CSB346 Lecture 8 Notes

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Cell and Systems Biology
John Peever

CSB346 Lecture 8 – Airway and Pulmonary Reflexes (March 19, 2013) Slide 2 – Central regulation of breathing - The last two lectures talked about how the CNS and PNS detect chemical stimuli (e.g., CO2 and O2) and how changes in those chemicals impact respiration. - How do mechanical stimuli affect respiration? This is called airway or pulmonary reflexes. They are not sensitive to changes in a chemical. How do airway and lung receptors affect the respiratory network? How do upper airway muscles affect the respiratory network? It is a mechanical message rather than a chemical message. Slide 3 – Reflexive signals - Airway reflexes encompass everything from the nostrils to the larynx. Anything below the larynx is a pulmonary reflex. Breathing rhythm is generated by a network of neurons in the brainstem. They control the motoneurons and muscles that allow thoracic expansion and contraction. This affects the pressure changes that ultimately drive thoracic expansion and contraction (e.g., ventilation). Slide 4 – Mechanical control of breathing - Mechanoreceptor is like an elastic. If the mechanoreceptor is not being stretched, it is not being activated. If the mechanoreceptor is being stretched, it affects how the mechanoreceptor would send information back up to the brain. We are going to focus on the different types of mechanoreceptors that are located within the lungs and the upper airways. Slide 5 – Airway receptors - Afferents are referring to the receptors that are doing the detection. There are a series of afferents (e.g., receptors communicate their information via nerves to the CNS). There are two sources of afferent pathways: lower airway and upper airway. - These are some of the signals that the afferents can detect. o Respiratory sensation (e.g., dyspnea) o Intraluminar pressure (e.g., within the tube of the airway) - In order to understand how reflexes are mediated, we need to think of the possible neural pathways that go from the airways to the CNS. o The carotid sinus nerve relays information from the CB to the brain. o In terms of lung tissue and airway tissue, what are the neural pathways that get from the sensory cells in those tissues to the brain? What are the afferent pathways? Slide 6 – Pulmonary receptors - The vagus nerve is the “super highway” of sensory information from the thoracic component of your body. An enormous number of afferents in the lung tissue are relayed to the brain via the vagus nerve. It is an important nerve in relaying information from the lungs to the brain. - The sensory receptors in the airways within the lung have key roles in controlling breathing and in various defenses. They get that information to the brain via the vagus nerve. The vagus nerve plays a key role in the mechanical control of breathing. - This shows where the vagus nerve is sitting. The vagus nerve is coming all along down the external carotid artery. The vagus nerve communicates with all the vagal afferents sitting in the lung. The vagus nerve has both descending and ascending projections. We are going to talk about the ascending afferent projections. The right vagus nerve relays information largely from the right side. The left vagus nerve relays information from the left side. The vagus nerve is carried up and it lands in the nodose ganglion. Slide 7 – Pulmonary reflexes and the vagus nerve - The vagus nerve has a whole bunch of branches coming off of it that are going to different places. This shows you the various branches of the vagus nerve. o We are going to talk about vagal afferents that are above the bifurcation. We are going to primarily talk about the pulmonary branches that feed information from all the receptors in the lungs. The vagus nerve has a whole bunch of branches coming into it that are above the pulmonary branches (e.g., RLN, SLN). o The dendrites for specialized receptors are sitting in the lung tissue, for example. Their afferents go all the way up. The bodies for the cells are sitting up here in the nodose ganglion. The specialized receptors (e.g., the dendrites) are sitting in the lung tissue. The axons terminate primarily in the NTS. The NTS is a huge integration center for the respiratory system. A lot of other receptors are sitting in various tissues all around. Their afferents are being relayed through various nerves. - Nerves of major importance that carry pulmonary afferents are the intrathoracic vagus (or the pulmonary branch), but the RLN is also another major branch that makes up the vagus nerve. These two types of nerves carry the afferent information from the trachea, larynx, and so on. The RLN is taking most of the information up from all of the structures around here. The pulmonary branch of the vagus is taking a lot of information from the lung. All of those branches are carried in the vagus nerve. The cell bodies for all of those afferents are sitting in the nodose ganglion. o All the specialized receptors are here. Their dendrites go up the vagus nerve to the cell body that makes them, which sits in the nodose ganglion. The axon goes up and terminates in the NTS. Slide 8 – The vagus nerve - This is the airway within the lung. The cell body is sitting in the nodose ganglion. It sends its information up into the NTS through the vagus nerve. - The cell body is not the receptor. It is specialized dendrite of these nerve cells. The cell body is sitting in the nodose ganglion. - There are laryngeal and pharyngeal branches. The pharyngeal is taking sensory information from the pharyngeal airspace. It is also relaying information up. It is part of the vagus nerve. - This is a picture of a brainstem. All of the things coming in it are the actual branches coming into the brainstem from all of the various sources. The white ones (#2) are the afferent inputs from the vagus nerve. They are all terminating in the NTS. Slide 9 – Pulmonary afferents in the vagus nerve - The vagus nerve is important in modulating breathing. There are stretch receptors in the airway and the lung tissue. The information from the pulmonary stretch receptors is thought to be carried in the vagus nerve to the brain. If we do a vagotomy (e.g., cutting the vagus nerve), you should see a profound change in breathing if it is relaying important information. - This is the phrenic nerve that goes to the diaphragm. This is the hypoglossal nerve that goes to the tongue. o A  This is when the vagus nerves are intact.  When you adjust tracheal pressure (e.g., by sucking air out or pushing air into the trachea), you can see that the tongue responds powerfully to the stimulus. This indicates the changes in airway pressure are detected by the tongue. The diaphragm doesn’t do too much. This is showing you that changes in tracheal pressure are sensed by the tongue. o B  Then we vagotomize the vagus nerve. When you remove the influence of the vagus nerve, both upper airway and phrenic activity change profoundly. It goes up in amplitude and breathing is slower. The breathing amplitude and frequency changed. - There is some piece of information being transmitted to the brain from the lungs that is changing the pattern and timing of breathing. When the vagus nerve is removed, it inhibits breathing. The inhibition makes it much higher in overall amplitude. There is something that slows breathing down in the vagus nerve. o This is the Hering-Breuer reflex. Slide 10 – The Breur-Hering reflex - The Breuer-Hering reflex is that the vagus nerve is an important part of the respiratory system. The Breuer-Hering reflex is telling you that distending the lung tissue has a profound effect on breathing. - This is intratracheal pressure. They put a pressure transducer into the throat of a dog. They measured the changes in pressure in the throat. As you breathe in, pressure drops inside the airway relative to the atmosphere. As you breathe out, pressure increases. This is the pressure gradient. As your chest expands, the pressure drops. The drop in pressure generates the airflow that moves into the lung. As your chest deflates, the pressure increases. This causes the air to move out of the lung. o You can measure pressure inside the throat and the chest. This gives you an index of inspiration and expiration. o When there is no pressure, the dog is inspiring and expiring. The deflections represent the pressure due to inspiration. Then there is a big change in pressure. They kept the dog’s airway closed. They disabled the dog’s ability to deflate its lungs. The deflections stopped. There was no pressure deflection. The dog stopped breathing. When they change the pressure, the dog doesn’t try to breathe. Then the dog takes a big breath. Then it doesn’t breathe. Then it takes another big breath. Then they let the pressure fall back to normal and the dog resumes to breathing normally. o The change in pressure is being sensed by the blood pressure. Every deflection is a heartbeat. When they clamp the airway, blood pressure drops. This is a standard response. o The increase is experimentally induced changes in pressure. When the pressure goes up, the deflections have stopped. This means the dog is not trying to breathe in. What is the point of breathing in when the lungs are maximally inflated? - What is causing the Breuer-Hering reflex? Why would the dog stop breathing? If they inflate the lungs, why isn’t the brain trying to send any information to breathe? The vagus nerves go to the lung. The vagus nerve is important in mediating the Breuer-Hering reflex. o They cut both of the vagus nerves. They did the same thing. The dog is breathing. Then they increase the pressure like before. The dog continues to breathe. Then they drop the pressure down and breathing is normal. o When the vagus nerve is cut and the pressure goes up, the dog keeps breathing. - This is evidence that there is something special when you keep the lungs inflated. The brain recognizes it because the dog doesn’t try to breathe. When they cut the vagus nerve, the brain doesn’t recognize that the lungs are inflated and they keep sending the respiratory signal down to the phrenic nerve. o The vagus nerve is carrying the information that tells the dog’s CNS that the lung is either inflated or deflated. The vagus nerve is important because when you get rid of it, the dog continues to breathe even though the intratracheal pressure has been artificially increased. - This tells us that mechanical deformation of the lungs affects the way the CNS sends respiratory signals to the muscles (e.g., diaphragm, airway). If you change pressure in the lung, you get a change in breathing. When you get rid of the vagus nerve, that response goes away. Therefore, the vagus nerve must be mediating that response. - What are the things that are doing the detecting to cause this Breuer-Hering reflex? Slide 11 – Types of pulmonary receptors - There are pulmonary receptors in the chest that are sending information to the brain. There are different types of pulmonary receptors. - SAR and RAR are mylinated, which means they send information quickly to the brain. Broncho- pulmonary C fibres are unmylinated, which means they send information slowly to the brain. o Mylinated neurons send information much more quickly than unmylinated. Slide 12 – Pulmonary afferents and their associated reflexes - When the broncho-pulmonary C fibres are stimulated, they have a variety of reflex responses. - Airway mucus secretion is a long-term type of response. Mucus secretion isn’t spontaneously produced and secreted. The unmylinated nature of broncho-pulmonary C fibres means that they don’t transmit their information as quickly to the brain. This is perhaps why these are unmylinated because getting mucus to be secreted isn’t something that takes split second time resolution. It takes some time to do it. - These fibres can trigger a range of different types of responses. These elicit a range of behaviours, which depend on the circumstance in which these receptors are being activated. There are a range of responses because there are two different stimuli. There are also different types of edema and different types of irritants. Slide 13 – Pulmonary afferents and their associated reflexes - Mechanical deformation is important. Edema affects the airway consistency. - These reflexes depend on a variety of things and conditions. Just remember that when you stimulate these receptors, you get a variety of reflex responses. I do not expect you to understand why you get cough, or augmented inspiration. Slide 14 – Pulmonary afferents and their associated reflexes - SARs are quite important. When the dog’s airway was inflated, there was no more inspiration occurring. SARs stop the brain from trying to inspire and inflate the lungs. Expiratory prolongation is not breathing in. - The airways can be distended by inflation or some other process. We will only talk about lung inflation causing airway distension. Slide 15 – Activity of pulmonary receptors - If you could record the activity of these receptors, what would it look like? - If you look at the discharge from the airway sensors (e.g., the receptors), you are recording the nerves that are going up to the brain in the form of action potentials. - A o You are recording the nerve that is sending information from the SAR in the airway smooth muscle. What do the action potentials look like in response to a change in airway pressure? o The top trace is showing how airway pressure is changing. The bottom trace is showing how a SAR responds to the change in airway pressure. o When airway pressure is increased (e.g., the lungs are being distended), there is an immediate response in the increase in the number of action potentials per unit of time. They stay fairly consistent. There is a burst of lots of APs. They still continue to fire but it slowly decreases to fewer action potentials per unit of time. o The stimulus is constant, but the receptors are slowly adapting by reducing the number of action potentials in response to the constant stimulus. - B o You cause an increase in airway pressure. Before there is an increase in airway pressure, the RARs are not discharging APs. When pressure goes up, they immediately sense that and they fire rapidly. They seem to stop firing APs. They rapidly adapt to that stimulus. - C o This is the C-fiber receptors. This is the discharge of the C-fiber receptTr. P is the pressure in the tracheal area, which is going up and down. The C-fiber receptor is not firing in any temporal correlation with tracheal pressure. These receptors aren’t necessarily listening to changes in the pressure. They are more interested in airway edema and chemical irritants. It makes sense that these receptors aren’t responding to pressure changes. - RAR and SAR are much more responsive to changes in airway pressure. Slide 16 – Activity of pulmonary receptors - This is a change in pressure associated with ventilation (left). This is an artificially induced change in pressure (right). - We are looking at sensory discharge from the SAR and the RAR. This figure demonstrates that increased lung volume activate both of the receptors. This is a natural increase in lung volume. These are increases in which air was forced into the lung. This is a natural change in pressure associated with inspiration and expiration (left). This is an artificial increase in pressure (right). - Both the SAR and the RAR are listening to the natural changes in airway pressure associated with inspiration and expiration. - Top (RAR) o When there is inspiration, airway pressure increases. The RAR immediately begins to fire. It stops listening to the pressure change. It largely stops firing. When the airway pressure increases again, the RAR increase their activity but they stop firing even before the pressure decreases. o By the artificial stimulus, you artificially keep the lung pressure higher by pumping air into the face by a mask. You can see that the RAR fire action potentials but then they rapidly adapt and stop firing APs even though the pressure is maintained. o They are rapidly adapting to the constant pressure change. - Bottom (SAR) o When pressure is increased and decreased across the natural respiratory cycle, look at the firing pattern of the SAR. They are always firing action potentials in comparison to RAR. They are increasing their firing during the increase in pressure associated with a natural inspiration. They don’t adapt too much. They are slowly adapting. They adapt somewhat. They don’t change much across the respiratory cycle. They are very closely listening to the changes in pressure associated with airway distension. o When the pressure is increased, the SAR increases their firing frequency. This suggests that they are increasing their firing frequency because of an increase in pressure. They don’t change their firing frequency even though the pressure stays constant. - This demonstrates that both the RAR and SAR are consistently active across the respiratory cycle. The SARs are firing more with increased pressure, but they still fire when the lungs are deflated. The RARs don’t seem to have too much activity before the increase in pressure, but they do fire across the respiratory cycle during inspiration and expiration. The SARs are much more “excitable”. The SARs are listening much more carefully to changes in pressure. The SARs are active during inspiration and expiration, but they are more active during inspiration because they are listening to the increase in pressure. Slide 17 – Stretch receptors  P-cells - How do these stretch receptors communicate with the brain? When you activate them, you have a series of respiratory reflexes. When these receptors are activated, the brain has to change breathing. These receptors are somehow communicating with the CNS and presumably the RRG centers to mediate those responses in breathing. How do they get that information to the brain? - We are going to focus on the SARs because they are constantly listening to changes in pressure more than the RARs. How do they get their information from the lung to the RRG to elicit changes in breathing? o The SARs are in the lung airway tissue. When they are stimulated, inspiration is terminated or expiration is prolonged. What is the evidence? - There are several steps. The first step is P-cells (e.g., pump cells). o They recorded cells in the area of the NTS and noticed that these cells would fire in relation to the pump.  Most of these experiments are done in ventilated cats. o They would be recording the respiratory cells in the DRG or the VRG, and they found a group of cells that seem to be listening to the pump when the cat’s lungs were inflating, rather than listening to the activity of the phrenic nerve that generates inspiration.  When the cat is being ventilated, the phrenic nerve can fire independently of the pump. The phrenic nerve could be firing, and the physical inflation and deflation of the lungs doesn’t have to be following exactly. This is because the vagus nerve that is relaying a lot of information to the brain about the status of the lung has been cut. You have a dissociation of the signals that the brain is generating and the physical/mechanical responses that the lungs are producing. o They noticed that P-cells would be firing in relation to when the pump was active, but not to the phrenic nerve that innervates the diaphragm.  The second trace is the activity of the phrenic nerve. The third trace is the recording a PSR. The first trace is the activity of the pump cell. There is a period where the pump cell doesn’t fire, but the phrenic nerve does.  The phrenic nerve is not driving the expression of the pump cell. There is some other stimulus that is causing the pump cell to be activated. It was thought that the inflation of the lung is causing this response. - Why are the pump cells not firing with inspiration? Why are the pump cells firing with lung inflation? The lungs are inflated because the ventilator is inflating the cat’s lungs. The cat is not able to inflate its own lungs because the phrenic nerves are cut from the diaphragm. o Maybe the SARs are driving the activity of the pump cells, which in turn tell the RRG system when to drive the phrenic nerve. Slide 18 – Projections of P-cells - How do the SARs located in the lung tissue get their information to the brain? We think it is the pump cells. The pump cells are sitting in the NTS. This is not part of the classic RRG system of the VRG/DRG/PRG. How do the pump cells get their information to the pontine and medullar brain structures that physically generate respiration? o The NTS is a giant relay station. A lot of sensory information from the vagal nerve afferents terminates in the brain at the NTS. Then
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