NROSCI BIOSC 1070 MSNBIO 2070 December 6, 2019 Developmental Physiology & Temperature Regulation

Developmental Physiology During the first half of pregnancy, the fetus’ own genetic program is the primary determinant of growth. During the second half of pregnancy, the patterns of growth and development are altered by epigenetic factors: placental hormonal environmental (e.g., maternal nutrition, disease, drugs, altitude) metabolic (e.g., diabetes)

Development of Cardiovascular System Circulation begins at 4th week to provide adequate nutrition to multicellular fetus. Many tissues produce red blood cells in the fetus, including blood vessel endothelium and liver. Many early red blood cells are nucleated. Fetal hemoglobin has a higher affinity for O2 than adult hemoglobin. After ~1 postnatal year, offspring starts synthesizing adult hemoglobin.

Development of Respiratory System Respiratory system development is not complete until near the end of gestation. Thus, premature infants have difficulty in breathing. Surfactant is not present until near the time of birth. Cortisol is a primary trigger for surfactant production. Women expected to deliver at 24-34 weeks are provided steroid therapy to induce surfactant production in the fetus. Together, glucocorticoid therapy and infusion of surfactant into the newborn trachea reduce the incidence of respiratory distress syndrome in premature infants.

Development of Nervous System Spinal cord and brainstem reflexes are largely present by 4 months gestation. Cortical development lags, and requires environmental inputs after birth. Nervous system development is not complete until several years after birth.

Development of Renal System The fetal kidneys begin to secrete urine during the second trimester. Fetal urine constitutes most amniotic fluid. However, transport properties of kidney are not as developed as in the adult. Thus, less water is reabsorbed, posing a dehydration risk. Acid-base control by the kidney is particularly poor in newborns.

Development of GI System In general, the GI system becomes functional near the middle of a normal pregnancy. The fetus consumes amniotic fluid, and excretes a waste product called meconium. However, liver function is diminished until after birth, partly because blood is shunted away from the liver during development via ductus venosus

Development of GI System The delayed development of hepatic function poses many problems for the infant: Bilirubin is not eliminated in bile; jaundice can occur, and in rare cases bilirubin encephalopathy Plasma protein levels drop, which can result in edema (due to retarded absorption by capillaries) Clotting factor levels drop in the blood; limited blood clotting potential Limited potential for gluconeogenesis. Newborn must receive nutrition often to avoid a drop in blood glucose

Metabolic Function: Insulin Insulin is not required for glucose transport by fetal tissues until near the time of birth. However, insulin is an essential growth hormone for the fetus. Hyperglycemia in mothers with untreated Type I diabetes results in a large production of insulin by the fetus. This can result in an increased growth rate. Overstimulation of b-cells by hyperglycemia in utero can result in too much insulin secretion in the newborn, and hypoglycemia. Hyperglycemia and placental transfer of insulin in mothers with Type II diabetes can have the same effect.

Metabolic Function: Insulin-Like Growth Factor Insulin-like growth factors from the fetal liver are necessary to stimulate mitosis and development of the fetus. Unlike in adults, secretion of these growth factors is not regulated by growth hormone. The insulin-like growth factors are even released in anencephalic fetuses with no growth hormone.

Metabolic Function: Thyroid Hormone Thyroid hormone is necessary for normal development, particularly of the nervous system. Prior to development of the hypothalamic-pituitary portal system during the second trimester, the thyroid hormone comes from the mother. Thus, hypothyroid mothers typically have offspring with diminished intellectual capacity. Mothers with autoimmune diseases that affect the thyroid gland pass the problematic antibodies to the fetus Lack of iodine results in diminished thyroid hormone production by both the mother and fetus, and severe cretinism. ~20 million have brain damage due to iodine deficiency during fetal life.

Ductus Arteriosus and Foramen Ovale In the developing fetus, two shunts divert blood away from the lungs. The foramen ovale is a shunt between the left atrium and right atrium. In addition, ductus arteriosus is a blood vessel connecting the pulmonary artery to the proximal descending aorta. Between the two, coupled with the extremely high resistance of the pulmonary circulation, practically no blood enters the lungs.

Ductus Arteriosus and Foramen Ovale Since practically no blood is moving from the lungs to the left atrium, left atrial pressure is extremely low in the fetus. Thus, the pressure gradient favors the movement of blood from the right to the left atrium.

Ductus Arteriosus and Foramen Ovale Pressures in the pulmonary artery and aorta are nearly equal in the fetus, or pressure is slightly higher in the pulmonary artery. This is due to relatively weak contractions of the developing left ventricle, as well as the fact that preload to the left ventricle is relatively low. Thus, blood moves from from the pulmonary artery to the descending aorta through ductus arteriosus.

Ductus Arteriosus and Foramen Ovale The trajectory of blood flow from the inferior vena cava favors movement through foramen ovale into the left atrium. The trajectory of blood flow from the superior vena cava favors movement through the tricuspid valve into the right ventricle, and then through ductus arteriosus to the descending aorta and placenta.

Ductus Arteriosus and Foramen Ovale At birth, the shunts must close immediately to permit the normal circulation to commence. Once the fetus is born and begins to breathe, pulmonary circulatory resistance drops precipitously. Blood thus begins to flow through the pulmonary circulation instead of ductus arteriosus, as resistance in the ductus arteriosus is higher.

Ductus Arteriosus and Foramen Ovale High pO2 after birth causes constriction of the smooth muscle in ductus arteriosus The patency of ductus arteriosus is dependent on prostaglandins that are produced in part by the placenta. The prostaglandins inhibit the contraction of smooth muscle within the wall of ductus arteriosus. The prostaglandin levels drop markedly at birth, causing the ductus to collapse as smooth muscle within contracts.

Development of GI System Ductus venosus, which shunts blood away from the liver, closes within a few hours of birth. The closure of ductus venosus allows portal blood flow through the liver. The mechanisms responsible for closure of ductus venosus are unknown. Failure of closure is rare in humans.

The First Breath Breathing movements start near the end of the 1st trimester. Breathing ceases just before labor for an unknown reason. In utero, the alveoli and airways are filled with fluid. Labor induces increases in catecholamines and arginine vasopressin, which cause resorption of the fluid. Fluid is also forced out of the lungs as the fetus moves through the birth canal. Hypoxia and hypercapnia are the main triggers for the first breath. The first breath induces changes in cardiovascular pressures that are responsible for closure of ductus arteriosus and foramen ovale. The first breath is normally the most difficult inspiration of a lifetime. A considerable negative pressure within the intrapleural space is necessary to overcome the effects of surface tension.

Immunity The placenta actively transports IgG to the fetus, which is essential to ward-off infections of the fetus. Maternal IgA, IgM, and IgE do not cross the placenta. The newborn receives IgA in colostrum and breast milk. IgG falls in the newborn as the antibodies transferred from the mother are eliminated. The infant slowly develops the ability to generate its own antibodies. Some maternal antibodies (e.g., to measles) decrease slower than others (e.g., to pertussis). Vaccination schedules must take this into account.

Physiological Effects of Aging Height declines after adolescence because of compression of the cartilaginous disks between the vertebrae and loss of vertebral bone. A loss of 5% height at age 70 is normal. Lean body mass declines during aging, while overall body mass stays constant or increases. Even athletes have an increase in adipose tissue during aging. There is a loss of muscle fibers during aging. This is partly due to death of motoneurons, which leaves muscle fibers uninnervated, causing their atrophy. Sometimes loss of motoneurons results in axonal sprouting and innervation of many muscle fibers by a particular motoneuron. This can affect the precision of movement.

Physiological Effects of Aging Although men do not exhibit the rapid loss of bone in their 50s that women experience, bone loss in the 60s and 70s in both sexes is similar. Osteoporosis is a concern in both elderly men and women. Articular (joint) cartilage thins and exhibits altered mechanical properties during aging. This plays a role in development of osteoarthritis, which often occurs when bones start rubbing together after cartilage is lost.

Physiological Effects of Aging Aging decreases the compliance of arteries, so systolic pressure becomes higher and diastolic pressure is lower. Overall, there is an increase in MAP, and the increased afterload results in thickening of the left ventricular wall. Aging increases the compliance of veins, so there is more peripheral blood pooling and increased susceptibility for orthostatic hypotension.

Temperature Regulation

The temperature of the human body is maintained within narrow limits over a wide range of environmental temperatures and during both low and high metabolic activity. Heat is continually being produced by exothermic biochemical reactions that occur in all body cells, and heat can be lost or gained by exchange with the environment. By analogy with the law of mass action, the following equation expresses heat homeostasis in the body: Heat Loss = Heat input + Heat Production

Normal Body Temperature “Normal” body temperature varies slightly among individuals, as well as in the same individual at different times. When measured rectally, the usual range of normal temperature is 36.2-37.8°C, and is about 0.2-0.5°C lower when measured orally. Body temperature shows a diurnal variation of approximately 0.6°C; it is lowest in the early morning and highest in the early evening. Menstruating women have a further monthly variation. The body temperature shows a slight elevation (0.2- 0.5°C) at the time of ovulation and remains elevated during the second half of the menstrual period. During strenuous exercise the body temperature may rise by 2-3°C. Even when the body is nude, body temperature can be maintained within the normal range over an environmental temperature range of 50°F to 130°F.

Heat Production In shivering thermogenesis, the body uses shivering (rhythmic tremors generated by skeletal muscle contractions) to generate heat for temperature regulation. Nonshivering thermogenesis is the metabolic production of heat specifically for temperature regulation. A form of nonshivering thermogenesis in laboratory animals and perhaps infants (but not adult humans) is produced by a type of tissue called “brown fat.” Brown fat is distinguished from the “white fat” that commonly occurs in humans in several ways. The mitochondria of brown fat cells contain a protein (called thermogenin) that dissociates ATP production and the flow of electrons and H+ through the electron transport system. In this uncoupled state, the energy that would normally be trapped in the high energy bond of ATP is released as heat. An increase in the pumping action of Na+/K+ ATPase also increases heat production in brown fat cells. The importance of nonshivering thermogenesis in adult humans is controversial, because of their very limited stores of brown fat tissue.

Heat Gain from the Environment External heat input comes from the environment through radiation or conduction. Radiant heat gain occurs when you are near a source of radiant energy, such as a fire. Conductive heat gain occurs when heat is transferred to your body by contact with a warmer object, such as a heating pad.

Heat Loss Heat loss from the body occurs through the following mechanisms: radiation, conduction, convection, and evaporation. Radiant heat loss occurs when you radiate heat to a cooler environment. Conductive heat loss occurs when you are in contact with a cooler object. Radiant and conductive heat loss are enhanced by convective heat loss, where air currents move warm air away from the body. Because there is a tendency for “warm air to rise,” heat radiated by the body to the air tends to move away and to be replaced by cooler air. This process is exacerbated when air currents flow over the body, as when you are standing in front of a fan. In contrast, clothing tends to trap the warm air near the body, so that it forms a layer of insulation. If there is little convection, radiant and conductive heat loss are minimized.

Heat Loss Evaporative heat loss occurs as water evaporates from a surface, such as the skin or the lining of the respiratory tract. The conversion of water from a liquid to a gaseous (vapor) state requires the input of substantial amounts of energy, so that evaporating water acts as a “sink” for heat. During sweating, evaporative heat loss occurs, thereby cooling the body.

Thermoregulation Neurons in the anterior hypothalamus and preoptic area act as temperature sensors. Some neurons in this region discharge when temperature is elevated, and others fire when temperature drops. In addition to these central thermostatic detectors, there are temperature-sensitive afferents in the skin. Both “warm” and “cold” afferents originate in the skin, but the cold afferents are far more plentiful. Furthermore, temperature-sensitive afferents are found internally in the body, mainly in the spinal cord, abdominal viscera, and near the great veins. Like in the skin, these internal temperature-sensitive afferents are mainly cold receptors.

Thermoregulation Thus, it appears that temperature sensitive afferents mainly act to prevent hypothermia, suggesting that the response to high body temperature is mainly triggered by the central thermoreceptors in the anterior hypothalamus. Signals from the central and peripheral thermoreceptors are integrated posteriorly in the hypothalamus, at the level of the mammillary bodies. The posterior hypothalamus in turn triggers the changes in hormone release, autonomic nervous system activity, and somatic motor activity that compensates for the altered body temperature. An important concept in temperature regulation is “set point”. The posterior hypothalamic temperature regulator elicits heat conservation or heat loss when body temperature differs from the set point temperature.

Autonomic Nervous System Contributions to Termoregulation An important factor in determining heat loss from the body is the amount of blood flow to the skin. The amount of blood flow through the cutaneous blood vessels can vary from close to zero to up to one third of the cardiac output. If core body temperature drops, the posterior hypothalamus selectively stimulates sympathetic neurons innervating α- adrenergic receptors on the cutaneous blood vessels. The vessels constrict, their resistance to blood flow increases, and blood is diverted to vessels in the core of the body to minimize heat loss. In warm temperature, the opposite happens: cutaneous vessels vasodilate. This vasodilation involves the withdrawal of activity of sympathetic adrenergic fibers in the skin. At least some of this vasodilation (in some species) is also mediated by sympathetic cholinergic vasodilator fibers that innervate the skin arterioles. Furthermore, the release of bradykinin from sweat glands contributes to the vasodilation.

Autonomic Nervous System Contributions to Termoregulation Surface heat loss is enhanced by the evaporation of sweat. It is estimated that the average human has 2-3 million sweat glands, with the highest concentrations found on the forehead, scalp, armpits, palms of hands, and soles of feet. Sweat glands are made largely from a single layer of transporting epithelial cells that can secrete hypotonic fluid at a very high rate—up to 23 LITERS/hour across the entire body. Sweat glands in the skin are innervated by cholinergic sympathetic neurons that trigger secretion of fluid into the lumen in the deep secretory portion of the sweat gland. As the fluid moves towards the skin surface, NaCl is reabsorbed from the lumen by mechanisms similar to those used by the transporting epithelium of the distal nephron, creating hypotonic sweat.

Autonomic Nervous System Contributions to Termoregulation Brown fat contributes to heat production in infants and many animal species. The sympathetic nervous system contributes to activation of the uncoupling protein (thermogenin) in brown fat. Piloerection can also contribute to heat conservation in animals. Sympathetic stimulation causes the arrector pilli muscles attached to the hair follicles to contract, which brings the hairs to an upright stance. This is not important in humans, but in animals the upright projection of the hairs allows trapping of a thick layer of “insulator air” next to the skin.

Somatic Nervous System Contributions to Thermoregulation The posterior hypothalamus, through its inputs to brainstem pathways that influence motoneuron excitability, can also induce shivering. In animals, a motor act involving the respiratory system—panting—is used to elicit evaporative cooling. Panting is triggered by the posterior hypothalamus, and involves pontine respiratory neurons. When an animal pants, it breathes in and out rapidly, so that large quantities of new air from the exterior come in contact with the upper portions of the respiratory passages. This cools the blood in the mucosa as a result of water evaporation from the mucosal surfaces, especially evaporation of saliva from the tongue. Typically, tidal volume drops considerably during the rapid breathing, so the net result is that alveolar PO2 and PCO2 do not change much even though the respiratory rate is very high.

Hormonal Contributions to Termoregulation Epinephrine can cause an increase in the rate of cellular metabolism of all body cells, particularly in animals lacking brown fat. Blood-borne epinephrine serves to activate the decoupling enzyme in brown fat, as does direct sympathetic influences on this tissue. Cooling of the “thermoreceptive area” in the anterior hypothalamus results in a release of thyrotropin-releasing hormone into the portal circulation, producing a release of thyroid-stimulating hormone into the systemic circulation. The thyroid-stimulating hormone in turn elicits the release of thyroxine from the thyroid gland. Increased thyroxine production results in an enhanced rate of cellular metabolism throughout the body, thereby increasing temperature. If levels of thyroid-stimulating hormone remain high for several weeks, the thyroid gland begins to hypertrophy and release much more thyroxine into the bloodstream. In animals and infants, thyroxine also stimulates brown fat to increase heat production.

Summary

Fever The development of fever involves a change in the “set point” of the posterior hypothalamic thermoregulatory area. When this occurs, the hypothalamic center acts as though temperature is low, and triggers cutaneous vasoconstriction and shivering which produce the feeling of chill that accompanies fever.  When a fever “breaks,” the set point falls towards the normal level, the posterior hypothalamus detects an elevated body temperature, and cutaneous vasodilation and sweating occur.

Triggers for Fever The fever with infection occurs when the immune system reacts to components of infecting organisms, called exogenous pyrogens. These substances cause monocytes and macrophages to release cytokines such as interleukins (especially IL-1β and IL-6) and tumor necrosis factor (TNF). These cytokines are referred to as endogenous pyrogens, and cause the production of arachidonic acid metabolites, including prostaglandin E2, in many tissues including the hypothalamus. The latter agents act locally in the hypothalamus to produce a change in the temperature set-point. Dehydration can also affect the hypothalamic thermoregulatory center and results in fever. Compression of the hypothalamus, which can occur during surgery near the base of the brain or by the growth of a tumor, can also alter the set point of the thermoregulatory center and lead to fever.

Treatment of Fever Drugs such as aspirin that block prostaglandin synthesis reduce fever. However, there are indications that fever is not a deviant physiological state, but an adaptation to destroy pathogens. The activity of white cells that are involved in the immune response is potentiated when body temperature is high. Furthermore, many invading microorganisms cannot thrive when body temperature is high. Nonetheless, a fever over 41°C (106° F) can damage the brain, and so high fever should always be counteracted with drugs.

Cyclooxygenase (COX) COX is a family of enzymes that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Non-steroidal anti-inflammatory drugs inhibit COX COX-1 is mainly responsible for producing mediators of “housekeeping functions” such as protection of the stomach lining and platelet aggregation COX-2 is mainly responsible for producing mediators of inflammation Selective COX-2 inhibitors (VIOXX or Celebrex) theoretically should eliminate inflammation without the harmful side effects of other NSAIDs

Clinical Note: Cox 1 vs Cox 2 Inhibitors Selective Cox-2 inhibitors include Vioxx® and Celebrex®

The Sad Story of Vioxx

Warning: No more material!