Abnormalities of the ECM Flashcards
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
Q
What is the morphology of Excessive ECM production?
A
- 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
Q
What substances are depsited in the ECM?
A
- Abnormal substances can be deposited in both normal and abnormal ECM
- Common substances:
- Amyloid
- Calcium
- Iron
- Excessive collagen
27
Q
What is Amyloid
A
- 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
Q
What are the common forms of Amyloid?
A
- 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)
-
Amyloid Light Chain (AL) protein
29
Q
Why is Amyloid deposited?
A
- 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
Q
Why does Amyloid accumulate?
A
- 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
Q
What is the morphology of deposited Amyloid?
A
- 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
- Eosinophilic, acellular, amorphous, fibrillar extracellular protein that displces normal tissue components
32
Q
What syndromes have been characterized by Amyloid deposition?
A
- Primary amyloidosis
- Secondary (reactive) amyloidosis
- Amyloidosis of aging
- Endcrine amyloidosis
- Familial amyloidosis
33
Q
What is Primary Amyloidosis?
A
- 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
Q
What is Secondary Amyloidosis
A
- 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
Q
What is amyloidosis of aging?
A
- 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
Q
What is Endocrine Amyloiosis?
A
- 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 protein is derived from a norml product of pancreatic islet ß cells
- Amyloid deposition can result in Type I diabetes mellitus
- Also occurs in some non-human primates and humans
37
Q
What is Familial Amyloidosis?
A
- 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
Q
What is Calcification?
A
- Calcium deposition can occur in either normal or abnormal ECM
- “Mineralization”
39
Q
What causes calcification?
A
- Mineralization can occur due to 2 basic prcesses
- Dystrophic mineralization
- Metastatic mineralization
40
Q
What is Dystrophic Calcification?
A
- 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
Q
What are common locations for Dystrophic calcification?
A
- Heart
- Skeletal muscle
- Inflammatory lesions
- Granulomas
- Skin
- Calcinosis cutis associated with hyperadrenocorticism
42
Q
What is Metastatic calcification?
A
- 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
Q
What are common metastatic calcification situations?
A
- Renal failure
- Vit D toxicity
- Pseudohyperparathyroidism
- paraneoplastic condition associated with PTH-like protein
- Neoplastic bone destruction
44
Q
What is the morphology of cacification?
A
- 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
Q
What are some ECM-associated Disease?
A
- Epidermolysis bullosa
- Collagen defects
- Muscular dystophies
- Osteoarthritis and intervertebral disk disease
- Vascular disease
- Neoplasia
- Diabetes mellitus
- Chondrodysplasia
46
Q
What is Epidermolysis bullosa?
A
- A group of conditions characterized by skin fragility and blistering
- Causes include abnormal collagen type VII, keratin, laminin, and integrins
47
Q
What collagen defects are ECM-associated disease?
A
- Osteogenesis imperfecta
- Abnormal Type I collagen
- Ehlers-Danlos Syndrome
- Defects in collagen or metalloproteinases
48
Q
How are muscular dystrophies ECM associated?
A
- Defects in laminin
- Defects in Type VI collagen
- decreased dystrophin levels
49
Q
How is Osteoarthritis and intervertebral disk disease ECM-associated?
A
- Degeneration of multiple matrix components
50
Q
Which Vascular diseases are ECM-associated?
A
- Atherosclerosis and aneuryms
51
Q
What parts of Neoplasia are ECM associated?
A
- Invasion
- Angiogenesis
- metastasis
52
Q
How is Diabetes Mellitus ECM associated?
A
- Excessive collagen glycation and cross-linking and stiffening
53
Q
How is Chodrodysplasia ECM-associated?
A
- Abnormal Type II collagen
