Functions of Skin and Subcutaneous Tissues PDF

Functions of Skin and Subcutaneous Tissue Prof. Thomas E. Adrian - [email protected] Skin Pore of sweat gland Stratum corneum Granular layer Epidermis Prickle cell layer Basal cell layer Skin has a surface containing melanocyte...

Functions of Skin and Subcutaneous Tissue Prof. Thomas E. Adrian - [email protected] Skin Pore of sweat gland Stratum corneum Granular layer Epidermis Prickle cell layer Basal cell layer Skin has a surface containing melanocytes area of about two Langerhan’s cells square meters in Nerve ending humans and Dermis Arrector pili muscle represents one of Sebacious gland the major barriers Hair shaft between us and our Vein environment Artery Subcutis Sweat Gland Fat Muscle Functions of Skin Barrier Sun and Radiation, Toxic substances, Microbes, Prevents Loss of Essential Body Fluids Excretion Toxic substances in sweat (some urea and creatinine is excreted too) Metabolic Formation of vitamin D and activation of cortisol from corticosterone Sensory Touch, Heat, Cold, and Pain Support Mechanical support for underlying tissues and protects the body from injuries Temperature Regulation Both Skin and Subcutis involved Barrier The skin, as an interface between the organism and the external environment, plays a major role in protecting and supporting the life it encloses Has the permeability barrier and provides defense or protection against Microorganisms: bacteria, viruses and parasites Harmful materials in the external environment Physical damage Thermal (protect from heat and cold) Ultra-violet light Oxidants Epidermal Barrier The epidermal permeability barrier function, which impedes the transcutaneous movement of water and important electrolytes, is important for terrestrial life (prevents loss of fluid and electrolytes) This barrier resides in the stratum corneum, a resilient layer composed of corneocytes and intercellular lipids Perturbation of the barrier is currently considered to be a primary pathophysiologic factor for many skin diseases and abnormal barrier function is associated with atopic dermatitis (eczema) and psoriasis  Permeability Barrier The stratum corneum is composed of two different structural components: the corneocytes (bricks) Stratum and intercorneocyte lipid matrix (mortar) corneum Both components are derived from keratinocytes through a terminal differentiation process Corneocyte Intercorneocyte lipids The corneocytes (terminal differentiated) provide structural support and act as hydrating reservoirs for adequate enzymatic processes (enzymes work in fluid media) The cornified envelope, that surrounds the corneocytes, is comprised of structural proteins with an outer membrane-bound lipid layer Barrier Functions of the Stratum Corneum li Antimicrobial, anti-oxidant UV and mechanical barrier and permeability barrier Corneodesmosomes Protective Functions The epidermis expresses proteins, such as keratins, and other molecules that perform the protective functions Inflammatory mediators (prostaglandins, leukotrienes, other eicosanoids, and cytokines) are synthesized and secreted from keratinocytes to regulate the skin's immune responses Melanin, vitamin D and C metabolites, and heat-shock proteins are also expressed in keratinocytes and play important roles in thermal and UV-barrier functions The antimicrobial systems in skin are primarily mediated through the surface lipids, skin surface acidification, iron-binding proteins (siderophores) and antimicrobial peptides Melanosome Transfer From Melanocytes to Keratinocytes Melanocyte Keratinocyte Pigment Globules Melanosomes Nucleus Nucleus Anti-Microbial Function Skin produces a number of antimicrobial peptides (AMPs) and proteins, including human defensins (many structurally-related small peptides) and cathelicidin (the precursor of LL-37 and FALL-39 in humans) AMPs that play a major role in innate defenses, are small, cationic polypeptides that inhibit the growth of bacteria, viruses and fungi and activate cellular and adaptive immune responses AMPs mediate inflammation, influencing cell proliferation, wound healing, cytokine and chemokine production and chemotaxis  Anti-Microbial Function β-defensins and cathelicidin (precursor of LL-37 and FALL-39) are localized in the lamellar bodies (LBs) which are essential for the epidermal barrier formation involved in antimicrobial function Abnormal expression of AMPs is seen in skin diseases showing disturbed skin barrier function, such as psoriasis and atopic dermatitis (AD) LL-37, hBD-2 and hBD-3 are up-regulated in psoriatic skin lesions and downregulation of these proteins is seen in atopic dermatitis. Anti-Microbial Function The expression of LL-37 and hBD-2 are down-regulated in atopic dermatitis (AD) lesions This correlates with the high susceptibility of AD skin to bacterial and viral infections Epidermal expression of LL-37 is increased by UVB exposure and 1,25-dihydroxycholecalciferol (cacitriol) Increases in AMPs explain the beneficial effect of UV phototherapy in AD [Free fatty acids, glucosylceramides and sphingosine, and hydrolytic products of ceramide also contribute to the antimicrobial barrier]  Sense Organs in the Skin We can detect: - Heat and cold (thermoreceptors) - Changes in Pressure (Pacinian) - Nociceptors sense pain - Meissner’s corpuscle senses touch Neural Receptors in Skin Meissner’s corpuscles: encapsulated nerve endings attached to the epidermis in the dermal papillae that detect changes in texture, light touch and low frequency vibrations Merkel‘s disks: arborizations of non-myelinated axons that end in terminals on specialized tactile cells, and which detect light touch and steady pressure, such as gripping something in the hand Pacinian corpuscles: respond to changes in pressure and high frequency vibrations Ruffini endings, encapsulated receptors that respond to skin stretch Skin Structure Light pressure, gripping in hand. Touch (very light Stretch pressure) and low frequency vibrations. Texture Transient pressure and high frequency vibrations Neural Receptors in Skin There are also free nerve endings that serve sensory functions These nerve endings respond to a variety of different types of touch-related stimuli They also serve as sensory receptors for both thermoception (temperature perception) and nociception (painful stimuli) In hairy skin there are also nerves that end along with the hair follicles for piloerection (causing the hair to “stand on end” or “goosebumps” in humans) Primary Afferent Axons Nerve fiber Myelin Sheath Axon Type Aα Aβ Aδ C Diameter (µm) 13-20 6-12 1-5 0.2-1.5 Speed (m/sec) 80-120 35-75 5-35 0.5-2.0  Sensory Receptors A-fibers – myelinated - fast conduction velocity A-α carry information related to proprioception A-β carry information related to touch A-δ carry information related to pain and temperature (instant pain from stimulus ) C-fibers – unmyelinated - low conduction velocity C-fibers carry information related to pain, temperature and itch Homework: Whack your thumb with a hammer and first you feel instant pain (A-δ fibers) and then throbbing pain (C-fibers) Sensory - Cutaneous Innervation Glabrous skin (palms of hands and soles of feet) has a high density of sensory receptors to elucidate touch and textures as well as for gripping. The exposed mucous membranes (lips, anal mucous membrane, external genital organs) are very densely innervated by ↓ “Free” (unencapsulated) nerve endings of myelinated axons are found within the dermis of those areas (Merkel’s) Distribution of Sensory Neurons The distribution of the sensory neurons within the skin accounts for the large and overlapping receptive fields of the skin The size of the receptive fields in turn explains why almost any given stimulus to the human skin can potentially activate a very large number of nerve terminals Therefore, it is more likely that a stimulus caused by the prick of a needle be detected by more than a hundred nerve endings all sharing the same receptive field, than for that same needle prick to be detected by only one nerve ending Types of Sensory Neurons The different kinds of stimuli that are picked up by sensory neurons are grouped into two categories: epicritic and protopathic Epicritic neurons detect gentle touch such as caresses; light vibrations; the ability to recognize the shape of an object being held; and two-point discrimination, or the spacing of two points being touched simultaneously Protopathic neurons are responsible for detecting pain, itch, tickle, and temperature This allows for a relative specificity between stimuli and receptor Pathways to the CNS The sensory neurons coming from the body synapse in the dorsal horn of the spinal cord, bringing in information about touch sensations (epicritic), or modalities of pain (protopathic) The area of the dorsal horn where they synapse and their pathway to the thalamus is different Neurons transmitting pain, temperature, touch, vibration, and proprioception sensations synapse in the dorsal horn to form reflex circuits, but also send axon branches to the brainstem While the neurons for touch sensations (epicritic neurons) ascend ipsilaterally, neurons for pain and temperature (protopathic neurons) ascend contralaterally to the thalamus and cerebral cortex The Sensory Neurons Have Their Cell Bodies in the Dorsal Root Ganglia Grey matter Receptor White matter Dorsal root ganglion Sensory neuron Pin Muscle Motor neuron Interneuron Ventral root The Pain Reflex UV Radiation UV rays make up only a small portion of the sun’s rays, but are the main cause of the sun’s damaging effects on the skin UV rays damage the DNA and skin cancers start when this damage affects the DNA of genes that control cell growth There are 3 types of UV rays from the sun: 1. UVA rays: age skin cells and damage DNA. These rays are linked to long- term skin damage such as wrinkles (arrugas), and play a role in some skin cancers 2. UVB rays: have more energy than UVA rays. They can damage skin cells DNA directly, and are the main rays that cause sunburns and skin cancers (B for bad) 3. UVC rays: high energy, but are absorbed by our atmosphere UV Penetration Into the Layers of Skin But what if ozone is damaged? UVA: wavelength 315-400 nm, low energy UVB: wavelength 280-315 nm, higher energy UVC: wavelength 200-280 nm, high energy Ozone layer UV Penetration Into the Layers of Skin Epidermal Melanin Melanin is a large bio-aggregate composed of subunits of different pigment species formed by oxidation and cyclization of the amino acid tyrosine Melanin exists in two main chemical forms: (1) eumelanin, a dark pigment expressed in the skin of heavily pigmented individuals (2) pheomelanin, a light-colored sulfated pigment resulting from incorporation of cysteines into melanin precursors Pheomelanin levels are similar between dark-skinned and light-skinned individuals It is the amount of epidermal eumelanin that determines skin complexion, UV sensitivity and cancer risk Eumelanin is much more efficient at blocking UV photons than pheomelanin Fair-skinned people who are almost always UV-sensitive and have high risk of skin cancer have little epidermal eumelanin UV Light and Skin Cancers Basal cell cancers account for more than a million cases in the USA each year and squamous cell cancers another 250,000 Each year more than 90,000 people in the USA are diagnosed with melanoma and more than 9,000 will die from the disease UV light is a major risk factor for basal cell and squamous cell carcinomas (which are very common and easily treated) and for melanomas (which are highly malignant) UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter Tanning beds increase the risk too Epidermal Melanin Content and Cancer Risk Low levels of Most amount of eumelanin eumelanin dark skin (highest level (lowest risk of skin of skin cancer) cancer)  Temperature Regulation Skin helps maintain an even core temperature (38oC), by giving off heat (vasodilation) or blocking this when the outside air is too cool (vasoconstriction – keeps you warm) The amount of heat which is thrown off at any time is proportional to the body surface area (small babies are more challenged for temp regulation) Skin has about 4 million sweat-glands and sweating is the method of getting rid of excess heat We are perspiring constantly, but usually to such a slight extent that we hardly notice the fact During exercise or in intensive heat can generate 3L sweat/h Sudoriferous Glands - Sweat Glands Glands in humans differ in structure, function, secretory product, mechanism of secretion and distribution Eccrine Glands: Found almost everywhere (except lips, ear canal, glans penis, etc.) with highest concentration on palms, soles and head; water/electrolyte secretion; cholinergic stimulation; provides a primary form of cooling (! 4 points) Apocrine Glands: Found in axilla, perineum, areola and reproductive organs; proteins and lipids in the secretion; do not provide cooling, and are most active in stress, fear, or sexual arousal, partly stimulated by adrenergic receptors (4) Sudoriferous Glands - Sweat Glands Apo-eccrine Glands: Larger than eccrine, but smaller than apocrine; found in axilla and perianal region; produce the most sweat of all; stimulated mainly by cholinergic receptors with some input via adrenergic receptors Ceruminous glands (earwax), mammary glands (milk), ciliary glands (eyelids) are modified apocrine (sweat) glands (so most likely adrenergic)  Pathways of Sweat Secretion The hypothalamus triggers sweating via sympathetic pathways The postganglionic fibers synapsing with sweat glands utilize acetyl choline acting on muscarinic receptors as the major pathway of stimulation Note this is an exception to the rule that most postganglionic sympathetic nerves produce norepinephrine Other exceptions are the adrenal medulla that produces mainly epinephrine and the kidney (dopamine as final NT here) Transmitters such as CGRP, VIP, NO contribute by stimulating vasodilatation at skin + enhancing loss of heat. Role of Sweating in Temperature Regulation Through exercise production of heat increases and sweating is induced via eccrine and apo-eccrine glands Almost entirely cholinergically driven Sweat is produced and collects on the skin Sweat glands can produce up to 2-3 liters of sweat/hour Can readily lead to fluid and electrolyte loss (have to replenish asap) It is estimated that fifteen per cent of the total body heat is given off through the skin, and ten per cent by the lungs Heatstroke In a warm environment the hypothalamus triggers cutaneous vasodilation to increase evaporation Exposed to a hot environment for a long time or if there is extremely high temperature or humidity then this evaporative loss will fail to normalize core temperature Body becomes depleted of fluid and salts, leaving nothing to maintain the evaporation process Core temperature soars above 39.5oC (threshold for heatstroke) Symptoms of Heatstroke Body temperature soars above 39.5oC Red, hot, dry skin Tachycardia Throbbing headache Nausea Dizziness Confusion – because of the lack of body fluid Unconsciousness Skin Response to Cold Environment Exposure to cold stimulates cold receptors of the skin which causes cold thermal sensations and stimulation of the sympathetic nervous system Sympathetic stimulation causes vasoconstriction in skin, arms and legs Central core temperature defense occurs at the expense of a decline in skin temperature Sympathetic stimulation also elicits the pilo-erectile reflex Alcohol Elicits a Warm Sensation But Actually Causes Cutaneous Vasodilation Saint Bernard dogs have been used for centuries for mountain rescue in the Alps Their acute sense of smell allows them to find people buried in snow Legend has it that they carry a flask of brandy to warm up and revive the people they rescue Excretion Eccrine Sweat Glands Some metabolic waste is excreted via the sweat glands This includes salts, urea, uric acid and lactic acid, aiding in osmoregulation Hair follicle Sebaceous gland The sebaceous Straight Duct glands secrete lipids Apocrine gland (secretory portion) Metabolic Functions Skin is involved with the production of vitamin D3 (calcitriol) from 7-dehydrocholesterol Skin is able to make active cortisol from cortisone, explaining how inactive cortisone is able to have potent anti-inflammatory properties when used topically on skin Sunlight Produces Vitamin D3 in Skin SUNLIGHT SPONTANEOUS Vitamin D3 7-Dehydrocholesterol Previtamin D3 SKIN (cholecalciferol) 25-Hydroxylase LIVER Other metabolites 25-Hydroxycholecalciferol 24-Hydroxylase KIDNEY 1α-Hydroxylase 24,25-Hydroxycholecalciferol 1,25-Hydroxycholecalciferol INACTIVE METABOLITE ACTIVE CALCITRIOL Activation of Cortisone in Skin by 11β - Hydroxysteroid Dehydrogenase 1 Kidney Skin Aldosterone Colon Adipose tissue Responsive Salivary gland Liver Tissues Placenta Lung Fetus CNS  Effects of Intrinsic Aging In intrinsic aging, the thickness of the epidermis decreases with no change in the outermost epidermal layer, the stratum corneum. The rate of generation of keratinocytes, which end their lives as the stratum corneum, slows with age (less production of keratin), aka less corneocytes The decreasing number of melanocytes reduces photoprotection, and the decrease of Langerhans cells reduces immune surveillance Intrinsic aging of the dermis affects mainly the extracellular matrix The amount of elastin (skin less stretchy) and collagen decreases, and structures change Glycosaminoglycan composition also changes (drier skin) As a result, the dermis thins by ~20% and becomes stiffer, less malleable, and more vulnerable to injury Effects of Aging on Skin Effects of Intrinsic Aging Aging reduces the number and function of sweat glands as well as the production of sebum by sebaceous glands (less lipid components being produced) The number of active melanocytes in hair follicles decreases, resulting in graying of the hair Nail growth also slows with increasing age. UV light (e.g. from tanning beds) increases the extent of intrinsic age changes in both the epidermis and dermis, and it has additional effects For example, photo-aging causes coarse wrinkles, which occur minimally or not at all because of intrinsic aging UV Exposure and Skin Aging Over time, the sun's UV light damages elastin fibers in the skin The breakdown of elastin fibers causes the skin to sag, stretch, and lose its ability to snap back after stretching The skin also bruises and tears more easily and takes longer to heal than younger people Sun damage will become evident later in life Effects can be minimized by avoiding too much direct sunlight (or wearing a suitable hat, using sunscreen, etc)  Extrinsic Aging Often thought synonymous with photoaging, but several other factors contribute Smoking Alcohol dries the skin Stress direct action of cortisol on skin thinness Diet (lack of vitamins, particularly ADEK) Oxidation However, an extensive French study concluded that extrinsic factors only contribute about 10% to normal aging Skin Structure