Skin

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Description

Skin is part of the integumentary system and is the largest and primary protective organ of the human body. It covers the body's entire external surface and serves as a first-order physical barrier against the outer environment.

Structure

The skin is made up of three layers.

• The epidermis, the outermost layer of skin, provides a waterproof barrier and contributes to skin tone.
• The dermis, found beneath the epidermis, contains connective tissue, hair follicles, blood vessels, lymphatic vessels, and sweat glands.
• The deeper subcutaneous tissue (hypodermis) is made of fat and connective tissue.

Epidermis

The epidermis is further divided into:

• 5 layers on thick skin like the palms and soles (stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum)
• 4 layers in other places (lacking the stratum lucidum)

The epidermis is a stratified squamous epithelium that contains four to five layers depending on its location:

1. Stratum Basalis (Basal cell layer): It is deepest and closest to the dermis. The stratum basale contains basal keratinocytes, immune cells such as Langerhans cells and T cells, and melanocytes that provide the skin with pigmentation. Keratinocytes from this layer evolve and mature as they travel outward/upward to create the remaining layers.
2. Stratum Spinosum (Prickle cell layer): This layer compromises most of the epidermis and contains several layers of cells connected by desmosomes who keep cells tightly bound to one another and resemble "spines"
3. Stratum Granulosum (Granular cell layer): This layer contains several layers of cells that contain lipid-rich granules. In this layer, cells begin to immortalize and lose their nuclei, as they move away from the nutrients located in the deeper tissue. Keratinocytes in the stratum granulosum contain cysteine- and histidine-rich granules, which bind keratin filaments together.
4. Stratum Lucidum: This layer is only present in the thick skin of soles and palms and consists of mostly immortalized cells. It is a thin, clear layer of dead keratinocytes. Instead of keratin, keratinocytes in the stratum lucidum contain eleidin, a clear intracellular protein, which gives this layer its transparent appearance.
5. Stratum Corneum (Keratin layer):  It is the outermost layer of the epidermis. This keratinized layer serves as a protective overcoat and due to keratinization and lipid content, this layer allows for the regulation of water loss by preventing internal fluid evaporation.

Dermis

Dermis lies deep to the epidermis. It is a thick layer of connective tissue consisting of collagen and elastin which contributes to skin’s strength and flexibility, respectively. It also contains nerve endings, blood vessels, and adnexal structures such as hair shafts, sweat glands, and sebaceous glands.

The dermis is divided into two layers:

• Papillary dermis (the upper layer): The apical layer of dermis folds to form papillae that extend into the epidermis like tiny finger-like projections and is referred to as the papillary dermis. It contains capillaries that facilitate the transport of nutrients.
• Reticular dermis (the lower layer): The lower layer of the dermis is referred to as the reticular dermis. It contains skin appendages such as hair follicles, sebaceous glands, and sweat glands. The presence of a dense concentration of collagenous and reticular fibers interwoven within this layer makes the reticular dermis is significantly thicker than the papillary dermis.

Both dermal layers contain fibroblasts, myofibroblasts, and immune cells such as macrophages, lymphocytes, and mast cells. Fibroblasts synthesize an extracellular matrix comprising of collagen, proteoglycans, and elastic fibers that provide the structural integrity of the dermis. 

Hypodermis

• The hypodermis is the third and deepest layer, consisting mainly of adipose tissue.
• Skin adipose tissue stores energy in the form of fatty acids and functions as an endocrine organ important for glucose homeostasis and lipid metabolism.
• This layer consists of fibrocytes and adipocytes and is rich in proteoglycans and glycosaminoglycans, which confer mucus-like properties to the layer. This layer also produces a variety of mediators such as growth factors, adipokines, and cytokines, and contains multiple immune cells.
• Subcutaneous fat serves as an insulating layer for the body, as fat is a poor conductor of heat.

Physiological Factors:

Thickness of skin:

• It varies based on its location, age, gender, medications, and health affecting the skin’s density and thickness. As explained above the varying thickness is due to changes in the dermis and epidermis. The palms and soles have a thick skin where there is marked keratinization and the stratum lucidum layer and thinner skin is found on eyelids, axillae, and genitals, as well as the mucosal surfaces exposed to the external environment such as oral mucosa, vaginal canal, and other selected internal body surfaces.
• The skin thins during the fifth decade of life, primarily due to changes in the dermis with loss of epithelial appendages, elastic fibers, and ground substance, among others.
• Genetics also influence natural skin contour. For example, people of African-American descent typically exhibit thicker and more lustrous skin compared to people of Anglo-Saxon ancestry.
• Environmental factors also affect skin thickness. For example, a person with an occupation requiring much outdoor exposure to the sun and ultraviolet radiation show premature skin aging signs sooner than a person working indoors.

Innervation

• The skin is innervated by sensory nerves expressing receptors that can sense pain (nociceptors), itch (pruriceptors), temperature (thermoreceptors), and touch (low-threshold mechanoreceptors). These receptors are present as nerve free endings.
  1. Nociceptive nerves are in close contact with hair follicles and epithelial cells with their free nerve endings terminating at various levels of the epidermis
  2. Merkel cells are involved in mechanosensation (light touch) theses are oval-shaped cells interspersed in the basal layer of the epidermis and innervated with sensory fibers. 
  3. Meissner’s corpuscles are localized in the papillary dermis and are sensitive to touch
  4. Pacinian corpuscles are located in the reticular dermis and are responsive to pressure and vibration. Both types of corpuscles are supplied by Aα and Aβ sensory nerve fibers that are situated in the sensory ganglia.
  5. Thermoreceptors, critical for sensing thermal differences between the skin and the external environment, are expressed on both heat- and cold-sensitive nerves, with the skin being more densely populated by cold-sensitive nerves. Activation of thermally sensitive nerves to either heat or cold results in vasodilation, vasoconstriction, sweating, or shivering.
• Other mechanoreceptors are present in the skin as corpuscles.
• Cell bodies of nerves innervating the skin are present in the trigeminal and dorsal root ganglia.

Blood Supply and Lymphatics

• The skin is highly vascularized and is supplied by plexuses found between the reticular and papillary layers of the dermis.
• The blood supply originates from an extensive network of larger blood vessels and capillaries that extend from regional branches of the systemic circulation to local sites throughout subcutaneous tissue and dermis, respectively.
• There is an extensive lymphatic framework that runs alongside many of the skin’s blood vessels, particularly those attached to the venous end of the capillary networks.

Muscles

Arrector pili muscles are the smallest skeletal muscles of the body, that are found in all areas of the skin that contain hair follicles. These muscles control the positioning of hairs and the activity of sebaceous glands in response to environmental induction, such as heat and abrasion. The arrector pili muscles contract and raise the hairs under conditions of stress when the sympathetic nervous system is activated such as during the fight or flight response.

Functions of the Skin

The functions of the skin are:

• Protection: Protects against microorganisms, dehydration, ultraviolet light, and mechanical damage. Skin is the first physical barrier that the human body has against the external environment.
• Sensation: pain, temperature, touch, and deep pressure.
• Mobility: allows smooth movement of the body.
• Endocrine: Skin initiates the biochemical processes involved in Vitamin D production, which is essential for calcium absorption and normal bone metabolism.
• Exocrine activity: by the release of water, urea, and ammonia. Skin secretes products like sebum, sweat, and pheromones, and also exerts important immunologic functions by the secretions of bioactive substances such as cytokines.
• Immunity development against pathogens.
• Temperature Regulation: Skin participates in thermal regulation by the conservation or release of heat and helps to maintain the body’s water and homeostatic balance

Clinical Relevance

Skin pigmentation

The melanin molecule plays a role in skin pigmentation. It offers photo-protection to the organism by absorbing the Sun's ultraviolet radiation. The melanic pigments and determine the colour of the skin, hair, and eyes.

• White color - lack of melanic pigment
• Black color - increased melanin density

The ratio between the two types of melanic pigments (eumelanin-pheomelanin) determines the differences in pigmentation of the human skin.

• Quantity of pheomelanin > quantity of eumelanin = Light color skin and has a higher susceptibility to sunburns.

Research shows that the skin with a higher quantity of pheomelanin has a cancer risk following the exposure of the sun ultraviolet radiation, as higher quantity of reactive species of oxygen are produced, leading to a cellular lesion and initiating the carcinogen process.

Skin response in wound healing

The wound healing process consists of four phases: hemostasis, inflammation, proliferation, and remodeling.

• Disruptions in any of the phases of wound healing result in impaired healing.
• A prolonged inflammatory phase may result in chronic wounds and inefficient wound healing.
• Perturbed proliferative and remodeling phases may lead to irregular wound closure, fibrosis, and scarring.

Common non-healing chronic wounds

Venous stasis ulcers, arterial stasis ulcers, pressure ulcers, and diabetic wounds are the most common non-healing chronic wounds.

Burns

• First-degree burn affects the epidermal layer of the skin
• Second-degree, which affects the dermis,
• Third-degree injury that goes as deep as the subcutaneous tissue.

Burn injuries are characterized by an intense inflammatory phase and edema. Blistering is also commonly found in burn patients with second-degree injuries. Severely burned patients usually present a variety of systemic complications, such as depressed or aggravated immune responses, electrolyte imbalance, sepsis and multiple organ dysfunction syndromes, and inflammation-associated psychological effects are seen in severely burned patients.

Early wound closure reduces the risk of infection and fluid losses and reduces mortality, length of hospital stay, and subsequent hypertrophic scarring.

Wound Complications

Infections

Impaired wound healing can lead to local or systemic infections.

Nerve damage

Wounds extensive in skin depth usually result in nerve damage. Patients with nerve damage suffer a partial or complete loss of sensory or motor functions in the affected area, numbness, and pain.

• A nerve can be transected during lacerations. 
• Burn injuries, especially third-degree burns, manifest nerve damage resulting in complete loss of sensation at the affected site.

Hypertrophic Scarring and Keloids

It is the result of overproduction of collagen in the wound bed by fibroblasts. Scar tissue is characterized by the lack of skin elements such as hair follicles and sebaceous glands. Hypertrophic scarring is common in burns and cutaneous injuries affecting the dermal layer of the skin.

Skin Microbiome

Skin is colonized by beneficial microorganisms that serve as a physical barrier to prevent the invasion of pathogens. The skin microorganisms play an essential role in protecting against invading pathogens, the education of our immune system, and the breakdown of natural products.

Staphylococcus epidermidis and Propionibacterium acnes are the major commensal microbes that inhabit the skin. They protect the host by competing for habitable space, preventing colonization of the skin by pathogenic microbes. Commensal strains can secrete their antimicrobial agents, such as bacteriocins, which inhibit the growth of pathogenic bacterial strains. Colonization of the skin by pathogenic strains is usually associated with low commensal strains.

The fungi kingdom is not very diverse and the viral microbiome is not well delineated and although not as diverse as the bacterial kingdom, it exhibits more diversity than that of fungi.

Skin as an Immune Organ

Skin protects the host from invasion by employing physical barriers, biomolecules, immune and non-immune cell intricate network and skin structures

Physical Barrier

Corneocytes in the Stratum Corneum contribute to the barrier function of the epidermis. These cells are arranged in “bricks and mortar” fashion interspersed by lipids such as ceramides, cholesterol, and free fatty acids.

• Each corneocyte contains a lipid envelope linked to keratin filament bundles that fill the intracellular compartments of the corneocyte, thus increasing its rigidity.
• The stratum corneum is made of three layers and it is both an outside‒in barrier to prevent the entry of foreign substances and microorganisms, and an inside‒out barrier to prevent water loss.
• Junction adhesion molecules and tight junction proteins (Claudin-1/zonula occludins-1) found in epidermal layers also add to the formation of the physical barrier.

Disruptions in the expression or function of these components may cause improper barrier formation or skin disorders or inflammatory conditions in the skin. Studies have shown that the skin of patients with atopic dermatitis has reduced expression levels of ZO-1 and claudin-1.

Skin pH

Skin pH is acidic and ranges between 4 to 6 The body’s internal environment maintains a near-neutral pH (7–9). There is a gradient of 2–3 units between the SC and underlying epidermis and dermis. Recent research suggests skin pH depends on several key enzymes involved in the synthesis and maintenance of a competent skin barrier. Age, anatomic site, sebum, sweat, genetic predisposition affect the pH along with the use of creams, soaps, and cosmetics. Various mechanisms maintain a low pH of the skin:

• Enzymatic processes and fatty acids, sweat glands in the SC lower the pH of the skin.
• Sweat glands secrete a vast collection of antimicrobial peptides, which restrain various microbes' growth on the skin. During rigorous physical exercise, dermcidin, an antimicrobial peptide, is secreted by the sweat glands onto the skin's epidermal surface. Research suggests that dermcidin gets activated in salty and slightly acidic sweat, which can perforate microbe membranes, allow water, and charged Zinc in sweat to gush across the cell membrane, kill the microbe.
• Besides, the physiological pH of the skin is for commensal bacteria such as Staphylococcus epidermidis, which helps in preventing pathogenic strains such as Staphylococcus aureus from establishing infections in the host.

Immune and Non-immune Cells

• Skin-resident immune cells promote tissue function in homeostasis and guard the body by actively sampling environmental antigens. Some resident immune cells migrate to lymph nodes to either induce peripheral tolerance to tissue self-antigens or initiate robust immune responses. In infections or tissue injury, immune cells resident in the skin and those infiltrating from the periphery interact to create an intricate defense network to resolve the insult and restore the tissue to its original state.
• Skin-resident myeloid cells include Langerhans cells, dermal dendritic cells, macrophages, mast cells, and eosinophils that contribute to skin homeostasis by secreting growth factors needed for the survival of keratinocytes, fibroblasts, and endothelial cells. They phagocytose debris and apoptotic cells and support vasculature integrity. In inflammatory conditions, myeloid cells respond immediately and produce pro-inflammatory mediators that drive cell activation and infiltrate the affected area by peripheral immune cells. Skin myeloid cells also serve as a link between the innate and adaptive immune systems.

Biomolecules

Antimicrobial peptides (AMPs) and lipids are the main classes of biomolecules that participate in skin defense by disrupting bacterial membranes.