1. Function of the Skin and Mucus Membranes:

     The internal structures of the body are entirely covered by a continuous layer of epithelial tissue. The part of this layer which is in contact with the outside environment is called the skin; those parts of it that lie within the body (and are yet outside it) are the mucus membranes.

     This idea of a structure being both inside and outside may be confusing, and it may help to consider the body as a long doughnut, the skin and mucus membranes corresponding to the outside of the doughnut and the internal structures being encased between them. The part of the doughnut which is around the hole corresponds to the mucus membranes, the rest to the skin. See also Figure 394.

     This continuous layer has a number of functions. Many of these are seen in the skin, and some are confined to it. Others, in contrast, are seen better in the mucus membranes and may not be seen in skin at all. One of the most important functions, that of protection against invasion, is shown by both.

     The skin, in most mammals, is exposed to an environment cooler than the internal organs. Together with hair and subcutaneous fat, all of which are good insulators, the skin prevents the loss of body heat. It does not act only as a mantle around the body; its functions in heat transfer are closely related to the temperature outside the body, and heat production inside. For example, animals exposed to cold divert blood to the deeper layers of the skin, which reduces heat loss, their body hair may grow longer, increasing the thickness of the insulating layer, and they tend to eat more, which increases the thickness of the subcutaneous fat layer.

     On the other hand, animals in hot environments divert blood to the superficial layers of the skin; they tend to shed hair and eat less; and perhaps most important, when the environment is very hot, they lose heat from the skin by the evaporation of water, released to the surface by the sweat glands. Each ml of evaporated water carries away a little more than half of a Calorie. The loss of a kilogram of sweat by evaporation represents 5.78 Calories, and would serve to cool the body of a 70kg man more than l4^oF. It must be noted here that sweat which does not evaporate does not cool the body at all. Whether or not sweat evaporates depends on the difference in vapor pressure of water in the air adjacent to the skin and the vapor pressure of water on the skin. Thus, a person exposed to air at 30^oC (86^oF) which is completely saturated with water vapor (vapor pressure 32 mm Hg), whose skin reaches a temperature of 35^oC(where the vapor pressure of water is 42 mm Hg) is quite capable of losing heat by evaporation, even though the humidity of the outside air is 100%. Men have been exposed to temperatures of l50^oC (300^oF) for short periods of time. If the air is dry, they are able to maintain body temperature quite easily, just by evaporating sweat.

     To a large extent, the use of clothing may reduce the ability of the skin to maintain body temperature at high outside temperatures, though it supports body temperature when outside temperature is low. Clothing through which water vapor passes slowly is particularly likely to produce discomfort when outside temperature is high, especially if the vapor pressure outside is also high, since water vapor is not carried away as well by moist air as by dry. At low temperatures, of course, clothing conserves heat, sometimes too effectively. Thus over-insulation at low temperatures, along with exercise may produce a microclimate around the skin, in which the air is saturated with water at body temperature and almost stationary. Sweating without evaporation results, and temperature is not regulated.

     The ideal hot weather clothing should be a good insulating material (several layers of any material separated by air or containing air will keep heat losses low), but on the other hand, it should be freely permeable to water vapor. Such clothing prevents losses of heat outside, where it is cold, and aid in the loss of heat by evaporation inside, where it is warm. Children going frequently from outside to inside and back will have a temperature problem if they wear leather or plastic clothing, since both are impervious to water. Cloth is much better.

     It is said that Eskimos keep warm with one layer of clothing. The parka, made of skin impervious to water and air, keeps them warm in the cold. When they are warm, they tilt out a bubble of warm, moist air by raising the front of the parka.

     There are two important sex differences in American and Europe with respect to the role of the skin in heat regulation. Women, who have much more subcutaneous fat than men, tend to suffer less from cold than men. They would tend to suffer more from heat, were it not for the fact that in general, women's summer clothing is lighter and much more pervious to water vapor than men's; it also covers less of their skin than men. The fact that women sweat less than men is attributable to these facts and is not directly related to sexual function. A minor sex difference has to do with body hair, and men have much more. It seems probable that the difference with respect to heat regulation is insignificant, but this is not certain.

     The most important function of the skin is related to the fact that it is further made up by a highly impenetrable, very dry epithelium. Bacteria and other organisms placed in contact with this surface find almost no foothold, very little nutrition, and no easy passageway to the extracellular space or blood. There are a few exceptions, some invading organisms can work their way through unbroken skin. The worm which causes schistosorniasis, a very common tropical disease, penetrates unbroken skin, and the agent which causes syphilis may penetrate normal skin, though some believe that small abrasions of the skin must be present. Other infectious organisms are usually barred, but exceptions exist and will be noted in Part 4.

     Similarly, most chemical agents, including highly poisonous toxins do not cross unbroken skin. Although it is not recommended, one may, if one likes, wash one's hands in sodium cyanide solution without particularly harmful effects, if the skin is unbroken. The toxin of tetanus can be handled with relative impunity, as can the botulinus toxin, the most toxic material known, for neither enter the body through unbroken skin.

     Some chemical agents, particularly those soluble in fat, can enter the body despite the skin's barrier against most substances. Estrogenic hormones can be administered in this manner, though it is an extremely inefficient method of introducing any drug. Some cosmetic manufacturers suggest the use of "hormone creams". This is good business, but bad physiology. It is said that some of the newer anti-cholinesterases and other agents usable in chemical warfare may penetrate unbroken skin; napa1m appears to, or at least is extremely adherent to skin.

     Mucus membranes usually play little role in the control of temperature because of their geometrical location. The mucus membranes of the nose, mouth, and pharynx are exposed to outside air as it goes in, but they are obviously unable to regulate body heat transfers by adding water vapor to entering air. Heat loss from the mucus membranes by evaporation is gained by the air entering the lungs. Air leaving the body is nearly saturated with water vapor and at body temperature, so that the mucus membranes cannot give up heat to it. This situation is probably altered in panting, when the "dead space" is a significant fraction of the tidal air. Since dead space air is essentially free of water vapor compared to alveolar air, significant exchanges of water and heat may occur by this route. This is best seen in dogs exposed to heat, but it is rather uncommon in man.

     The mucus membranes of the digestive tract and the urogenital tract, which play no role in heat regulation, are highly adapted for secretory activity. They are usually covered with their own secretions, which, as will be shown below, tends to diminish their protective role.

     The skin, which is quite dry, is in a state of continuous growth. The lowest layer of cells in the skin, which is in closest contact with the extracellular compartment and best nourished, is displaced upward by new cells, and these, in turn, are displaced by the next generation. Eventually the epithelium is stratified, the outermost layers are dry and dead, though still acting to protect the next lower layers, which act to protect those below them, and so forth.

     Mucus membranes constantly exposed to watery secretions lose their outermost layers more rapidly than the skin. This depends partly on the fact that these dead layers are wet, and in the digestive tract, on the fact that they are digested. They tend to be replaced rapidly by new growth, but the balance between new growth and loss may tip either way. When the losses exceed the growth, the mucus membranes erode. Peptic ulcer may result in this fashion, which was been discussed in Chapter 20.

     It is quite likely that the mucus membranes do erode, even to the level of blood vessels, in almost everyone. Toxic materials, even those not absorbable by normal mucus membranes, can now gain access to the blood stream. Cyanides are absorbed directly, and while the botulisa toxins proteins of molecular weight 19,000 to 900,000 are quite resistant to digestion, they seem nevertheless to be able to enter the blood stream through the mucosa of the intestine.

     Very likely, some intact food proteins enter the blood stream through areas not covered at the time by the intestinal mucosa. These may lead to immunity and hypersensitization to these proteins (Chapter 30).

2. Structure of the Skin and Mucus Membranes:

     The average thickness of skin is less than a millimeter. This excludes the subcutaneous tissues, which are much thicker. The surface increases with size, though less with weight than with height. It is about 1.5 m² in women and about 2.0 m² in men.

     The layers of the skin are separated by the growing area, or stratum germinatiuum. Below this area, there are blood vessels, sensory receptors, nerve fibers, etc. Above it are cells which have been pushed upward by the growth of new cells in the germinative layer. These cells are not supplied directly with blood. The further removed they are from the germinative layer, the more degenerative changes they show. The outermost cells, though quite dead, retain their property of adhering to each other, still forming a protective coat. The whole layer above the germinative layer is called epidermis.

     The germinative layer is deeply folded. The corium, or true skin, lies below it. In addition to blood vessels, touch receptors and nerve endings, it contains the hair follicles and associated structures and sweat glands. The hairs, originating in the true skin, pass through the epidermis, and the ducts of the sweat glands do the same.

     A belief cherished by most people is that there are no sweat glands in the skin of most animals, except in highly localized areas where there is no fur. The source of the belief is not clear. Horses sweat quite obviously, and most animals studied show sweat glands in intimate association with the hair follicle. Some animals have sweat glands not associated with obvious hairs, an attribute is shared with man, whose the hairless palms and soles sweat.

     Hair follicles originate deep within the corium. They are twisted in curly haired people. They cover most of the body, though the palms and soles, the red portions of the lips, the glans and prepure of the penis are exceptions. Most of the rest of the body seems to be hairless, but actually there are very fine hairs visible to the unaided eye everywhere, which are more numerous than they are in "hairy apes".

     Attached to each hair, there are sebareous glands the erectorpili, a small smooth muscle so arranged that when it contracts the hair becomes upright, nerve fibers, and, as mentioned, a sweat gland. The sebareous glands secrete a waxy material called sebum, which coats the hairs and keeps them almost unwettable and also makes the hair appear glossy. It has been mentioned that fat soluble materials can penetrate the skin, which they probably do so by way of the sebum. The smooth muscles attached to the hairs are innervated by the sympathetic nervous system. This can be activated by exposure to cold; the hairs, standing on end, make a thicker insulating layer. The nerve fibers attached to the hairs are extremely sensitive to stimuli which move the hair. All these structures are located in the corium.

     The structure of the skin is shown in Figure 395. Figure 396 shows the structure of the hair, the hair follicle, and the associated structures. The hair follicle is continuous with the germinative layer of the skin; thus, though it begins in the corium, the hair is an epidermal structure. When a hair is pulled, the germinative layer usually remains so that it grows back. As the hair formed in the deep germative layer rises through the corium, it picks up cells from the chorion and the layers above it, as well as sebum. The emerging hair has a fairly complicated structure. One generalization can be made about hair above the skin: it is solid throughout--there is no blood supply--and there are no fluids. A hair is shown in cross section in Figure 397.

     Nails: An infolding of the corium makes a double germinative layer. The growth of the nail, which is entirely epidermal, begins at the angle formed by the infolding. The germinative layer adds epidermal material throughout the nail bed. For reasons not well understood, there is only a very thin layer of living cells between the germinative layers and the nail itself. The reason for the transparency of nails is also unclear, for though there is a thin layer of epidermis which looks transparent, there are opaque layers both above and below it.

     The infolding of the corium occurs at the base and at the sides of the nail, so that the nail edges are covered by overlying skin. The structure of a nail is shown in Figure 398.

     Mucus membranes vary in structure according to their location. The mucus membranes of the gastrointestinal tract illustrate many properties of other mucus membranes.

     Since the mucus membranes line the inside of hollow organs which empty to the outside, the term lumen will be employed to avoid confusion. The lumen of hollow organs lined by mucosa is continuous with the outside, and the mucosa is continuous with the skin.

     In the intestine, the part of the mucus membrane nearest the lumen is only one cell thick. The infoldings which form the villi make its surface much greater without increasing the thickness. The cells, which correspond to the germinative layer of the skin, are columnar. Their arrangement is such that their secretions enter the crypts between the villi. Some of the cells are secretory, and others may be involved in absorption.

     Just below the basement membrane, the mucosa contains a rich network of blood vessels, lymphatics, nerves, and muscles. These muscles should not be confused with the muscles of the intestinal wall. They are specifically designated as the muscularis mucosae.

     Quite obviously, mucosal surfaces offer much less protection to the body than the skin. They are thinner, and, because they are almost invariably moist, they offer a favorable environment for the growth of micro-organisms. The structure of a typical mucus membrane is shown in Figure 399.

3. Cellular Defense Systems Within the Body:

     Though the skin and mucus membranes offer a certain degree of protection against invasion, they do not protect the body completely. They may, in a way, be considered the body's first line of defense. Behind this line of defense there are two others. One type is chemical and will be considered in the next chapter, and one type is cellular. The two cannot be considered as strictly separate, and the order in which cellular and chemical factors are involved is not the same for different types of invasion. The cellular defense system, phagocyctosis, will be taken up first for convenience.

     When a foreign material, living or non-living, penetrates through an epithelium or mucus membrane, there is a sequence of events ordinarily called inflammation. Near the area of injury, capillaries become permeable; proteins spaces, including fibrinogen and leukocytes of all types, find their way into the tissue through the leaky capillary.

     The over all effect is the "walling off" of the foreign material. Fibrinogen and other proteins produce a clot which the foreign body cannot penetrate easily. The leukocytes, particularly the neutrophiles and the monocytes, attack the foreign body, while neutrophiles produce digestive enzymes which tend to break the foreign body down while monocytes tend to engulf or surround it.

     These effects serve to re-enforce the natural barrier, which is fairly strong, and the cellular barrier of tissue which is of the same nature as the above, but quite weak. Some connective tissue cells, probably wandering monocytes, may behave like monocytes from the blood and wall off the invasion.

     There is no shortage of speculation concerning the mechanisms which increase capillary permeability and attract fibrinogen and the phagocytes to the site of the injury, and many clever names have been devised for the substances which are supposed to accomplish these effects. In some cases, naturally occurring substances have been implicated. Unfortunately, there is very little convincing evidence for the involvement of most of them. There is, however, convincing evidence that injury sufficient to cause pain will dilate local arterioles and increase local blood flow, which occurs by way of sensory nerve collaterals and has been mentioned before (Chapter 12).

     In any case, the injured area is usually reddened, because of the increased blood flow, warm, for the same reason, swollen, because tissue and blood factors accumulate at the site of the injury, and painful, partly because the injurious agent stimulates pain endings and partly because of the swelling. The Latin terms for these are, in order, rubor, calor, tumor, and dolor. These are the cardinal signs of inflammation.

     The injurious agent may be sealed off by these processes; if it is, it may be destroyed, removed a little at a time or expelled to the outside. If not, particularly when bacteria are involved, the interstitium may be extensively invaded. Such invasion may exaggerate the "sealing off" process. An abscess may form within the barrier, and it may eventually break to the outside and drain. This occurs when there is liquefaction through enzyme activity within the barrier; the liquid is called pus. Often, however, the injurious agent is sealed off and does not liquefy, leading to a swelling which disappears little by little as the offending material is carried away.

     When the injury involves microorganisms, it may be walled off by the mechanism described. On the other hand, the walling off mechanism may be ineffective. In such a case, the multiplying bacteria may gain access to the lymphatic system or to the blood stream.

     When lymphatic capillaries are invaded, the organisms travel to the lymph nodes on their way to the circulation. These nodes, which contain large numbers of lymphocytes in intimate contact with the lymph, may respond to the distant infection. The lymphocytes tend to increase in number, and they may be capable of stopping the organisms. On the other hand, they may serve as a breeding ground for them, exaggerating the original infection. Lymph node enlargement is almost invariably indicative of disease, and such enlarged nodes are popularly referred to as "swollen glands".

     If the first lymph nodes are unable to contain the infection, secondary nodes may. Again, the infection may breed in these nodes and progress to the blood stream. Very often the progress of an uncontained infection can be tracked by observing reddening of the lymphatic capillaries between the nodes. It should be mentioned that in many infectious processes, the cells of the lymph node, ordinarily lymphocytes, are largeley replaced by granulocytes. Further, the lymphocytes are involved in chemical immunity (Chapter 30). A diagram of the arrangement of lymph nodes and capillaries is shown in Figure 400.

     Infections that remain uncontained and progress to the blood stream, as well as infections entering true blood capillaries directly, usually result in the greater production of leukocytes. Which kind of leukocyte will be produced depends on the infecting organism, and the type of leukocytosis is not always the type best suited for defense against that organism. If the organism is contained by the leukocytes of the blood stream, the bacteremia disappears; if not, the invading organisms are spread throughout the host, invading all tissues, in septicemia. The effects of a septicemia are dependent on the nature of the organism, its distribution, tissue resistance, chemical immune mechanisms, and antibiotic treatment. It should, however, be remembered that the occurence of septicemia, can in itself be taken as evidence that the organism has not coped adequately with the infection and may not be prepared to cope with it. Antibiotic treatment should be considered as soon as there is evidence of septicemia.

     The cellular response to invasion is depressed by the glucocorticoids. This depression, which is sometimes useful in controlling an inappropriate response, may be dangerous when glucocorticoids are given over a long period of time.

4. Diseases of the Mechancical Defense System:

     The structure of the skin usually serves to protect the contents of the body from invasion. However, the protective layer is very thin at the base of hair follicles. Ordinarily, microorganisms are denied access to this layer, sebum and the epidermis filling the space around the hair.

     The production of sebum may occur at so great a rate that the minute space which exists between the hair and its crypt is quite sealed. Greater production of sebum may result in the breakdown of the crypt wall, and sebum may enter the corium. Some bacteria grow in sebum; they may grow in the channel made available by the sebum plug and enter the corium. All of these events, which occur in most teenagers, result in acne, a disease whose only redeeming feature is the almost certain knowledge that it will not last very long. There is no really satisfactory treatment for the disease.

     Acne tends to occur in multiple locations on the face; rarely the trunk. A single hair follicle, plugged by excessive secretion of sebum, may distend slowly and reach quite a large size without rupturing the crypt wall. This is called a sebaceous cyst, or wen. The treatment is usually surgical removal.

     Some bacteria gain access to the deep layers of the skin, probably by way of the hair follicle. Their growth may be walled off, but it may reach a fairly large size first. Boils, furuneles and carbuncles, represent such invasion by staphylococci. They may be treated by the use of antibiotics, although more and more of them are caused by antibiotic resistant organisms. Incision and drainage with caution, because of the risk of spreading the organisms to the blood stream, are required in many cases.

     The space between the nail and its overlying skin (See Figure 398) may become infected. These infections are painful and troublesome (hangnail-paronychium). They may be treated by soaking in hot water, which, by loosening the epidermal connection between the overlying skin and the surface of the nail, allows drainage. Some require surgical opening, and in some cases, removal of the nail is necessary.

     Psoriasis is a mild disease which affects 2 to 3% of white adults, and almost no blacks. It is usually confined to the elbows, knees, chest, back, and buttocks. Psoriasis in the scalp is often confused with dandruff. The epidermal cells in the affected areas appear to become unusually adherent to each other, so that they are not shed for a long time; when they are shed, they come off as scales, and the epidermis left behind may be so thin as to expose the red corium. It may also fissure. Despite considerable interest in the disease, its cause is not known. There are numerous treatments, all temporary. The most distressing thing about psoriasis is that its victims can be reasonably sure that it will last throughout their lives.

     Seborrheic dermatitis, or dandruff, usually involves the scalp. Scaling, like that of psoriasis, is common. Unlike psoriasis, which cannot be cured, seborrheic dermatitis responds to a number of treatments and may disappear entirely.

     Diseases of the mucus membranes: Many of these have already been considered. The mucus membranes of the respiratory tract are easily invaded by viruses and bacteria. The mucus membranes of the urogenital tract are subject to a variety of infections. Gonorrhea is one of the most serious of the common ones. It is caused by the gonococcus, a microorganism which is usually spread by genital contact and tends to invade the terminal portions of the male genital tract, producing pus, which is discharged by way of the urethra. The breakdown of the mucosa, exposing the nerves of the submucosa, usually lead to pain on urination. In the female, there are often no symptoms, though the endometrium, including the tubal endometrium, may be extensively involved. The disease is not serious if it is treated; neglect (or shame) which results in the delay of treatment may have extremely serious consequences in both sexes, though they tend to be more serious in women.

     Some of the diseases of the mucosa of the digestive tract have been considered in Chapter 20. On the whole, the mucosa of the gastro-intestinal tract, suited as it is for the absorption of foodstuffs, and vulnerable as it is to breakdown (by digestive enzymes, by mechanical factors, and by the fact that it is a single layer of cells in a moist environment) is probably the most easily broken down of the mechanical defenses of the body. This vulnerability is probably remedied, in part, by the extraordinary rate of growth of the gastrointestinal mucosa. Some idea of this growth rate can be obtained by considering that, outside of undigested matter, which is normally about one third of the whole, and a few excretory products (bile pigments) in feces must be derived from the gastrointestinal mucosa. The weight of the feces varies considerably, 200 grams per day being a rough average. Because the statement that feces are made largely of bacteria form very little of the food taken in, it seems a safe assumption that their appearance in the feces does not result from the synthesis of matter, but rather on the conversion of the shed gastrointestinal mucosa into bacterial cell bodies. In other words, the gastrointestinal mucosa is probably lost at the rate of 100-150 grams/day. This is of course replaced as fast as it is lost, in most cases. The growth rate is the highest of any tissue known, including cancers. It may be noted that a number of agents which suppress growth have been used in some malignant tumors, particularly leukemia. Their usefulness is limited by the fact that thoroughly effective doses also stop the replacement of the gastrointestinal mucosa, which results in ulceration, nausea, vomiting and diarrhea.

     The sealing off of invasion by cellular elements is often a useful response, but sometimes it is not. As has been noted, the glucocorticoids depress it. This antiinflammatory effect may sometimes relieve the patient of symptoms while advancing his disease process. In some conditions, the inflammatory effect is the disease process, and in these conditions the glucocorticoids may be used profitably.

     The responses of the leukocytes to invasion often give valuable clues to the nature of the disease. For example, an abdominal pain which is associated with an increased neutrophile count suggests appendicitis, while one which is associated with a low neutrophile count suggests mesenteric lymphadenitis. Large numbers of lymphocytes are usually seen in whooping cough. An increased eosinophile count is common in infections with worms, though its significance is unknown.

     Deficiency in the cellular defense systems is often seen in the blood as a low white cell count, leukopenia. This is expected after X-ray treatment of, for example, leukemia. It occurs regularly after treatment with certain drugs, some of which are designed to treat leukemia, while others are used in transplantation operations (Chapter 3l). Leukopenia is often seen in certain persons in response to drugs which do not cause leukopenia in others. This type of leukopenia often results from bone marrow destruction in sensitive persons, and removal of the drug does not restore the normal white cell count. Such persons, lacking their second line of defense against invasion, fall prey very easily to infections which are normally inconsequential. The same may be observed in patients with transplanted organs, whose rejection mechanisms are sometimes too thoroughly disabled.

Continue to Chapter 30.