The Dermis (including diseases) Flashcards
From what cell line does the dermis originate?
Mesoderm
What are the functions of the dermis?
Fibrous components resist tensile forces
Soluble macromolecules resist or dissipate compressive forces
Most tensile strength and elasticity of the skin
Regulation of cell growth, proliferation, adhesion, migration, differentiation
Modulates wound healing
Nutritional support for epidermis
Thermal regulation
Water binding
What are the insoluble fibers of the dermis?
collagens and elastin
What is the extracellular matrix of the dermis?
The insoluble fibers and soluble polymers
What are the soluble polymers of the dermis?
proteoglycans and hyaluronan
What are the two main layers of the dermis?
Superficial (papillary in humans, not in dogs due to lack of dermal papillae)
Deep (reticular in human)
What is unique about the scrotal dermis?
It contains numerous large smooth muscle bundles
What is unique about the equine dermis?
There is a 3rd dermal region - “horse mirror” aka Ross-Spiegel
On the rump (sacral/gluteal), back, and upper half of chest (+/- neck)
Fine collagenous fibers interwoven with fine elastic and reticular fibers organized in tree like arrangement
Shiny on gross examination
What is the major cell type in the dermis?
Fibroblasts
Why do fibroblasts have an extensive endoplasmic reticulum?
To make extracellular matrix proteins
What are the primary functions of fibroblasts?
Make the extracellular matrix
Wound healing
Degrade matrix proteins (MMPs)
Synthesis of cell mediators (growth, differentiation, migration, inflammation)
What stain highlights collagen on histopathology?
Masson Trichrome
Which cells create collagen?
Fibroblasts, but collagen is completed extracellularly
What percent of the dry weight of the dermis does collagen (all types) comprise?
75-80%
How many collagens are there?
At least 28
What is the function of collagen?
Tensile strength
Also have roles in morphogenesis, tissue repair, cellular adhesion, cellular migration, chemotaxis, platelet aggregation
Amounts of what in the urine is directly correlated with collagen turn-over?
Hydroxylysine, 4-hydroxyproline
What is the basic structure of collagen?
Triple helix of α-chains
Each α-chain has repeating triplets of amino acids
Typically glycine-X-Y
X is usually proline, Y is usually hydroxyproline, but can be any
Which are the fibril-forming collagens found in the skin?
I *
III *
V *
XI
What is the collagen composition of the normal adult dermis?
Type I: 80-87%
Type III: 10%
Type V: 3-5%
What is the primary difference between fetal and adult collagen?
Fetal skin contains primarily Type III
Which collagen is produced first during wound healing?
Type III
Where are collagen Type III and Type V concentrated in normal adult skin?
Around blood vessels
What is the primary difference in the structure of Type I and Type III collagen?
Type III has more hydroxyproline, glycine, and cysteine
Which collagens are important for the basement membrane?
IV (lattice of lamina densa)
VII (anchoring fibrils)
XVII (transmembrane, BPAG2)
What does Type VI, XII, and XIV collagen do?
Support the stability of the larger fibril forming collagens
What are the major stimulators/promoters of collagen synthesis?
Ascorbic acid (vitamin C) *
TGF-B
IL-1
IL-4
IGF-1 (somatomedin C)
IGF-2
Superoxide generating systems
Bleomycin
PDGF
What are the major inhibitors of collagen synthesis?
Glucocorticoids
Retinoids (may also stimulate)
Vitamin D3
Parathormone
Prostaglandin E2
IFN-y
D-penacillamine
Minoxidil
How do corticosteroids inhibit collagen synthesis?
Reduce activity of prolyl hydroxylase (rate limiting step of collagen synthesis)
How do retinoids affect collagen synthesis?
Modulate type I collagen expression in vitro and vivo
Stimulate quiescent non-proliferating cells to activate collagen gene expression
But mostly inhibit it according to recent resident review
What are the 4 (overview) steps in collagen synthesis?
1) Gene transposition and translation
2) Intracellular modifications
3) Packaging and secreting of procollagen
4) Fiber formation and crosslinking
Hydroxylation of prolyl and lysyl residues occurs during intracellular modifications in collagen synthesis. Why is this important?
It is needed for proper folding of the α chains into triple helices
Hydroxylation of prolyl and lysyl residues occurs during intracellular modifications in collagen synthesis. What co-factors are needed for this?
Molecular oxygen
Iron
α-ketoglutarate
A reducing agent (ASCORBIC ACID)
What is one reason (related to collagen synthesis) that hyperbaric oxygen chambers are thought to help wound healing?
Increases hydroxylation of prolyl residues
What happens to procollagen?
The amino and carboxyl groups are cleaved by proteases to make collagen
What is dermatosparaxis?
a rare, inherited connective tissue disorder that causes skin fragility and laxity resulting from deficiency of procollagen peptidase so procollagen cannot be cleaved to collagen
The last stage of collagen formation is crosslinking, of which lysyl oxidase is an important enzyme. What is required as a cofactor?
Copper
How can legumes affect collagen production?
Lathyrism
They contain β-animopropionitrile
Can inhibit lysyl oxidase
Crosslinking of collagen fibrils via covalent bonds can’t occur
Also are neurological with muscle weakness
What is primarily responsible for the degradation of collagen?
MMPs (mostly MMP-1)
What metals are important for the function of MMPs?
Zn and Ca
What is denatured collagen called?
Gelatin
What percentage of the dry weight of the normal adult dermis is elastin?
1-2% (4% of ECM)
Where do elastin fibers have the highest concentration?
aorta, arteries, lungs
What do elastin fibers primarily do?
Form a mesh between collagen fibers
Describe the structure of mature elastin fibers.
A core of elastin surrounded by microfibrils like fibrillins, fibulins, and type VI collagen
Which cells produce elastin?
Fibroblasts
What special stains do you use for elastin?
Verhoff-van Gieson
acid orcein-Giemsa
Weigert
What are the types of elastic fibers found in the dermis?
Elastin
Elaunin
Oxytalan
What are oxytalan fibers?
Composed of thin elastic microfibrils
Anchor deep dermis to superficial dermis and superficial dermis to BMZ
How are elastin fibers arranged in the deep dermis?
Horizontally
How are oxytalan fibers arranged in the deep dermis?
Vertically
What are elaunin fibers?
associated with elastin
small amounts of amorphous crosslinked elastin
found in the superficial dermis with an arcadelike arrangement
What is the basic molecular unit of elastins?
tropoelastin
What is the first step of elastin production?
formation of tropoelastin
How is the molecular structure of elastin similar to that of collagen?
1/3 of the amino acids are glycine
evenly distributed in collagen, not in elastin
What are the two most common amino acids in tropoelastin?
valine and proline
What happens to tropoelastin in the extracellular space?
it spontaneously associated with microfibrils and crosslinks are formed to make elastic fibers
Why are elastin fibers insoluble?
crosslinks between the amino acids that are unique to elastin (desmosine and isodesmosine)
What is a key enzyme that is essential in the formation of crosslinks in collagen and elastic fibers?
lysyl oxidase
What will copper deficiency do to elastic fibers?
make them unstable due to poor lysyl oxidase activity (poor crosslinking)
What will copper deficiency do to the dermis?
Poor/unstable collagen and elastic fibers
What are the main stimulators/promotors of elastic synthesis?
TGF-B
IGF-1
What are the main inhibitors of elastin synthesis?
TNF a
Vitamin D3
Colchicine
What do glucocorticoids do to elastin production?
Glucocorticoids can both increase and decrease elastin production depending on the type of cell and the stage of development
What are elastases?
Enzymes mostly responsible for breaking down elastic fibers
Most are serine proteases but some are MMPs
What does the ground substance of the dermis consist of?
proteoglycans and glycosaminoglycans
What is the structure of a proteotypical proteoglycan?
Single core protein linked to one or more glycosaminoglycans (GAGs)
What are the common glycosaminoglycans (GAGs)?
Hyaluronic acid ** most important in skin, unique
Heparan sulfate
Chondroitin sulfate
Keratan sulfate
Dermatan sulfate
What are glycosaminoglycans?
A polysaccharide usually found bound to proteoglycans
Are soluble
Which glycosaminoglycan is unique and why?
Hyaluronic acid
Produced without attachment to a core protein
it is never sulfated
Is just synthesized at the plasma membrane and released into the extracellular space
What are the functions of the dermal ground substance?
Allow things to pass through
Water storage
Homeostasis
Wound healing
Resisting compressive forces
Which proteoglycan is found intracellularly?
Serglycin in secretory granules of mast cells, leukocytes, and eosinophils
What does serglycin do?
Carries heparin sulfate and is important for storing and packaging secretory granule components, such as histamine, proteases, and serotonin in immune cells
Which proteoglycans are found on the cell surface?
Syndecans and glypicans
What is the major functions of syndecan?
Abundant on keratinocytes through differentiation
Is involved in wound repair (1 and 4)
Has decreased expression during malignant transformation
Which is the primary proteoglycan found extracellularly in the dermis?
Versican
What does versican do?
binds hyaluronic acid and allows aggregation
Which proteoglycan is primary involved in solar elastosis?
Versican
What upregulates versican?
TGF-B
What is decorin?
A small, extracellular matrix proteoglycan that decorates collagen I
What are the primary functions of hyaluronic acid?
Aids in skin flexibility
Wound healing
Cellular movement
Expanding the ECM
Why does fetal skin not scar?
Collagen III and more hyaluronic acid
Which glycoproteins form the filamentous portion of the extracellular matrix?
Fibrillins
Fibulins
Fibronectin
Vitronectin
Tenascin
Mucins
Laminin
Trombospondins
What is mucin?
A glycoproteins
Concentrated around appendages
Main component is hyaluronic acid
Why do Shar-Pei’s have increased mucin in their dermis?
hyaluronan synthetase
What color does mucin stain on H&E?
Blue
What stain is best to highlight mucin?
Alcian blue*
You can also use colloidal iron or mucicarmine
What are three inherited diseases of the connective tissue that are characterized by a similar phenotype which presents as excessive skin fragility and hyperextensibility?
Cutaneous asthenia
Ehlers-Danlos
Dermatosparaxis (specific type of Ehlers-Danlos)
What is cutaneous asthenia?
In veterinary medicine describes a skin fragility phenotype
In people it is limited to both collagen and elastin being affected
What gene mutation is associated with dermatosparaxis?
ADAMTS-2
What species has dermatosparaxis been reported in?
-Cattle
-Sheep
-Humans
-Himalayan cat
-Doberman pinscher dog
What happens to tears in the skin of a veterinary patient with cutaneous asthenia?
Tears easily
Often wide and gaping
Heal readily but leave “cigarette paper” scars
What is the clinical appearance of a veterinary patient with cutaneous asthenia?
Soft, pliable and thin skin
Skin is hyperextensible with decreased elasticity
Skin may hand in folds around legs and throat
Minimal trauma can result in tears with little bleeding
Can see joint laxity and ocular changes (microcornea, sclerocornea, lens lux, cataracts)
What is the skin extensibility index?
(vertical height of skin fold on dorsum/body length) x 100
- Pull dorsolumbar skin as far as possible without pain
- Base of tail to occipital crest is body length
- Dog: affected if >14.5%
- Cats: affected if > 19%
What are the histopathologic findings of a veterinary patient with cutaneous asthenia?
Normal to striking dermal abnormalities
Masson trichrome can highlight collagen changes
Eosinophilic collagen that is blurred, fragmented, short and disoriented
Collagen in irregular bundles, improper interweaving with mucinosis
How do you treat a veterinary patient with cutaneous asthenia?
be careful, treat like coagulopathy animal
give vitamin C as its necessary for collagen synthesis
What gene mutation is typically associated with cutaneous asthenia in dogs and cats?
COL5A1
What breed of horse is hereditary equine regional dermal asthenia typically seen in?
Stock horses (Quarter, Appaloosa, Paint) and their crosses
What is the genetic mutation associated with hereditary equine regional dermal asthenia?
PPIB (peptidylprolyl isomerase B) gene on chromosome ECA1
Abnormal protein cyclophilin B formed so collagen folding is altered
Autosomal recessive
When do patients first present with hereditary equine regional dermal asthenia?
When first start to be ridden
Is not regional but lesions typically happen where the saddle goes
What are the causes of acquired skin fragility syndrome in cats?
Spontaneous or iatrogenic Cushing’s disease
Diabetes
Excessive progesational compounds
Occasional liver disease (lipidosis, cholangiohepatitis, cholangiocarcinoma), phenytoin administration, dysautonomia, nephrosis, histoplasmosis, FIP
How is the clinical appearance of acquired skin fragility syndrome different from hereditary causes?
Skin becomes thin and fragile but is not hyperextensible
More commonly presents in middle-age to older patients
What is scleroderma?
Disease that involves thickened/fibrotic deep dermal collagen
- localized version is called morphea
- generalized form progresses to fibrosis of other organs
Recognized in humans and horses
What is fragile foal syndrome?
- lethal, autosomal recessive disorder
- mutation in PLOD1 = non-functional lysyl hydroxylase
- fragile skin, joint laxity, incompletely closured abdominal wall
- mostly in Warmbloods and thoroughbreds
What is cutis laxa?
A (poly)genetic disorder that causes skin laxity and sagging over joints
Not yet reported in veterinary medicine
frequently caused by defects in fibulin 4 and 5 in humans
What is solar elastosis?
Degeneration of collagen and elastic fibers of the superficial dermis due to solar irradiation
Why is solar elastosis thought to occur?
UV light upregulating collagenase production in fibroblasts
Increased tropoelastin mRNA and protein secretion
Increased versican proteoglycan in elastotic fibers
What does solar elastosis look like on histopathology?
Sad blue spaghetti
Can stain with van Geison or PAS
Solar elastosis
What is the best stain for proteoglycans on histopathology?
PAS
What are the causes of cutaneous mucinosis?
Breed (Shar-Pei)
Hypothyroidism
Acromegaly
Dermatomyositis
DLE
Alopecia mucinosa
What is Shar-Pei fever?
AKA Shar Pei autoinflammatory disease (SPAID)
Fever, arthritis, hyaluronosis, amyloidosis, otitis
Due to different genes being transmitted together
How do you treat hereditary cutaneous hyaluranosis (mucinosis) of the Chinese Shar-Pei?
Steroids
Treat hypersensitivity if associated
Could consider pentoxifylline
How is hypothyroidism related to mucinosis?
Thyroid hormone regulates production of dermal GAGs
Accumulation of mucin leads to myxedema –> tragic facial expression
Can exhibit mucinous nodules or vesicles in severe cases
Cutaneous asthenia
HERDA
What is Marfan syndrome?
Autosomal dominant mutation in FBN1 (fibrillin 1 gene)
Described in humans and cattle
Can affect skeletal system, eyes, lungs, skin, and cardiovascular (aortic dissection or aneurysm)
What is nodular dermatofibrosis?
Autosomal dominant, lethal mutation in the folliculin (FLCN) gene
Occurs in GSD
Develop multiple firm nodules (dermatofibrosis) in the skin typically by 6 years of age
Develop bilateral, multifocal tumors (cystadenocarcinoma) in the kidney
Also associated with uterine leiomyoma
What is feline perforating dermatitis?
Rare, due to elimination of abnormal collagen (unknown etiology)
crusted papules and plaques or crusted ulcers containing contained central, exophytic, cone-shaped, firm, yellow-orange hyperkeratotic material, tightly adherent to the underlying skin
usually localized on the upper and lower extremities, on the face and occasionally on the trunk
What is the histopathologic findings associated with feline perforating dermatitis?
collagen extruding from the underlying dermis
mixed inflammation in the dermis
