Abnormalities of the ECM Flashcards
(53 cards)
1
Q
What is the Extracellula Matrix
A
- Structural framework in which cells organize, move, and interact
- Proveds sites for cell adhesion and a conduit for exchange of cell nutrients and wastes
2
Q
What are some of the properties of teh ECM?
A
- Dictates tissue architecture and organization
- Has specific feature for each tissue/organ
- bone, liver, brain, lung, intestine, skin, etc
- Has specific feature for each tissue/organ
- Regulates or modifies many cell c\activities
- Serves as a reservoir of growth factors and bioactive molecules
- Constantly remodeling and changing
3
Q
What processes are influenced by the ECM?
A
- Play a major role in:
- Embryogenesis
- Fibrosis
- Wound healing
- Cell behvor
- Morphogenesis, differentiation, adhesion, migration, apoptosis
- Carcinogenesis
- Tumor invasion nd metastasis
4
Q
What are the components of the ECM
A
- The “matrisome” conssts of over 300 different proteins
- 3 categories:
- Structural
- Absorptive
- Adhesive
5
Q
What are teh structural components of the ECM?
A
- Build the framework for cells to exist upon and within
- Include:
- Collagen - many types
- Elastin - prominent where elasticity is needed
6
Q
What are the collagen types?
A
- at least 28 types
- I - structural collagen of most tissues
- Fibrous tissue, bone
- II - major component of cartilage
- IV - Basement membranes
7
Q
What is Marfan Syndrome
A
- Collagen Disorder
- A mutation in the gene encoding fibrillin-1
- Fibrillin-1 is a structural component of microfibrils and regulates formtion of elastic fibers
- Elevated levels of TGF-beta also occur and contribute to the disease
- Features include tall, slender build, disprportionally long fingers and toes, lsn dislocation , and Aortic weakening among others
- Dr. Abraham Gordon Proposed in 1962 that Abraham Lincoln had Marfan Syndrome
8
Q
What is Ehler-Danlos Syndrome?
A
- A group of inherited connective tissue disorders characterized by defective collagen synthesis
- Loose and very fragile skin
- Dermatoporaxis is one variant of this condition
9
Q
What are the Absorptive parts of the ECM
A
- Absorb water and other soluble substances whibh bath surrounding cells
- Major absoptive components:
- Glycosaminoglycans (GAG)
- Proteoglycans
- Exert important osmotic pressures to help maintain water balance
10
Q
What are Glycosaminoglycans?
A
- Polysaccharides consisting of 4 main groups:
- Hyaluronic acid
- Heparan sulfate
- Chondroitin/dermatan sulfate
- Keratan sulfate
11
Q
What are proteoglycans
A
proteins with GAG side-chains
12
Q
What is Edema?
A
- The excessive accumultion of fluid in the ECM or within body cavities
- Vacious causes, one of which is a chang in concentrations or properties of absorptive molecules in the ECM
13
Q
What is the Adhesive part of the ECM?
A
- Sites of attachment for structural ECM components nd cells
- Adhesive components:
- Fibronectin
- Laminin
- Many others
- Mediate interactions of fixed or mobile cells with the ECM
14
Q
What is Fibronectin and what is its role in would healing?
A
- A glycoprotein that attaches to integrins (cell membrane receptor proteins) as well as ECM prteins such as collagen, fibrin, and proteglycans
- Critiacl for wound healing
- provides binding sites for macrophages, endothelium, and fibroblasts during tissue repair and healing
- Contributes to formation of the granulation tissue matrix
- Can influence cel function and protein expression
15
Q
What are the other roles of Fibrnectin besides wound healing?
A
- Cell migration and differentiation during embryogenesis
- Hemostasis - in conjuntion with fibrin
- Carcinogenesis - may promote tumor growth nd survival
16
Q
How can Fibronectin affect embryogenesis
A
- Deficiency can lead to embryonic death or defects in neural and vascular development
17
Q
What are the general patterns of injury?
A
- Increased destruction
- Decreased production
- Excessive production
- Deposition of abnormal substances
18
Q
What is increased destruction of ECM?
A
- ECM exists in a dynamic balane of production and degradation
- Fibroblasts produce collagen
- Matrix metalloproteinases among other enzymes degrade collagen
- MMP 1 collagenase
- Decreased ECM occurs when the balance of degradation exceeds production
19
Q
What are causes of inceased destruction of ECM?
A
- Excessive MMP activity
- associated with various condition, including vascular disease, neoplasia, skin and musculoskeletal disorders
- Inflammation
- Lysosomal enzymes are released into the ECM
- Excessive amounts of MMPs
- Collagenaes and elastases
- Excessive amounts of MMPs
- Oxygen free radicals and cytokines damage ECM
- Lysosomal enzymes are released into the ECM
- Immunologic reactions
- Immunologic activation of inflammatory responses
20
Q
Increased destruction of ECM
A
- Morphology:
- Gross:
- Corresponds to the different types of necrosis
- Histologic:
- Collagen is swollen, uniformly eosinophilic, fragmented or absent
- Inflammation is usually present
- Gross:
21
Q
What causes decreased production of ECM?
A
- Most cases occur as inheited diseases of collagen formation
- Collagen dysplasias
- Nutritional deficienceis can influence ECM production
- Vit C is a critical element for collagen formation and maintenance
22
Q
What is the morphology of decreased production of ECM?
A
- Gross:
- skin is very distensible and fragile
- Tears in the skin
- Histiologic:
- No abdormlities in some cases
- Collagen of variable size and shape
- Abnormal collagen organization
23
Q
What is excessive production of ECM?
A
- Predominantly associated with healing in irreversibly dmaged tissue
- Fibrosis and scar formation
- Excessive fibrosis can interfere with tissue and organ funtion
- Can have major detrimental effects when located in criical tissues
24
Q
What are causes of excessive ECM production?
A
- Upregulation of collagen-producing cells
- predominately fibroblasts
- a shift in ECM homeostasis or a metabolic problem
- Any stimulus resulting in irreversibly damaged tissue
- Tissue is replaced by collagen as part of healing
25
What is the morphology of Excessive ECM production?
* Gross:
* Dense, white fibrous tissue replacing normal tissue
* Abnormal relationships between tissues and organs
* Excessive fibrosis can interfere with organ function
* Histologic:
* Densely packed collagen
* Initially increased fibroblasts
* Later mainly collage with few fibroblasts
26
What substances are depsited in the ECM?
* Abnormal substances can be deposited in both normal and abnormal ECM
* Common substances:
* Amyloid
* Calcium
* Iron
* Excessive collagen
27
What is Amyloid
* Amyloid is a chemically diverse protein that has a ß - plated sheet conformation
* Composition:
* 95% fibrillar proteins
* 5% other proteins
* Serum amyloid P protein
* Proteoglycans
* Glycosaminoglycans
28
What are the common forms of Amyloid?
* Over 30 biochemically distinct forms of disease-associated amyloid havebeen described
* Most common forms:
* **Amyloid Light Chain (AL) protein**
* consists of immunoglobulin light chains
* **Amyloid-Associated (AA) protein**
* This is deried from serum AA produced by the liver
* **Aß amyloid:**
* A fragment derived from amyloid precursor protein (AAP)
29
Why is Amyloid deposited?
* Amyloid deposition occurs due to abnormal folding of amyloid proteins
* Deposition is usually due to:
* Normal proteins that have tendency to misfold when produced in excess
* Abnormal proteins formed due to mutations
30
Why does Amyloid accumulate?
* Misfolded amyloid can NOT be degraded and accumulated extracellularly in ECM
* May be a defect in normal degrdative processes
* May be an abnormal protein that can't be degraded
31
What is the morphology of deposited Amyloid?
* Gross:
* Deposition can occur either locally or systemically
* Affected organs are enlarged, firm and discolored
* Detectable with Lugol's iodine and sulfuric acid
* Histologic:
* Eosinophilic, acellular, amorphous, fibrillar extracellular protein that displces normal tissue components
* Some types can be intracellular as well
* Stains with Congo Red dye
* Produces apple-green fluorescence with polarized light
32
What syndromes have been characterized by Amyloid deposition?
* Primary amyloidosis
* Secondary (reactive) amyloidosis
* Amyloidosis of aging
* Endcrine amyloidosis
* Familial amyloidosis
33
What is Primary Amyloidosis?
* Usually associated wih immunological dyshomeostasis and deposition of AL protein
* Most commonly associated with plasma cell neoplasia
* Neoplastic cells produce excessive amounts of immunoglobulin and immunoglobulin light chains
34
What is Secondary Amyloidosis
* Usually associated with chronic inflammation and tissue destruction with deposition of AA protein
* Cytokines and cell damage associated with chronic inflammation increases production of SAA
* Abnormal breakdown of SAA or structural abnormalities in the SAA results in deposition in teh ECM
* Most common form in domestic animals
35
What is amyloidosis of aging?
* Deposition of Aß amyloid can occur in the brain (neurons and neurovascular tissue) of old dogs
* this type s characteristic of Alzheimer's disease of humans
* Deposition less often occurs in the heart, GI tract and lungs of old dogs
36
What is Endocrine Amyloiosis?
* Amyloid is deposited in teh pancreas (islets) of cats
* Amyloid protein is derived from a norml product of pancreatic islet ß cells
* Islet amyloid polypeptide
* Amyloid deposition can result in Type I diabetes mellitus
* Also occurs in some non-human primates and humans
37
What is Familial Amyloidosis?
* Systemic deposition of AA amyloid occurs specifically in some breeds of dogs and cats
* Abyssinian and Siamese cats
* Shar-pei dogs
* Hereditary
* SAA may be abnormal
* There may be some chronic inflammatory component in some cases
* Kidney and liver are most commonly affected
38
What is Calcification?
* Calcium deposition can occur in either normal or abnormal ECM
* "Mineralization"
39
What causes calcification?
* Mineralization can occur due to 2 basic prcesses
* **Dystrophic mineralization**
* **Metastatic mineralization**
40
What is Dystrophic Calcification?
* This process occurs in necrotic tissue
* Calcium binds to damaged membrane phospholipids and initiates calcium crystal formation
* Cell can no longer prevent calcium influx into the cytosol
* A reflection of local tissue damage and NOT a systemic disturbance in calcium homeostasis
41
What are common locations for Dystrophic calcification?
* Heart
* Skeletal muscle
* Inflammatory lesions
* Granulomas
* Skin
* Calcinosis cutis associated with hyperadrenocorticism
42
What is Metastatic calcification?
* This occurs in normal, viable tissue
* It is a reflection of calcium dyshomeostass
* mainly occurs secondarily to hypercalcemia
* Calcification is initiated by local alkaliniity and alterations in collagen structure
* Often systemic
43
What are common metastatic calcification situations?
* Renal failure
* Vit D toxicity
* Pseudohyperparathyroidism
* paraneoplastic condition associated with PTH-like protein
* Neoplastic bone destruction
44
What is the morphology of cacification?
* Gross:
* Gritty and white deposits in tissue
* Histologic:
* Purple material that either incorporates into normal structures or disrupts the normal morphology of the tissue
45
What are some ECM-associated Disease?
* Epidermolysis bullosa
* Collagen defects
* Muscular dystophies
* Osteoarthritis and intervertebral disk disease
* Vascular disease
* Neoplasia
* Diabetes mellitus
* Chondrodysplasia
46
What is Epidermolysis bullosa?
* A group of conditions characterized by skin fragility and blistering
* Causes include abnormal collagen type VII, keratin, laminin, and integrins
47
What collagen defects are ECM-associated disease?
* Osteogenesis imperfecta
* Abnormal Type I collagen
* Ehlers-Danlos Syndrome
* Defects in collagen or metalloproteinases
48
How are muscular dystrophies ECM associated?
* Defects in laminin
* Defects in Type VI collagen
* decreased dystrophin levels
49
How is Osteoarthritis and intervertebral disk disease ECM-associated?
* Degeneration of multiple matrix components
50
Which Vascular diseases are ECM-associated?
* Atherosclerosis and aneuryms
51
What parts of Neoplasia are ECM associated?
* Invasion
* Angiogenesis
* metastasis
52
How is Diabetes Mellitus ECM associated?
* Excessive collagen glycation and cross-linking and stiffening
53
How is Chodrodysplasia ECM-associated?
* Abnormal Type II collagen
