Department of Physiology: Cell Physiology and Body Fluids-Offline information

Plasma Expanders: Plasma expanders can be used to increase blood volume temporarily, over a period of hours. They are often used to buy time for lab work to determine a person’s blood type. (Transfusion of the wrong blood type can kill the recipient.) Isotonic electrolyte solutions such as normal (physiological) saline can be used as plasma expanders, but their effects are short-lived due to diffusion into interstitial fluid and cells. This fluid loss is slowed by the addition of solutes that cannot freely diffuse across plasma membranes. One example is lactated Ringer’s solution, an isotonic saline also containing lactate, potassium chloride, and calcium chloride ions. The effects of Ringer’s solution fade gradually as the liver, skeletal muscles, and other tissues absorb and metabolize the lactate ions. Another option is isotonic saline solution containing purified human albumin. However, the plasma expanders in clinical use often contain large carbohydrate molecules, rather than proteins, to maintain proper osmotic concentration. These carbohydrates are not metabolized, but phagocytes gradually remove them from the bloodstream, and blood volume slowly declines. Plasma expanders are easily stored. Their sterile preparation avoids viral or bacterial contamination, which can be a problem with donated plasma. Note that plasma expanders provide a temporary solution to low blood volume, but they do not increase the amount of oxygen carried by the blood. Red blood cells are needed for that function.

The cytokine Network: Cytokines are a large family of messenger proteins which act in an autocrine (i.e. influencing the cell which produces them) or paracrine (i.e. influencing neighbouring cells, travelling to them by diffusion) fashion. For quite sometime, we knew only a few of them which mediate inflammatory or cell-mediated immune responses. But now more than 100 cytokines have been identified, and new ones continue to be discovered. Further, their functions also cover a wide range. For example, interleukin-6 (IL-6) not only promotes B cell differentiation but also mesangial cell proliferation, growth of keratinocytes, and the activity of osteoclasts. Currently cytokines are understood to be part of a complex communication network which also includes hormones and neurotransmitters. The cells which produce cytokines sometimes have receptors for hormones and neurotransmitters, and endocrine cells or neurons have receptors for cytokines. Thus the body has a complex system of communication which uses a chemical signaling language. The system regulates embryonic development, homeostatic responses, immune responses, inflammatory responses and tissue repair mechanisms. Cytokines have been variously named interleukins (IL-1, IL-2, and so on up to at least IL-22), interferons, tumor necrosis factors, colony stimulating factors, etc. In general, interleukins regulate the division and differentiation of immune cells and a variety of other cells; interferons limit the spread of viral infections; tumor necrosis factors activate macrophages, granulocytes and cytotoxic cells; and colony stimulating factors regulate the division and differentiation of precursors of blood cells in the bone marrow. Most of the cytokines are secreted by cells of the immune system, specially lymphocytes, but some cytokines are also known to be secreted by fibroblasts, epithelial cells, endothelial cells, and even muscle cells. In the body, it is unlikely that a cell is ever exposed to only one chemical messenger. If each messenger is considered to be a word, the cell is exposed to at least a sentence. The behavior of the cell depends on what the sentence means. Cytokines act through receptors on the target cell membrane. The ligand-receptor interaction triggers a cascade of reactions in the cytoplasm, finally giving rise to substances which modify gene expression in the nucleus. Resolution of the complex network of cytokines has been facilitated by molecular genetics. It is possible to knock out genetically a cytokine or its receptor. The resulting abnormality indirectly reveals the normal function of the cytokine which is missing or unable to act (if the receptor has been knocked out) in the knockout mice. For example, if IL-7 is knocked out, there is a marked reduction in the thymic and peripheral lymphoid cells, suggesting that IL-7 is required for normal development of the immune system.

CLINICAL CORRELATION: As she passed her coach and friends at the 15-mile mark of the Boston Marathon, the 28-year-old runner smiled and waved cheerily. She looked good as she passed Heartbreak Hill, about 6 miles from the finish. Two miles later, she stopped to drink a cup of fluid. Another runner remembers her saying she felt dizzy and disoriented. She began to falter and told a friend running next to her that she felt rubber-legged, and then tumbled to the pavement. When she reached the hospital, she was unresponsive with stable vital signs. After endotracheal intubation, a blood serum sodium value was found to be very low at 113 mmol/L. Computed tomography of the brain and chest radiography showed diffuse cerebral and pulmonary edema. She was given intravenous isotonic saline (150 mmol/L) but never regained consciousness. Diffuse cerebral edema was found at postmortem examination. A few days later, the newspapers reported she died from a condition called hyponatremic encephalopathy. Hyponatremia, defined by a blood sodium concentration less than 135 mmol/L, may lead to hypotonic encephalopathy with fatal cerebral edema. It is usually caused by drinking excessive amounts of fluid that exceed the kidney’s capacity to excrete water during exercise. Mild cases can be managed by restricting fluids until the onset of urination. Manifestations of hyponatremic encephalopathy indicate the need for emergent treatment with hypertonic solutions such as 3% saline (513 mmol/L). Na⁺ and Cl^- account for most of the osmotic strength of the serum. If Na⁺ levels are low, the serum will be hypotonic and water will move into all the cells of the body causing them to swell (edema). This can have serious effects in the brain because it is in the closed space of the cranium and the swollen tissue will restrict blood flow and therefore oxygen supply. Swelling may cause herniation of the brain through the tentorium and foramen magnum, compressing the brainstem and causing respiratory arrest. Blood sodium level is influenced by salt and water intake, sweating, and urinary secretion and is regulated by the endocrine system. The recommendation for marathon runners is to drink only when thirsty.

Drugs and the Plasma Membrane Many clinically important drugs affect the plasma membrane. For some anesthetics, such as chloroform, ether, halothane, and nitrous oxide, potency is directly correlated with its lipid solubility. Presumably, high lipid solubility accelerates the drug’s entry into cells and enhances its ability to block ion channels or change other properties of plasma membranes and thereby reduce the sensitivity of neurons and muscle cells. However, some common anesthetics have relatively low lipid solubility. For example, the local anesthetics, procaine and lidocaine, affect nerve cells by blocking sodium channels in their plasma membranes; this blockage reduces or eliminates the responsiveness of these cells to painful (or any other) stimuli. Although procaine and lidocaine are both effective local anesthetics, procaine has very low lipid solubility.

Dehydration & overhydration

[A] Dehydration (volume contraction) states: They are of three types:

[1] Isomotic dehydration which is primarily caused by loss of isotonic fluid from ECF compartment. It can be caused by haemorrhage, plasma exudation through burned skin, and gastrointestinal fluid loss (as in vomiting and diarrhea). In this type of dehydration:

ECF volume decreases while the osmolarity of the ECF is kept constant.
Because osmolarity of ECF is unchanged, water does not shift between the ECF and ICF compartments.
Therefore, the ICF volume and osmolarity do not change.
The plasma protein concentration and haematocrit (Hct) are increased because the ECF volume is decreased.
Arterial blood pressure is decreased.

[2] Hyperosmotic dehydration which is primarily caused by loss hypotonic fluid (water) from ECF compartment. It can be caused by diabetes insipidus, diabetes mellitus, alcoholism, administration of lithium salts (drugs), fever, and excessive evaporation from skin through heavy loss of sweat (which is hypotonic). In this type of dehydration:

ECF volume decreases while the osmolarity of ECF is increased.
Because osmolarity of ECF is increased, water shifts from ICF to the ECF.
As a result of this shift, ICF volume decreases while ICF osmolarity increases until it equals the ECF osmolarity.
The plasma protein concentration is increased while the haematocrit (Hct) remains unchanged because water shifts out of the RBCs, decreasing their volume and offsetting the concentrating effect of the decreased ECF volume.

[3] Hyposmotic dehydration: This is primarily caused by loss of hypertonic fluid from ECF compartment. It can be caused by renal loss of NaCl because of adrenal insufficiency as in Addison's disease. In this type of dehydration:

The osmolarity of ECF decreases.
Consequently, water shifts from ECF to ICF.
As a result of this shift, ECF volume is decreased while the ICF volume is increased with ICF osmolarity equals ECF osmolarity.
Plasma protein concentration increases because of the decrease in ECF volume. Haematocrit (Hct) increases because of the decreased ECF volume and because of RBCs swell as a result of water entry.

[B] Overhydration (volume expansion) states: They are of three types:

[1] Isosmotic overhydration which is primarily caused by addition of isotonic fluid to the ECF compartment. It can be caused by any condition that is responsible to cause edema and also can be caused by oral or parenteral administration of large volume of isotonic NaCl (150 mmol/L). In this type of overhydration:

The ECF volume is increased while the osmolality of the ECF is kept constant. Because osmolarity of ECF is unchanged, water does not shift between the ECF and ICF compartments.Therefore, the ICF volume and osmolarity do not change.

The plasma protein concentration and haematocrit (Hct) are decreased because the ECF volume is increased.
Arterial blood pressure is increased.

[2] Hyperosmotic overhydration which is primarily caused by addition of hypertonic fluid to the ECF compartment. It can be caused by oral or parenteral intake of large amounts of hypertonic fluid. In this type of overhydration:

The ECF osmolarity is increased.
Consequently, water shifts from ICF to ECF.

As a result of this shift, ECF volume is increased while the ICF volume is decreased with ICF osmolarity equals ECF osmolarity.
The plasma protein concentration and haematocrit (Hct) are decreased because of the increase in ECF volume.

[3] Hyposmotic overhydration which is primarily caused by addition of hypotonic fluid to the ECF compartment. It is caused by ingestion of a large volume of water or renal retention of water due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In this type of overhydration:

The volume of ECF increases because of water retention while ECF osmolarity is decreased.
Consequently, water shifts from ECF to ICF.
As a result of this shift, ICF volume increases and ICF osmolarity decreases until it equals ECF osmolarity.

The plasma protein concentration decreases because of the increase in ECF volume. Haematocrit remains unchanged because water shifts into the RBCs, increasing their volume and offsetting the diluting effect of the gain of ECF volume.