) should be completely parallel to the hoof wall.
During acute laminitis P3 has separated from the epidermal lamellae leaving a cavity. Eventually P3 can penetrate right through the sole.
What are they two hypothesis for causes of laminitis?
- Vascular: digital ischemia
2. Toxic- Metabolic: damage to the epithelial cells of the laminae or to the basement membrane
Describe the events occurring during ‘Chronic Laminitis’
Whole weight of the animal is on the hoof.
The DDFT is pulling on P3.
Weakened structure of lamellae and basement membrane, allowing stretching and separation.
–> ALL OF THIS LEADS TO DISPLACEMENT OF P3 AND COLLAPSING OF THE FOOT.
What are the 3 main categories for the causes of laminitis?
Inflammation
Weight bearing
Endocrine
Describe the inflammatory causes of laminitis..
- Retained fetal membranes - inflammatory disease occurring somewhere else in the body can enter circulation.
- Severe illness (GI disease) COLIC
- Black Walnut Shavings
- Feeding accidents: Grain overload.
Describe the wt. bearing causes of laminitis..
If horse is lame in one limb, can cause laminitis in the contralateral limb since trying to stay off of the lame limb. All of the animals weight pressure will be on the contralateral limb. ESPECIALLY IN FORELIMBS SINCE 2/3 OF WEIGHT IS DISTRIBUTED HERE.
Describe the endocrine causes of laminitis..
- Glucocorticoids: Equine Cushings patients are more prone to laminitis (Iatrogenic)
- Insuline Resistance: Pasture associate laminitis, Equine Metabolic Syndrome
What is Equine Metabolic Syndrome?
- Syndrome of obesity, laminitis and insulin resistance (hyperinsulinaemia). It may be the high insulin that is the cause of laminitis rather than insulin resistance!!!
- Primary disorder is insulin resistance and high levels of insulin where glucose cannot be taken up from the blood stream. This causes disturbed glucose and insulin regulation. This does NOT CAUSE DIABETES but is similar and will cause laminitis.
Ponies are more prone to horses in this disease.
From a histological standpoint, what can be expect to see in:
a. Endocrinopathic laminitis
b. Inflammatory laminitis
a. Stretching of primary and secondary lamellae. No inflammation. Stretching of SEL. Cell death followed by proliferation. BM lesions minimal.
b. Separation of epithelial cells from basement membrane. Loss of BM.
What are the 4 categories of tissue?
- CT
- Epithelial
- Muscle
- Nervous
What is connective tissue and what is it made of?
Tissue that supports, binds, or separates other tissues and organs.
Made up of ECM and mesenchymal cells.
When is repair by connective (fibrous) tissue necessary?
- When there is damage to CT (ECM & mesenchymal cells) in addition parenchymal cells, or epithelial cells.
- Non-dividing cells are injured.
These tissues cannot repair by regeneration alone because they are not mitotically active there fore they are replaced with fibrous tissue. Usually repair is a combination of CT repair and regeneration.
What is meant by erosion?
Only epithelium is injured therefore can regenerate and no scar is formed.
What is meant my ulcer?
Ulceration is through the basement membrane and into the dermis. Regeneration is inadequate for an injury this deep because cells are non dividing therefore need repair by connective fibrous tissue in which case a scar will be formed. (Raised margins due to scar formation)
Describe the process of regeneration/ CT repair in regards to Liver injury..
Note: Liver hepatocytes are NOT labile (dividing) cells, rather they are stable tissues that are quiescent and CAN proliferate in response to injury but have a limited capacity to do so.
If just the hepatocytes are injured –> regeneration will occur via proliferation of residual cells with an intact matrix.
If the cells and CT matrix are injured: Deposition of connective tissue AND proliferation of cells, repair will occur by scarring.
VAST MAJORITY OF TIME: SCAR TISSUE WILL FORM.
Histologically, what would we mainly expect to see in end stage liver cirrhosis?
Micro/ Macronodules accompanied with fibrous tissue bridging hepatic lobules together. However, gross and histological appearance are not adequate to indicate the cause of disease.
What is the four step process to repair?
- Angiogenesis: formation of new BV
- Migration and proliferation of fibroblasts.
- Fibroblasts (type of mesenchymal cell) deposits ECM [(interstitium + BM)– made by mesenchymal cells)
- Maturation and reorganization of fibrous tissue= remodeling.
What are the two processes by which angiogenesis will occur?
A. angiogenesis by mobilization of Erythroid Progenitor Cells (EPCs—stem cells) from the bone marrow into circulation.
B. Angiogenesis from pre existing vessels.
What is granulation tissue?
Tissue named due to pink, soft, granular, gross appearance (usually beneath a scab)
Forms within 3-5 days once tissue repair begins. Tissue repair begins within 24 hours.
Forms by same process of repair:
- angiogenesis.
- Proliferation of fibroblasts
- fibroblasts deposition of ECM
- maturation and reorganization of fibroblasts.
Histologically, what orientation would we expect to see BV and fibroblasts in granulation tissue? “Character appearance”
BV would be perpendicular to surface whereas fibroblasts are parallel to the surface.
Comment on the relationship between neovascularization and edema..
New vessels are leaky so granulation tissue is often edematous (when we have the granulation tissue forming some interstitial fluid seeps out).
Histologically speaking, will see clear spaces between the fibroblasts = edema.
What stimulates the proliferation of fibroblasts and ECM deposition?
- Growth factors
- Activated endothelial cells.
- Inflammatory cells
- Macrophages: important component of granulation tissue:
Clear away inflammatory debris and pull in fibroblasts.
REMEMBER, inflammation always comes first before tissue repair.
Describe the process resulting from tissue injury beginning with normal tissue and ending with scar tissue.
Normal Tissue Injury Inflammation (must inflame to get granular response) Formation of Granulation tissue Scar formation
Describe the process of Scar formation and the transition from granulation tissue to mature scar tissue.
As healing progresses:
- Get decreases numbers of proliferating fibroblatss
- Vascular regression = Pale
Transition:
With granulation tissue we have a loose connective tissue with edema
With scar tissue wit have dense collagenous tissue with increased ECM (especially collagen)
