NROSCI/BIOSC 1070 & MSNBIO 2070 October 4, 2017 Respiration 1

10/4/2017 Respiratory 1

The fluid carried by the cardiovascular system—bloodBlood is essentially a two-phase fluid consisting of formed cellular elements suspended in a

liquid medium, plasma. The formed elements are red cells (erythrocytes), white cells (leukocytes), and platelets. If a blood sample is centrifuged in a tube, the cellular elements will settle to the bottom. The red cells will lye on the bottom of the tube, and will occupy 40-45% of the total volume of blood. The white cells, being less dense, will settle on top of the red cells, and will occupy < 5% of blood volume. The remaining 50-55% of blood volume is contributed by the plasma.

The volume of red blood cells present in blood is referred to as the hematocrit. Red blood cells contain hemoglobin, which has a remarkable capacity to bind with and transport oxygen. The white cells are mainly involved with immune processes and with bodily defense. The platelets are vital elements in blood coagulation, as we will see later in this lecture.

Blood plasma contains a variety of plasma proteins (e.g., albumin, globulin), electrolytes, hormones, enzymes, and blood gases.

After birth, red blood cells are produced exclusively in the bone marrow; in adults, the production is confined to membranous bones (e.g., rib). In the bone marrow, pluripotential hemopoietic stem cells are generated that differentiate to form all the cellular elements of blood. A number of different differentiation inducers can influence the differentiation process. Any chemical factor that influences the growth or differentiation of blood cells is called a cytokine. One cytokine is erythropoietin, a hormone made by the kidney in response to poor tissue oxygenation. As its name implies, erythropoietin acts to increase erythrocyte production. If erythropoietin levels are low, few red blood cells will be produced. Some cytokines whose amino acid sequence is known are called interleukins. Most of the interleukins are released by one type of white blood cell and have effects on another, and are important in the function of the immune system as we will see later in the course.

NROSCI/BIOSC 1070 & MSNBIO 2070October 4, 2017Respiration 1


An important constituent of erythrocytes is the oxygen-carrying molecule hemoglobin. We will discuss the binding of oxygen to this iron-containing molecule during the respiratory lectures.

Red blood cells can circulate in the blood for several months. Damaged red blood cells are removed from the circulation by the spleen.

Obviously, a lack of red blood cells can cause a deficiency in the ability of the blood to carry oxygen. A lack of red blood cells is referred to as anemia. There are several types of anemia, including that associated with hemorrhage, damage to bone marrow (aplastic anemia), and genetic diseases that result in erythrocytes being easily damaged or malformed (hemolytic anemia including sickle-cell disease). Furthermore, lack of iron consumption (required for production of the heme group of hemoglobin) will also result in anemia.

The production of too many erythrocytes can also be harmful, as blood viscosity increases. This condition is called polycythemia, which is often associated with pulmonary disease.


Platelets and Coagulation

If a break develops in a blood vessel, that hole must be repaired while allowing blood to flow through the blood vessel to reach the tissues that it perfuses. This process is called hemostasis. Furthermore, the repair must be very secure as the blood is under considerable pressure. As a first step, pressure in the vessel must be decreased until a mechanical seal in the form of a blood clot is produced. Once the clot is in place and bleeding has stopped, more permanent repair mechanisms can begin. As the wound heals, enzymes gradually dissolve the clot and scavenger white blood cells ingest and destroy the debris.

Platelets as well as plasma proteins play an important role in the clotting process. Platelets are cell fragments produced in the bone marrow from huge cells called megakaryocytes. Platelets are smaller than red blood cells, are colorless, and have no nucleus; their cytoplasm contains mitochondria, smooth endoplasmic reticulum, and many granules filled with clotting proteins and cytokines. Platelets are present in the blood at all times, but they are not active until damage has occurred to endothelial cells lining the blood vessels. Platelets typically have a life span of about 10 days in the bloodstream.

As discussed previously in the course, endothelin released from damaged endothelial cells induces local vasoconstriction; this mechanism is an early step in hemostasis. Next, platelets stick to the damaged blood vessel wall (platelet adhesion) and to each other (platelet aggregation). This collection of platelets forms a platelet plug which blocks the hole in the vessel. The exposure of collagen from the damaged endothelial cells as well as other chemical factors released from the cells activates the platelets and induces the clotting process. Serotonin and other factors released from the aggregating platelets induce more platelet aggregation as well as local vasoconstriction. Next, the coagulation cascade begins. Inactive plasma proteins are converted into active enzymes, and these activated enzymes in turn activate other inactive plasma enzymes. In the last stages of the cascade, thrombin converts the plasma protein fibrinogen into fibrin fibers that intertwine with the platelet plug. Another chemical factor converts the fibrin into a cross-linked polymer that stabilizes the platelet plug. This completes the formation of the clot.

Some chemical factors involved in the coagulation cascade also promote platelet adhesion and aggregation. As you can see, the clot formation process operates in a positive feedback manner. If this process were unchecked, the clot would spread throughout the circulatory system. Fortunately, undamaged endothelial cells release a modified 20-carbon fatty acid called prostacyclin that blocks platelet aggregation and adhesion. Nitric oxide, which is released from endothelial cells when exposed to sheer stress, also inhibits clot formation. This makes sense, as nitric oxide release normally occurs when blood is accumulating in an area. Under such conditions, the triggering of clot formation could be detrimental. Thus, a combination of platelet attraction to an injury site and repulsion from uninjured tissue limits the size of the blood clot.

In addition to inhibiting clotting, both prostacyclin and nitric oxide produce vasodilation of both the pulmonary and systemic arterioles. As we will see during a subsequent lecture, inhaled prostacyclin analogs are being used to treat pulmonary hypertension.


As cell growth and division repairs the injured blood vessel, the clot retracts and slowly dissolves due to the presence of plasmin within the clot. This enzyme’s precursor, plasminogen, is present within the clot from the beginning, and is activated when the injured tissues and endothelial cells release tissue plasminogen activator once they begin to heal. Tissue plasminogen activator converts plasminogen into plasmin, which then starts the slow process of clot degradation. Plasmin acts by breaking down fibrin in a process called fibrinolysis.


As you can see, a large number of chemical factors participate in the clotting process. Many of these have been numbered (e.g., factor VII or factor IX). However, this numbering scheme is based on when a factor is discovered, and not its place in the coagulation cascade. Furthermore, these chemical factors often have several names. Many of these chemical factors are part of the intrinsic and extrinsic pathways that lead to thrombin production. The so-called intrinsic pathway requires nothing that is not ordinarily present in plasma, and is induced when collagen becomes exposed to plasma. The extrinsic pathway is activated when a substance called tissue factor (factor III) is released from the damaged tissue. Both the intrinsic and extrinsic pathways work in a coordinated fashion as shown in the diagram below.


However, the inability to form blood clots can also be life-threatening, as even small injuries that sever blood vessels can result in severe bleeding. Because most of the blood clotting factors are synthesized in the liver, liver diseases such as hepatitis and cirrhosis can negatively impact on the ability to form blood clots.

A genetic disorder, hemophilia, also leaves an individual less capable than normal in forming blood clots. Hemophiliacs typically lack Factor VIII (although a small fraction with “Hemophilia B” lack Factor XII). Almost all of the people who suffer from hemophilia are male, as the defective gene is on the X chromosome. In females, if only one of the X chromosomes has the appropriate gene, no symptoms will occur, although the individual has a 50% chance of passing the disease to each of her male offspring. It is very simple to treat hemophilia: all that is necessary is to inject Factor VIII. In the past, this factor was isolated from human blood, but today a genetically-engineered form of this agent is given to hemophiliacs.

A few individuals lack platelets, a condition called thrombocytopenia. In most cases, it is completely unknown why the patient cannot manufacture platelets.

There are many points at which the coagulation cascade can be inhibited. As noted earlier, prostacyclin blocks platelet aggregation and adhesion. Another naturally-occurring anticoagulant is heparin, which interferes with the actions of a number of the clotting factors. Mast cells near the lung capillaries secrete heparin, which makes sense as clots often start to form in slowly-flowing venous blood. It is practical to inhibit this clot formation before blood reaches the first capillary bed after the venous circulation, that in the lungs. Heparin is also commonly used in the laboratory to prevent blood samples from clotting in collection tubes. Daily aspirin consumption is recommended for persons at risk of heart attack, as this drug helps prevent platelet aggregation (and lessens the chance that a blood clot will block a narrowed coronary artery). Many new drugs are being developed to antagonize clot formation, thereby lessening the risk of sudden coronary artery blockage.

Coumadin

Another condition that impedes blood clot formation is Vitamin K deficiency. Vitamin K is necessary for formation of several of the clotting factors (particularly II, VII, IX and X), so absence of this cofactor will abolish the ability for clotting. This information was utilized by a pharmaceutical company (Bristol-Myers Squibb) in developing an important new anticoagulant drug: Coumadin (Warfarin Sodium), which acts by inhibiting (but not preventing) the synthesis of vitamin K dependent clotting factors. Coumadin is often prescribed to patients who suffered a heart attack and have a potential for blood clots to block narrowed arteries.


Respiratory SystemFunctions of the Respiratory System

The most obvious function of the respiratory system is to rid the body of CO2 and to acquire O2. In order to do this, a moist and thin exchange surface that lets the gases pass into and out of the blood is needed. In terrestrial creatures such as us, this presents a challenge: how do you expose a moist surface to air without a tremendous amount of fluid loss from the body. The problem is complicated further by the fact that the gas exchange surface must be huge: in humans, on the order of 75 m2 area (the size of a racquetball court).

We have selected to solve the problem of gas exchange by placing the exchange surface inside of our body. This helps to keep the surface warm and moist. However, muscular pumps are then needed to pull air over the exchange surface. The so-called respiratory muscles accomplish this func-tion. Respiratory muscles are typical skeletal muscles, whose motoneurons are located either in the brainstem or the spinal cord. To complicate matters further, the respiratory muscles have additional functions to moving air over the exchange surface, which makes controlling the process of ventilation very difficult. In fact, the respiratory muscles are chiefly involved in the most precise motor act that humans engage in: speech. Other functions of the respiratory muscles include posture adjustments and protective responses such as coughing and vomiting.

If we had to narrow the functions of the respiratory system to a list, it would include the following:

1) Exchange of gases between the atmosphere and the blood2) Homeostatic regulation of body pH3) Protection of the respiratory membrane from inhaled pathogens and irritating substances4) Specialized motor functions unrelated to gas exchange

How is gas exchange accomplished?

The exchange of gases involves the following 4 steps:

1) Movement of air into and out of the lungs, in a process called ventilation. Inspiration is the movement of air into the lungs, whereas expiration is the movement of air from the lungs.

2) The exchange of oxygen and carbon dioxide between the lungs and the blood3) The transport of oxygen and carbon dioxide by the blood4) The exchange of gases between blood and the cells

We will consider each step in sequence.


The players--structure of the respiratory system

There are three main components of the respiratory system:

1) The “conducting system,” or passageways for air to reach the exchange surface from the external environment.

Air enters the upper respiratory tract and passes into the pharynx, a common passageway for both ingested materials and air. It then passes through the larynx into the trachea, or windpipe. Note that the larynx contains the vocal cords, connective tissue bands which are tightened or loosened by the actions of muscles to create sound when air passes past them. The trachea itself is a semi-flexible tube held open by C-shaped rings of cartilage. The trachea subdivides into a pair of primary bronchi, one for each lung. Like the trachea, the bronchi are semi-rigid tubes supported by cartilage rings.

A number of upper airway muscles act as valves that regulate air flow through the upper respiratory tract. These upper airway muscles include laryngeal and pharyngeal muscles, as well as muscles that move the tongue. We will discuss these muscles more when we discuss respiratory control next week.

Within the lung, the bronchi branch to become bronchioles, small collapsible pas-sageways with smooth muscle walls. The bronchioles continue to branch until they end at the exchange surface.

The diameter of the airways becomes progressively smaller as they branch, but cross sectional area becomes larger. This is a similar arrangement as with the cardiovascular system, and the same rules (e.g., Ohm’s law) still apply.

The conducting system serves to moisten and warm air that has been taken-in and protect the lung from harmful irritants and particles.

2) The alveoli, or exchange surface of the lungs, where oxygen and carbon dioxide move between the air and the blood.

The bulk of lung tissue is composed of alveoli. Two types of alveolar cells exist, in approximately equal numbers. Type I alveolar cells are the thin gas-exchange cells, whereas Type 2 alveolar cells synthesize a chemical called surfactant. Surfactant acts to ease the expansion of the lungs during inspiration.

Many connective tissue fibers, or elastin fibers, exist between alveoli. These fibers contribute to elastic recoil when lung tissue is stretched.

The surface of Type I alveolar cells is covered with blood vessels to permit gas exchange. Often these lung epithelial cells adhere to the capillary endothelial cells, so that the interstitial space is small. This specialization enhances gas exchange between the alveoli and the blood.


3) The bones and muscles of the thorax and abdomen which produce the forces that move air into and out of the lungs.

As will be discussed below, the size of the closed thoracic cavity can be altered by the actions of the respiratory “pump” muscles. The enlargement of the thoracic cavity increases negative intrathoracic pressure, which “sucks” air into the lungs (like a vacuum cleaner). The major inspiratory muscle is the diaphragm. When this muscle contracts, the lungs are pulled downward. During expiration, the muscle relaxes, and elastic recoil causes air to be forced out of the lungs. During heavy breathing, ad-ditional force is required to push air out of the lungs. This force is mainly supplied by the abdominal muscles, which force the abdominal contents up against the bottom of the diaphragm.

Muscles that move the ribcage also participate in respiration. Expansion of the rib cage assists in gen-erating inspiration. The most important muscles for this purpose are the external intercostal muscles. In addition, the sternocleidomastoid, anterior serrati, and scaleni muscles participate in expanding the ribcage and enhancing negative intra-thoracic pressure.

The ribcage is compressed by the actions of the internal intercostal muscles, which participate in expiration.

Other Structural Specializations in the Respiratory System:

Both the outer coverings of the lungs and the walls of the thoracic cavity are composed of pleura, or layers of elastic connective tissue permeated with many capillaries. The pleural tissue is held together with pleural fluid. This fluid provides a moist, slippery surface so that the lungs can easily slip along the walls of the thorax. Furthermore (and more importantly), the fluid tends to hold the lungs against the thoracic wall. This is important, as the lungs could collapse without this support.

The pulmonary circulation also has many specializations. It should be recalled that cardiac output from the left and right heart has to be matched, so the same amount of blood flows through the lungs per minute as flows through the rest of the body! The length of the vessels in the lungs is much shorter than in the body, and lung arterioles are usually dilated (offering little resistance to flow). Because of these factors, flow rate through the lungs tends to be high. Furthermore, blood pressure generated by the contraction of the right ventricle is low: 25/8 mm Hg


Osmotic Relationships in Lung Capillaries

Pressures in lung capillaries are much lower than in systemic capillaries. Pc is only 10 mmHg (and varies little between the arterial and venous ends of the vessels). Interstitial hydrostatic pressure (Pi) is near 0. Since plasma protein content does not change between the systemic and pulmonary circulation, so pc is the same in both (~25 mmHg). A difference, however, is that interstitial plasma concentration in the lung is very high: pi is near 19 mmHg. This high interstital protein level is related to the low rate of water movement through the pulmonary interstitial space.

As such, fluid flow in the pulmonary circulation is:

Jv ≈ ([10 — (0)] — [25 — 19]) or 4 mmHg

This calculation shows that fluid is lost in the lung into the interstitial space. However, little fluid remains in the interstital space due to the high efficiency of the pulmonary lymphatic system. The lymphatic system can clear the fluid from the interstitial space as long as capillary hydrostatic pressure remains less than 25 mmHg.

Physics of Gas Exchange

In order to understand how the respiratory system works, 4 basic laws must be understood:

1) Dalton’s law. Dalton’s law states that the total pressure of a mixture of gases is the sum of the pressures of the individual gases. Atmospheric pressure at sea level is 760 mm Hg, so if nitrogen is 78% of air, then the partial pressure exerted by nitrogen is 760 * 0.78 =593 mm Hg. Oxygen comprises 21% of air, so the partial pressure exerted by oxygen is 0.21*760=160 mm Hg.

2) Gases move from regions of high pressure to regions of low pressure. This applies to a mixed gas, and to a single gas (that moves from a region of higher partial pressure to a region of lower partial pressure).

3) Boyle’s law. If the volume of a container of gas changes, the pressure of gas will change in an inverse manner. In other words, if a sealed vessel containing a fixed number of gas molecules gets smaller, then the number of collisions of gas molecules in that chamber will increase and pressure will increase. If a gas is at a pressure of 100 mm Hg, and the volume of the container holding it doubles, then its pressure will fall to 50 mm Hg.

4) The amount of gas that will dissolve in a liquid is determined by the partial pressure of the gas, the solubility of the gas, and the temperature. In general, the latter variable can be ignored in humans (T is always about constant).


Physics of Ventilation

1) As noted above, the airway serves to warm and moisturize air and to filter out foreign particles. If all of these things do not occur, then the alveoli would be damaged. The nasal passages are lined with mucus which serves to warm and moisturize air before it reaches the trachea. The trachea and bronchi serve to filter air. These passageways are lined with mucus-covered cilia, which constantly move the mucus towards the pharynx (a process called the mucus elevator).

2) Air flow into the lungs is largely explained by Boyle’s law and Ohm’s law (Q = ∆P/R). As noted above, the thoracic cavity and lung enlarges during inspiration, so that a pressure gradient exists between the environment and the lung. As a result, air moves down its pressure gradient into the lung.

Lung Compliance

Recall from the cardiovascular lectures that Compliance (C) = ∆V/∆P. Compliance is also very important for the control of respiration, since the lower the compliance, the more difficult it is to expand the lungs (∆V) at a particular distending pressure.

As the distending pressure (generated by the con-traction of the respiratory muscles) increases, the chest expands and the volume of the lung increas-es. The relationship is dictated by the compliance of the lungs. Note that compliance changes as the lungs inflate. At low lung volumes the compliance is relatively high. At high lung volumes, the com-pliance is relatively low. This is due to how the elastic components of the lungs respond to stretch-ing. Note that the pressure-volume curve differs during inspiration and expiration. There are dis-agreements why this occurs. Chest wall compliance is additive with lung com-pliance, and must also be overcome to allow for lung expansion and filling.

NROSCI/BIOSC 1070 & MSNBIO 2070 October 4, 2017 Respiration 1

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