2. FUNCTIONS OF SKIN
BARRIER FUNCTIONS
• Permeability Barrier
• Barrier to UV radiation
• Barrier to penetration of microorganisms
• Mechanical function
THERMOREGULATORY FUNCTIONS
SENSORY AND AUTONOMIC FUNCTIONS
IMMUNOLOGICAL FUNCTIONS
VITAMIN D SYNTHESIS
VITAMIN E SECRETION
XENOBIOTIC METABOLISM
ANTIOXIDANT FUNCTION
SOCIOSEXUAL COMMUNICATION
3. I. BARRIERFUNCTIONS
Barrier between inside and outside of the body
Inside outside barrier – Regulates water loss
Outside inside barrier – Protects from the
environment
4. A. PERMEABILITY BARRIER
Two way permeability barrier
Determines inward and
outward diffusion of
substances
Prevents entry of Polar
molecules
Cannot prevent penetration of
non polar molecules
Brick Mortar model
1.Protein rich cells - corneocytes
2.Cornified envelope
3.Intercellular cement
5. 1. PROTEIN RICH CORNEOCYTES
Corneocytes collapse into a flattened shape
Aggregation into tight bundles
Alignment of Keratin filaments under influence
of filaggrin
Cells of outer most
layer of epidermis
Flattened cells
Lost their nuclei and
organelles
6. 2. CORNIFIED ENVELOPE
Present within plasma membrane
Highly insoluble due to formation of glutamyl – lysyl
isodipeptide bonds between envelope proteins
ENZYMES INVOLVED :
Transglutaminases catalyse isopeptide bonding between γ-
amide of glutamine and ε-amino group of lysine
Transglutaminases 1, 2 and 3
Transglutaminases 1 and 3 are important in envelope
formation
Transglutaminase 3 accounts for 75% activity in epidermis
7. ENVELOPE PROTEINS
1. INVOLUCRIN
(i) Decorates cytoplasmic face of envelope
(ii) 26% residues are glutamine
(iii) Expressed in stratified squamous epithelium but detected in lower stratum spinosum in benign epidermal hyperplasia
2. SMALL PROLINE RICH PROTEINS
(i) SPR 1 (cornifin) and pancornulin
(ii) Contains internal peptide repeating units of 8 or 9 aminoacids, upto 40% proline
3. SKALP/ELAFIN
4. KERATOLININ/CYSTATIN
5. LORICIN
(i) Major component of cornified envelope
(ii) 315 aminoacid cystein rich protein
(iii) Cross linked by isopeptide bonds
6. PROFILAGGRIN
7. MEMBRANE ASSOCIATED PROTEINS
(i) Envoplakin (210 kDa)
(ii) Periplakin (195 kDa)
(iii) 61 kDa protein
8. FORMATION OF ENVELOPE
Dead cells which are durable and flexible
Have mechanical and water permeability barrier functions
Most desmosomal components are degrades
But keratin IFs are crosslinked to desmoplakin and envoplakin remnants
Reinforcement
By addition of SPR, repetin, trichohyalin, cystatin α, elafin and LEP/XP5
Formation of glutamine residues
By esterification of ceramides secreted from lamellar body
Cross linking
Between plakins and involucrin by transglutaminases Between other desmosomal proteins (scaffold)
Rise in calcium
Intracellular calcium increases
9.
10. ODLAND BODIES
1. STRUCTURE
Lamellated membrane bound organelle of 0.2 –
0.3 micron diameter
Seen in upper stratum spinosum and stratum
granulosum
Contain phospholipid, glycolipid, free sterol,
hydrolytic enzymes, lipases and glycosidases
Lipid bilayers are arranged in the form of discs
that represent flattened unilamellar liposomes
FUNCTIONS
Important for epidermal cohesion and
waterproofing
Hydrolytic enzymes convert polar lipids to non
polar lipids thus contributing to epidermal
permeability barrier
Also degrade corneodesmosomes leading to
aqueous pore formation and desquamation
Degrade non lipid extracellular material
Intercellular cement is the product of the
lamellar body
11. SECRETION
Discharge contents into intercellular space
Fusion with Plasma membrane
Movement towards Plasma membrane
Increase in calcium concentration
Movement through the granular layer
Assembly of Lamellar body in Granular cell membrane
12. REMODELLING OF EXTRUDED LIPIDS
Modified and rearranged into
uninterrupted intercellular
lamellae parallel to cell surface
At SG-SC interface, polar
lipids are converted to non
polar lipids enzymatically
Lipid precursors –
Glucosylceramide,
Cholesterol,
Glycerophospholipid,
Sphingomyelin
Lipid precursors are converted
into non polar lipid products
13. EPIDERMAL LIPID SYNTHESIS UNDER BASAL CONDITIONS
Skin synthesizes lipid @ 100 mg/day
1.CHOLESTEROL
Mostly synthesized in situ
Only basal cells are capable of reabsorbing
cholesterol from circulation
Rate limiting enzyme – Hydroxymethyl glutaryl
co A reductase
Increased during permeability barrier repair
Helps in cell cohesion
14. 2.FREE FATTY ACIDS
Skin contains both free fatty acids and bound fatty acids
Only saturated fatty acids and mono-unsaturated fatty acids are
synthesized in epidermis
Rate limiting enzymes – Acetyl CoA carboxylase and Fatty acid
synthase
ESSENTIAL FATTY ACID DEFICIENCY SYNDROME
Rough, scaly and red epidermis
Disturbed permeability barrier
Bacterial infections
Impaired wound healing
Alopecia
15. 3.CERAMIDES
Forms 30 – 40% of lipids in stratum corneum
9 types
Type A and B are bound to cornified envelope
proteins
Synthesis by hydrolysis of glucosyl ceramide
and sphinogomyelin
16. STRATUM CORNEUM ACIDIFICATION
1.Deamination of filaggrin derived histidine to urocanic acid by histidinase
2.Hydrolysis of phospholipids to free fatty acids by secretory phospholipase
A2
3.Sodium Proton antiporter (NHE1) acidifies localized membrane domains of
SC-SG interface
IMPORTANCE OF ACID MANTLE
Activation of glucocerebrosidase and sphingomyelinase
Regulation of stratum corneum integrity and cohesion and restricts mature
desquamation
Earliest cutaneous proinflammatory events may be triggered by loss of
normal SC acidification
Antimicrobial function is dependent on stratum corneum acidification
17. CONTRIBUTION OF SUBCORNEAL EPIDERMAL LAYER IN
BARRIER FUNCTION
1. TIGHT JUNCTIONS
Second line epidermal barrier
Seal neighbouring cells and
control paracellular movement
of molecules
Confined to stratum
granulosum and upper stratum
spinosum
In Psoriasis, Lichen Planus,
Eczema, Ichthyosis vulgaris,
they are found in deeper layers
also
18. 2. DESMOSOMAL AND ADHERENS
JUNCTION PROTEINS
Desmogleins stabilize cell cell
adhesion
In eczema, there is a reduction in
keratinocyte membrane E cadherin
3. CONNEXINS
Connexin on adjoining cells form gap
junctions
Allows passage of ions and small
molecules between cells
Connexin 26 is highly upregulated in
psoriatic plaques
19. 4. PROTEASES
Transglutaminases form highly stable isopeptide bonds in cornified
envelope
Mutation in Transglutaminase 1 causes lamellar ichthyosis
Netherton syndrome is caused by mutation in SPINK5 that encodes
serine protease inhibitor LEKTI
5.CYTOKINES
Very important for barrier repair
IL-1, TNF and IL-6 released from keratinocytes stimulate lipid
synthesis
20. 6. EPIDERMAL ION LEVELS
Intracellular calcium regulates exocytosis of lamellar body
Calcium regulates protein synthesis and transglutaminase 1 activity in epidermis
Extracellular calcium is important for cell to cell cohesion and epidermal
differentiation
Disturbed regulation of calcium metabolism seen in Darrier disease ( loss of
cohesion between supradermal cells) and Hailey-Hailey disease
7. NEUROTRANSMITTER RECEPTORS
Ionotropic receptors: topical application of calcium channel agonists delays
barrier repair and vice versa
G protein coupled receptor regulate intracellular cAMP. Increase in intracellular
cAMP in epidermal keratinocytes delays barrier recovery and vice-versa
22. PERCUTANEOUS ABSORPTION
Even healthy adult human skin
allow some penetration of almost
every substance
Three compartment model of skin
Composite membrane with
anatomically three distinct layers
1.Stratum corneum (10 micron)
2.Viable epidermis (100 micron)
3.Upper most papillary layer of
dermis (100 – 200 micron)
PENETRATION PATHWAYS
Intercellular pathway
Follicular Penetration
Intracellular pathway
23. PERCUTANEOUS ABSORPTION
Diffuse through dermal and hypodermal tissues to reach underlying tissue
Gain access into systemic compartment through vascular system
Diffuse into and through viable epidermis into dermis
Penetrates stratum corneum
Compound is released from reservoir
Formulation and upper follicular channels form reservoir
24. FICK’S LAW
Compounds applied topically to the skin
surface migrate along concentration gradient
according to the laws of diffusion
Fick’s First law describes the diffusion of
uncharged compounds across a membrane
Steady state flux (J) of a compound per unit
path length () is proportional to concentration
gradient and diffusion (∆C) coefficient (D)
J= -D(∆C/ ∆)
25. FACTORS INFLUENCING RATE OF ABSORPTION
Stratum corneum
Appendages
Viable tissue
Resorption
VARIATION IN SKIN BARRIER FUNCTION
Anatomical site
Temperature and humidity
Individual Variation
Age
Physical trauma
Formulations and vehicles used
26. B. BARRIER TO UV RADIATION
1.Melanin barrier
2.Protein barrier
3.Epidermal lipids
They function by
absorbing radiation and
minimizing damage to
DNA and other cellular
constituents
Absorption maxima (גmax)
– Wavelength that have
the highest probability of
absorption
27. MELANIN
Formed in melanosomes
Two types – Eumelanin (dark, brown
black & insoluble) and Pheomelanin
(light, red yellow, sulphur containing and
soluble)
Indole derivatives of DOPA
Rate limiting step – Conversion of
tyrosine to L – DOPA by tyrosinase
FUNCTIONS OF MELANIN
Provides protection against UV induced
DNA damage
UV absorbed by melanin is converted to
heat
Eliminates genetically damaged cells by
phototoxic mechanism
Take part in oxidation reduction reactions
28. SYNTHESIS OF MELANIN
Transfer of melanosomes to surrounding
keratinocytes
Transport of melanosomes to the tip of
melanocyte dendrites
Sorting of melanogenic proteins into
melanosomes
Transcription of proteins required for
melanogenesis
Stem cells differentiate in epidermis (basal layer)
and hair follicle
29. ADAPTIVE RESPONSES OF SKIN AFTER UV EXPOSURE
1. TANNING RESPONSE
An increase above baseline skin
pigmentation
Protects against future UV radiation
Immediate tanning and delayed
tanning
2. HYPERPLASIA
Hyperplasia of dermis, epidermis and
stratum corneum
Occurs following UVB/UVC
Results from marked increase in cell
mitosis, DNA, RNA and protein
synthesis rates
Plays a role in photoprotection in
light skinned
IMMEDIATE
TANNING
DELAYED
TANNING
UVA and visible
light
UVB & UVA
Occurs with 5 – 10
minutes
Occurs within 3 – 4
days
Fades within
minutes to days
Fades over weeks
No photoprotection Photoprotection
30. 3. ANTI OXIDANT DEFENSES
Various enzymatic and non enzymatic anti
oxidants protect against oxidative damage in
UV exposed skin
Deplete after UV exposure
Superoxide dismutase, catalase, thioredoxin,
vitamin A, C, E, Glutathione
31. C. BARRIER TO PENETRATION OF
MICROORGANISMS
An intact stratum corneum prevents invasion of skin by normal skin
flora or pathogenic microorganisms
Glycophospholipids and free fatty acids of stratum corneum are
bacteriostatic
Sebaceous lipids are bactericidal
ANTIMICROBIAL PEPTIDES
Present on epithelial surface such as epidermis and its appendages
First line of immune defense
Produced by activated keratinocytes
Delivered to skin surface in lamellar bodies
Defensins and Cathelicidins
32. 1. DEFENSINS
α-DEFENSINS
6 α-Defensins
α-Defensins 1,2,3,4 – Human
Neutrophil peptides 1-4
HD 4 and HD 5 – Paneth cells
& epithelial cells of female
urogenital tract
HNP 1-3 - Expression of TNF-
α & IL-1
HNP 1-4 - Oxygen
independent killing
β-DEFENSINS
4 β-Defensins
Broad spectrum anti microbial
activity
33. 2. CATHELICIDINS
37 amino acids long and 2 leucine residues (LL-
37)
Requires proteolytic activation from its precursors
by neutrophil elastase and proteinase
Broad spectrum anti microbial activity
Chemoattractant
Participate in innate immune response
36. 1. RESPONSE TO PULL
Can be stretched reversibly by 10 – 50%
Involves reorientation of collagen fibres
towards load axis and a decrease in their
convulsion
The tonus of skin is maintained by elastic
fibres
2. FURTHER STRETCHABILITY
Gradually stretches if it is maintained taut for
long time
Either individual collagen fibrils slip relative
to each other or whole fibrils slip with the
ground substance – viscous slip/viscous
extension/viscous creep
Dermatan sulphate helps in restraining
viscous slip
Elastin fibers
37. 3. COMPRESSIBILITY
When a small object is pressed into skin,
skin becomes moulded round the object
exerting force
Compression is because of flow of ground
substance between collagen fibres in
dermis
4. ELASTICITY OF STRATUM CORNEUM
A network of structural proteins allows
spread of exogenous forces throughout the
tissue
Stratum corneum protein, lipids and LMW
by products of keratohyaline breakdown –
Natural Moisturizing factors
They bind and retain water in stratum
corneum thus maintaining elasticity
38. II.THERMOREGULATORYFUNCTIONS
Warm receptors, Cold
receptors and Pain receptors
Distributed irregularly over
skin
Cold receptor are 3 – 10
times more than that of
warm receptors
Peripheral detection of
temperature mainly
concerns detecting cool and
cold instead of warm
temperature
Major role in behavior than
modifying core temperature
39. BODY HEAT
LOSS BY
PERCENTAGE
OF HEAT LOSS
AT 21*C
Radiation &
Convection
70
Vaporization of
sweat
27
Respiration 2
Urination and
defecation
1
CUTANEOUS VASCULATURE
Extremely compliant
Blood flow through papillary loops
are major determinant of heat
exchange through vasodilatation
Arteriovenous anastomosis in
glabrous skin are less efficient in heat
transfer
Blood flow through skin is regulated
by noradrenergic vasoconstrictors and
cholinergic vasodilators
ECCRINE SWEATING
Eccrine sweating cools skin by
evaporation of sweat from skin
surface
Sweat secretion is regulated by
sympathetic cholinergic nerves
EFFECTOR FUNCTION
Heat is lost from skin surface by
radiation, convection, conduction,
evaporation
40. REGULATION OF BODY TEMPERATURE
Warm and cold sensitive Thermoreceptors
distributed irregularly over skin
Stimulated by changes in temperature
Signal sent to hypothalamus
Temperature regulating mechanisms
41. REGULATION OF BODY TEMPERATURE
Increase in skin
temperature
Increase in core
temperature
Stimulates preoptic area &
Anterior hypothalamus
Inhibits sympathetic
nervous system
Sweating, Vasodilatation
& Rapid breathing
Decrease in skin
temperature
Decrease in core
temperature
Stimulates posterior
hypothalamus
Activates sympathetic
nervous system
Shivering and
vasoconstriction
42. III.SENSORYAND AUTONOMICFUNCTIONS
AUTONOMIC NERVOUS SYSTEM
Maintains cutaneous homeostasis
Post ganglionic cholinergic parasympathetic nerves
Adrenergic and cholinergic sympathetic nerves
Maintenance of body temperature
Flight or fight reaction
NEUROTRANSMITTERS
Acetylcholine, adrenaline, noradrenaline and neuropeptides
Acetylcholine – Sweat production
Adrenergic fibres – Vasoconstriction
Acetylcholine, VIP, PMH – Vasodilators
Adrenergic fibres – Arrector pili contraction
43. NEUROPEPTIDES
C and A fibres release a variety of neuropeptides in
response to noxious stimuli
Tachykinins
Substance P
Neurokinin A
Calcitonin gene related peptide
FUNCTIONS
Function as neurotransmitter in regulating synaptic function
Involved in Nerve transmission
Mediates inflammation
44. PATHWAY OF ANS
Sympathetic ganglia
Post ganglionic fibres
Co distributed with sensory neurons
Terminate in autonomic plexus
Supplies sweat glands, blood vessels &
arrector pili muscle
45. SENSORY INNERVATION OF SKIN
Afferent system
conducting stimuli from
skin to CNS
Myelinated A fibers
Unmyelinated C fibers
In the upper dermis small
myelinated nerves lose
their nerve sheaths and
together with
unmyelinated C fibres end
in free nerve endings or
specialized sensory
receptors
46. MECHANORECEPTORS
Slowly adapting
mechanoreceptors
respond continuously to
persistent stimulus
Rapidly adapting
mechanoreceptors
respond at the onset and
end of a stimulus
Hairy skin: Predominant
mechanoreceptor in hairy
skin is hair follicle
receptor – mediate touch
Glabrous Skin
(Superficial)
Meissner
Corpuscle (Rapid)
Merkel Receptor
(Slow)
Hairy & Glabrous
skin
(Deep)
Pacinian
corpuscle (Rapid)
Ruffini’s
corpuscle (Slow)
47. THERMORECPTORS
WARM RECEPTOR
Steady discharge at 32-45*C
Warming causes acceleration of the discharge
COLD RECEPTOR
Normal skin temperature is 34*C
Cold receptors are activated 1-20*C below normal skin temperature
NOCICEPTORS
Mechanical nociceptors – strong mechanical stimulus
Heat nociceptor – skin temperature > 45*C
Cold nociceptor – cold noxious stimuli
Polymodal nociceptor
48. Cerebral Cortex (Anterior cingulate cortex, Brodman Area 24)
Thalamus
Crossover to contralateral spinothalamic tract
Synapse with secondary neurons
Enters dorsal column of spinal cord
Polymodal Nociceptors PATHWAY SENSATION
Dorsal Column Touch, Pressure,
Vibration,
Proprioception
Ventral
Spinothalamic tract
Touch, Pressure
Lateral
spinothalamic tract
Pain, temperature
PATHOPHYSIOLOGY OF ITCH SENSATION AND PATHWAYS
49. IV. IMMUNOLOGICALFUNCTIONS
ANTIGEN PRESENTING CELLS
Langerhan cells in epidermis
Dendritic cells in dermis
T – LYMPHOCYTES
Found in dermis, grouped around post
capillary venules and appendages
Intraepidermal T cells – Only 10% of
total T cells
Recognize antigens only if present by
APCs
Cytotoxic T cells (CD8+) – MHC I
Helper T cells (CD4+) – MHC II
50. SKIN AS IMMUNOLOGICAL BARRIER
1. Alternate pathway of complement activated by microbial
substance in absence of specific antibodies
2. CYTOKINES: IL 1 – Initiates inflammation and repair, IL 7
– Regulates epidermal lymphocyte survival & proliferation,
TGF-β regulates growth of keratinocytes, fibroblasts and
leucocyte development. Keratinocyte cytokines can
(i) initiate inflammation (IL-1, TNF-α, IL-6),
(ii) modulate LC function (IL1, GM-CSF, TNFα, IL10, IL15)
(iii) T cell activation (IL15 and IL18)
(iv) T cell inhibition (IL10, TGF)
3. CHEMOKINES : Govern influx and efflux of leucocytes in
and out of the cell
51. Change
• Phenotypic & Functional
Leave
• Epidermis
Enter
• Dermal Lymphatics
Migrate
• Paracortical areas of draining
lymph node
Present
• Antigen-MHC complex to TCR
Express
• Primed T cells express various
receptors
4. ANTIGEN PRESENTATION
52. V. VITAMIND BIOSYNTHESIS
UVB (295 – 315 nm)
7-dehydrocholesterol is
converted to
cholecalciferol(D3)
First hydoxylation in liver
(25-hydroxy
cholecalciferol)
Second hydroxylation in
kidney (1,25-
dihydroxycholecalciferol)
53. VI. VITAMIN E SECRETION
Sebaceous glands secrete vitamin E into the upper
layers of facial skin
Protects skin surface lipids and stratum corneum from
harmful oxidation
VII. ANTIOXIDANT FUNCTIONS
Skin contains antioxidant enzymes (superoxide dismutase,
catalase, glutathione peroxidase ) and non enzymatic
antioxidant molecules (vitamin E, coenzyme Q,
ascorbate and carotenoids).
54. VIII. XENOBIOTIC METABOLISM
Skin has a wide range xenobiotic metabolizing
enzymes including phase I oxidative, hydrolytic,
reductive enzymes and phase II conjugating enzymes
IX. SOCIOSEXUAL COMMUNICATION
Improves visual appeal and sexual attraction
Apocrine sweat gland’s secretion acts as
-Sexual attractants (Pheromones)
- Territorial markers
- Warning Signals
