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Asthma syndrome Paper

Asthma

Asthma is a syndrome that is characterized by obstruction of the respiratory tract preventing proper airflow into the lungs.  Asthmatics harbor a type of inflammation in the airways that makes them more responsive to a wide range of triggers compared to non-asthmatics.  This leads to excessive narrowing of the airways with consequent reduction in the airflow producing symptoms like difficulty in breathing and wheezing.  Inflammation is seen from trachea to the terminal bronchioles, but is predominantly observed in the cartilaginous bronchi (Fauci, et al., 2008).

The mechanism behind airway narrowing in sudden asthmatic attacks includes contraction of airway smooth muscle, production of thick mucus plugs in the airway lumen, and thickening of the bronchial mucosa, the lining of the bronchus.  Of these causes, contraction of smooth muscle is the most easily reversed by available therapy.  On the other hand, reversal of bronchial mucosa thickening requires prolonged treatment with several anti-inflammatory agents.  In this paper, our focus will be on drugs classified as bronchodilators that prevent the contraction of the smooth muscles of the bronchus resulting to their relaxation (Katzung, 2007).

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To understand more the mechanism on how bronchodilators act, knowing the anatomy of the airways is essential.  The airway is divided into the upper and lower airway.  The upper airway consists of all structures from the nose to the vocal cords.  On the other hand, the lower airway consists of the trachea, airways (main bronchi to respiratory bronchiole) and alveoli (Figure 1).  Since inflammation is predominantly seen in the bronchi, we will limit our discussion to the anatomy of this part of the airway (Berne, Levy, Koeppen, & Stanton, 2004).

The main bronchi, or the extrapulmonary bronchi, closely resemble the trachea in structure.  It only differs from trachea in that bronchi are smaller in diameter.  In the main bronchi, cartilage rings, which function as support, are also incomplete like in trachea; the posterior deficiency (at the back) is occupied by smooth muscles.  The main bronchi branch off and give rise to intrapulmonary bronchi (Figure 1) (Leeson, Leeson, & Paparo, 1985).

Figure 1. A diagram of the lower airway from the trachea to the terminal bronchioles

(Berne, Levy, Koeppen, & Stanton, 2004)

The intrapulmonary bronchi differ from the main bronchi in that they are rounded in outline and do not show posterior flattening that is seen in trachea and extrapulmonary bronchi.  This is due to the absence of C-shaped cartilaginous rings, which are replaced by irregular plates of hyaline cartilage (Figure 2).  At the junction of submucosa and mucosa, the elastic tissue is reinforced by an outer sheet of smooth muscle fibers.  These smooth muscle fibers are not arranged in a definite layer, but take the form of interlacing bundles arranged in open spirals around the bronchus (Leeson, Leeson, & Paparo, 1985).  When these smooth muscle contracts, it “squeezes” the bronchus resulting to the narrowing of the airway.  Similarly, when these smooth muscles relax, they make the airway more patent allowing air to flow easier with less obstruction.

Bronchi become smaller with successive division of the bronchial tree, but the basic structure as described above remains the same.  However, the smallest bronchi contain less cartilage and the lining epithelium become taller and ciliated, which is interspersed with cells producing mucus called goblet cells (Leeson, Leeson, & Paparo, 1985).

Submucosa

Lamina propria

Cartilage plates

Bronchial epithelium (mucosa)

Smooth muscle

Figure 2. Transverse section of an intrapulmonary bronchus (Leeson, Leeson, & Paparo, 1985)

In contrast to Figure 2 showing the normal anatomy of a bronchus, Figure 3 shows the changes brought about by the long-term inflammation in asthma.  In asthmatics, the lumen of the bronchus is occluded with a mucous plug.  The airway wall is also thickened, with an increase in basement membrane thickness and airway smooth muscle (Fauci, et al., 2008).

Figure 2.  Changes in the microscopic anatomy of a small airway in asthma

(Fauci, et al., 2008)

Regulation of smooth muscle contraction

Figure 4. Regulation of smooth-muscle cell calcium concentration and actomyosin ATPase-dependent contraction (modified from Fauci, et al., 2008).  (NE, norepinephrine; PIP2, phosphatidylinositol 4,5-biphosphate; PLC, phospholipase C; DAG, diacylglycerol; G, G-protein; VDCC, voltage-dependent calcium channel; IP3, inositol 1,4,5-trisphosphate; PKC, protein kinase C; SR, sarcoplasmic reticulum; NO, nitric oxide; ANP, antrial natriuretic peptide; pGC, particular guanylyl cyclase; AC, adenylyl cyclase; sGC, soluble guanylyl cyclase; PKG, protein kinase G; PKA, protein kinase A; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase)

Smooth muscle contraction is mainly controlled by the phosphorylation or the addition of a phosphate group to a muscle protein called myosin light chain (MLC).  Activation of myosin light chain depends on the balance between the actions of two enzymes: the myosin light chain kinase (MLCK), an enzyme that phosphorylates MLC, and myosin light chain phosphatase (MLCP), an enzyme that dephosphorylates or removes the phosphate group from MLC.  MLCK is activated by calcium through the formation of a complex called the calcium calmoudulin complex.  After the activation of MLCK, it then phosphorylates the MLC resulting to its increased ATPase activity, which in turn leads to muscle contraction (Fauci, et al., 2008).  ATPase is an enzyme that hydrolyze or “split” the high energy molecule containing three phosphate molecules called adenosine triphosphate or ATP into a low energy molecule containing only two phosphates (adenosine diphosphate or ADP) and inorganic phosphate (Pi) (ATP à ADP + Pi), a reaction that would release energy to be used for muscle contraction (Berne, Levy, Koeppen, & Stanton, 2004).  In contrast to this, MLCP dephosphorylates MLC, reducing myosin ATPase activity and contractile force (Fauci, et al., 2008).

But how does MLCK get inactivated to cause smooth muscle relaxation?  We know that in order for a locked door to be open, a key should fit into the lock and turn the lock open.  This analogy could be applied to understand the concept of receptor and ligand better where the receptor represents the lock and the ligand represents the key.  A very specific ligand should be present and should bind to the receptor in order for the desired effect to occur, i.e. for the door to open.  In our discussion, the receptor will be called the β2-receptor, the predominant receptor in the lungs and bronchi, whereas the ligand will be called the β2-agonist implying that it actually increases the activity of the receptor.  Examples of selective β2-agonist are the drugs for asthma, albuterol, terbutaline, metaproterenol, and pirbuterol.  The effects of β2-agonist are mediated by G-protein-coupled β2 receptors (Figure 4), which activate an enzyme called adenylyl cyclase.  Adenylyl cyclase converts ATP into a molecule referred to as cyclic AMP.  Cyclic AMP, in turn, activates a phosphorylating enzyme, protein kinase A, which in turn inactivate the myosin light chain kinase.  Since active myosin light chain kinase is necessary for the muscle contraction to proceed, inhibition of this enzyme causes smooth muscle relation and decreases the smooth muscle tone.  Overall, β2-agonists cause smooth muscle relaxation and dilation of the airway (Fauci, et al., 2008).

Autonomic influence on the smooth muscle tone of the airway

Smooth muscle cell tone is governed by the autonomic nervous system through a tightly regulated control networks.  The autonomic nervous system generally refers to the sympathetic and parasympathetic nervous system (SNS and PNS, respectively), which function to assist the body in maintaining constant internal environment or homeostasis and participate in appropriate and coordinated responses to external stimuli (Berne, Levy, Koeppen, & Stanton, 2004).

The sympathetic innervations of the lungs and bronchi came from the superior cervical sympathetic ganglion.  A ganglion is a collection of nerve cell bodies outside the central nervous system.  Sympathetic nerves arise from this ganglion to reach the smooth muscles of the lungs and bronchi, which allows these organs to be connected and controlled by the SNS.  When the sympathetic nervous system is activated, the sympathetic nerve cell membrane is depolarized; meaning the charge inside the nerve cell becomes positively charged (from being negative) while the charge outside the cell becomes negative (from being positive).  The depolarized membrane then increases its permeability to calcium by opening calcium channel increasing the influx of calcium ions into the axon terminal.  This triggers the fusion of a fraction of the vesicles containing the cathecolamine neurotransmitter, epinephrine (Berne, Levy, Koeppen, & Stanton, 2004).  Although norepinephrine can also be released by sympathetic nerve cells, it is epinephrine that predominantly binds to β2-receptors present in the smooth muscles of the bronchi; whereas, norepinephrine mainly acts on α2-receptors present elsewhere (Katzung, 2007).  The empty vesicles are coated with clathrin, the molecule that facilitates degradation, are rapidly internalized, and subsequently fuse with early endosome.  Meanwhile, epinephrine crosses the synaptic cleft – the space between the nerve terminal and surface where the receptors are – via diffusion, binds to and activates the β2-receptor in the smooth muscles of the bronchi and causes smooth muscle relaxation in the same manner as the β2-agonist albuterol (Berne, Levy, Koeppen, & Stanton, 2004).

Figure 5. Schematic diagram of a generalized noradrenergic junction and the synaptic vesicle cycle.  (NT, neurotransmitter; modified from (Berne, Levy, Koeppen, & Stanton, 2004 and Katzung, 2007)

The sympathetic effects on different organs

It is a popular notion that activation of the SNS mediates the “fight-or flight” response during an intensely stressful or threatening situation.  The sympathetic activation actually produces a variety of responses by releasing adrenergic hormones like norepinephrine and epinephrine that act to a variety of organs in the body.  Adrenergic hormones cause the increase in heart rate and blood pressure; dilation of the bronchiole; inhibition of intestinal motility and secretion; increase in glucose metabolism; dilation of the pupils; contraction of the smooth muscles of the blood vessels of the skin and gastrointestinal circulation resulting to their constriction called vasoconstriction; as well as the relaxation of the smooth muscles of the blood vessels that supply the skeletal muscle resulting to vasodilation (dilation of the blood vessels) (Berne, Levy, Koeppen, & Stanton, 2004).

But how does the sympathetic nervous system produce different effects on different organs?  The answer lies on the differences between the adrenergic receptors present on these organs.  Different receptors mediate different effects on the end-organ.  Aside from β-receptors discussed above, another type of receptor called α-receptor also exists.  α and β receptors belong to the group of receptors called adrenoreceptors.  These receptors respond to adrenergic neurotransmitters like norepinephrine and epinephrine, which act as signal molecules and are released when sympathetic nerves are activated.  α and β-receptors are further classified into β1, β2, α1, and α2 (Katzung, 2007).  Table 1 shows the different receptors present on the different organ as well as the different sympathetic actions on them.

Table 1. Direct effects of the sympathetic nervous activity on some organ systems.
Organ
Action1
Receptor2
Eye

Iris radial muscle
Contracts
α1

Ciliary muscle
[Relaxes]
β
Heart

Sinoatrial node
Accelerates
β 1, β 2

Ectopic pacemakers
Accelerates
β 1, β 2

Contractility
Increases
β 1, β 2
Blood vessels

Skin, splanchnic vessels
Contracts
α

Skeletal muscle vessels
Relaxes
β 2

[Contracts]
α
Bronchiolar smooth muscle
Relaxes
β 2
Gastrointestinal tract

Smooth muscle

Walls
Relaxes
α 2, β 2

Sphincters
Contracts
α 1
Genitourinary smooth muscle

Bladder wall
Relaxes
β 2

Sphincter
Contracts
α1

Uterus, pregnant
Relaxes
β 2

Contracts
α

Penis, seminal vesicles
Ejaculation
α
Metabolic functions

Liver
Gluconeogenesis
β 2, α

Liver
Glycogenolysis
β 2, α

Fat cells
Lipolysis
β 3

Kidney
Renin release
β 1

1Less important actions are shown in brackets.

2Specific receptor type: α= alpha, β = beta

Looking at Table 1, we can see that in contrast to the bronchiolar smooth muscle having β2-receptors, the smooth muscles of blood vessels on the skin and the splanchnic (gastrointestinal) have α-receptors.  And instead of mediating smooth muscle relaxation, α-receptors mediate the contraction of the smooth muscles resulting to vasoconstriction of the skin and splanchnic vessels.  This is because binding of adrenergic neurotransmitters to α-receptors initiates a set of events different from the reactions occurring when neurtoransmitters are bound to β2 receptors.  As shown in Figure 4, instead of mediating smooth muscle relaxation via the mechanism described above, ligand binding to α-receptors results to the activation of phospholipase C (PLC) with hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and generation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).  These products, in turn, activate protein kinase C leading to the increased intracellular calcium, which triggers smooth muscle contraction.  In addition, IP3 also binds to its specific receptor found in the sarcoplasmic reticulum membrane to increase calcium efflux or release from this calcium storage pool into the cytoplasm triggering muscle contraction (Katzung, 2007; Berne, Levy, Koeppen, & Stanton, 2004).  Thus, although both α and β receptors are bound to the same adrenergic neurotransmitter ligand, the effects that they produce differ in that α-receptor activation results to smooth muscle contraction while β2 receptors mediate its relaxation.

The sympathetic-mediated responses to exercise

The smooth muscles on the blood vessels supplying the skeletal muscles primarily have β2-receptors that mediate its relaxation during sympathetic activation like in the case of exercise.  Smooth muscles on the blood vessels supplying this organ also have α-receptors that mediate its contraction, but the contribution of this is only minor compared to the β2-receptors.  During exercise, after stimulation of the heart occurs, the SNS changes the peripheral vascular resistance – the degree of constriction of the blood vessels, i.e. the more constricted blood vessels, the higher is the vascular resistance.  In the skin, kidneys, splanchnic (gastrointestinal) regions, and inactive muscles, the sympathetic-mediated constriction of the blood vessels (vasoconstriction) increases the vascular resistance, and thus diverting the blood away from these areas.  The increased in vascular resistance in these organs has also been noted to persist throughout the period of exercise.  Although their blood supply decreases, these organs, however, do not become compromised because they are “less active” during exercise and therefore require less blood supply (Berne, Levy, Koeppen, & Stanton, 2004).

The blood that was diverted away from the “less active” organs is then shunted to the active exercising muscles.  As the blood flow to the muscles increases, visceral blood flow (i.e. to the splanchnic and renal vasculature) progressively decreases.  Increase in the blood flow to the muscles occur, in part, because of the SNS-mediated vasodilation in their vascular bed allowing them to be supplied adequately with oxygen and other metabolic needs (Berne, Levy, Koeppen, & Stanton, 2004).

Moreover, the blood flow to the active heart muscles (myocardium) also increases, whereas the flow to the brain remains unchanged to keep the brain from experiencing oxygen shortage or hypoxia.  Although the blood flow to the skin initially decreases, supply to the skin increases as the body temperature rises with increments in the duration and intensity of exercise to allow dissipation of heat produced by the exercising muscles (Berne, Levy, Koeppen, & Stanton, 2004).

In addition to increasing the blood flow to the active muscles, sympathetic activation during exercise also dilates the bronchioles.  The mechanism for this has already been discussed above.  But why does the sympathetic nervous system have to do that?  We already know that during exercise the body’s requirement for oxygen increases.  Contracting muscles also avidly extract oxygen from the blood perfusing them.  In fact, it has been observed that oxygen consumption may increase as much as sixtyfold during exercise.  This implies that for the muscles to work better and for the brain to not be deprived of oxygen, one has to take in more oxygen compared to when one is at rest.  To accomplish this, the bronchioles have to dilate such that air could flow with ease into the lungs allowing better oxygenation of the blood and better oxygen delivery to the organs (Berne, Levy, Koeppen, & Stanton, 2004).

In summary, the changes in blood flow to organs according to their activity are necessary to ensure that the “active” organs receive adequate oxygen supply for their respiration and the sympathetic nervous system, via its action on different organ systems, is one of the mechanisms that ensure that a specific organ gets what it needs.

References
Berne, R. M., Levy, M. N., Koeppen, B. M., & Stanton, B. A. (2004). Physiology (5th ed.). Philadelphia: Elsvier, Inc.

Fauci, A. S., Braunwald, E., Kasper, D. L., Hauser, S. L., Longo, D. L., Jameson, J. L., et al. (Eds.). (2008). Harrison’s Principles of Internal Medicine (17th ed.). USA: McGraw-Hill Companies, Inc.

Katzung, B. G. (Ed.). (2007). Basic and Clinical Pharmacology (10th ed.). USA: McGraw-Hill Companies, Inc.

Leeson, C. R., Leeson, T. S., & Paparo, A. A. (1985). Textbook of Histology (5th ed.). Philadelphia: W. B. Saunders Company.

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