Chapter 6: The Respiratory System

Think of your respiratory system as a highway system. Air enters through the on-ramp (nose or mouth), travels down an increasingly narrow series of roads (pharynx, larynx, trachea, bronchi, bronchioles), and finally arrives at the parking lot where actual business happens (alveoli). Everything before the alveoli is just getting air to the right place - the conducting zone. The alveoli are the only place where gas exchange actually occurs - the respiratory zone.

This distinction matters for the MCAT: the conducting zone warms, humidifies, and filters air but does zero gas exchange. The respiratory zone is where oxygen enters your blood and CO2 leaves it.

The Upper Respiratory Tract

The upper respiratory tract includes the nasal cavity, pharynx, and larynx. These structures sit above the trachea and serve as the entry point and first line of defense for incoming air.

The Nasal Cavity

Air enters through the nostrils and passes into the nasal cavity, which is divided by the nasal septum. Three bony projections called nasal conchae (or turbinates) protrude into each side of the cavity. These conchae create turbulent airflow, forcing air to swirl and make maximum contact with the mucosal lining.

The nasal cavity performs three critical functions simultaneously:

• Warming - A rich blood supply in the mucosal lining heats incoming air to body temperature
• Humidifying - Mucus and serous secretions add moisture, protecting the delicate lower airway tissues
• Filtering - Nasal hairs (vibrissae) trap large particles, while mucus produced by goblet cells captures smaller particles and pathogens

The nasal cavity also contains the olfactory epithelium in its superior region, which is responsible for the sense of smell.

The Pharynx

The pharynx is a shared passageway for both air and food. It is divided into three regions:

The pharynx is where the respiratory and digestive pathways cross. This crossover is why you can choke - food can accidentally enter the airway instead of the esophagus.

The Larynx

The larynx (voice box) sits at the top of the trachea and serves two functions: sound production and airway protection.

The epiglottis is a flap of elastic cartilage that covers the opening of the larynx during swallowing, preventing food from entering the airway. When you swallow, the larynx elevates and the epiglottis folds down like a trap door over the glottis (the opening between the vocal cords).

The vocal cords (vocal folds) stretch across the larynx. Air passing between them causes vibration, producing sound. Tension in the cords controls pitch - tighter cords produce higher-pitched sounds.

The Lower Respiratory Tract

Below the larynx, the lower respiratory tract begins with the trachea and extends through the bronchial tree to the alveoli.

The Trachea

The trachea (windpipe) is a tube roughly 10-12 cm long that connects the larynx to the bronchi. It is reinforced by 16-20 C-shaped cartilage rings that keep it open during pressure changes. These rings are C-shaped (not complete circles) because the open side faces the esophagus posteriorly, allowing the esophagus to expand when you swallow food.

The trachea is lined with pseudostratified ciliated columnar epithelium containing goblet cells. This is the beginning of the mucociliary escalator - a defense system where mucus traps particles and cilia beat in coordinated waves to push the mucus upward toward the pharynx, where it is swallowed or expelled.

The Mucociliary Escalator

The mucociliary escalator deserves special attention because it is one of the respiratory system’s most important innate defense mechanisms. Here is how it works:

1. Goblet cells secrete sticky mucus that lines the airways
2. Cilia on epithelial cells beat in coordinated waves (about 10-20 beats per second)
3. The beating cilia propel the mucus - along with any trapped bacteria, dust, or debris - upward toward the pharynx
4. At the pharynx, the mucus is swallowed (and destroyed by stomach acid) or coughed out

Smoking paralyzes cilia and increases mucus production simultaneously. This is why smokers develop a chronic “smoker’s cough” - without functioning cilia, coughing becomes the only way to clear mucus from the airways.

Other Respiratory Defenses

The mucociliary escalator is not the only defense mechanism. The respiratory system also uses:

• Lysozyme - an enzyme found in nasal secretions, tears, and saliva that attacks the peptidoglycan cell walls of gram-positive bacteria
• IgA antibodies - mucosal surfaces are coated with secretory IgA, which binds pathogens and prevents them from attaching to epithelial cells
• Alveolar macrophages (dust cells) - immune cells that patrol the alveolar surfaces, engulfing bacteria and particles that make it past the upper defenses
• Mast cells - immune cells in the lungs with antibodies on their surface. When triggered, they release inflammatory chemicals. Mast cells are also responsible for allergic reactions in the airways (like asthma)

Thermoregulation

The respiratory system plays an important role in temperature regulation. As air passes through the nasal cavity and upper airways, the rich capillary beds in the mucosal lining warm incoming air to body temperature and humidify it to near 100% humidity. This protects the delicate lower airways from cold, dry air damage.

During exhalation, heat and water vapor are carried out of the body with the exhaled air. This represents a source of evaporative heat loss. When body temperature rises (during exercise or fever), increased respiratory rate accelerates this heat loss. In some animals, panting is a primary thermoregulation mechanism - rapid shallow breathing maximizes evaporative cooling from the respiratory surfaces.

Conducting Zone vs. Respiratory Zone

This is a critical distinction for the MCAT:

The conducting zone is called anatomical dead space because air sitting in these passages is not participating in gas exchange. Typical anatomical dead space volume is about 150 mL. This means that of a normal 500 mL tidal breath, only about 350 mL actually reaches the alveoli for gas exchange.

If the trachea is the trunk of a tree, the bronchi are the main branches, the bronchioles are the smaller twigs, and the alveoli are the leaves - tiny, numerous, and where the real work happens. Your lungs contain about 300 million alveoli, creating a total gas exchange surface area roughly the size of a tennis court (about 70 square meters). All of that surface area is packed inside your chest because the alveoli are incredibly small - each one is only about 0.2 mm in diameter.

The Bronchial Tree

At the carina (the ridge where the trachea divides), the trachea splits into the right and left main (primary) bronchi. Each main bronchus enters its respective lung at the hilum - the medial surface where blood vessels, nerves, and lymphatics also enter.

The branching pattern is:

1. Main (primary) bronchi - one per lung; the right is wider, shorter, and more vertical than the left
2. Lobar (secondary) bronchi - one per lobe (3 right, 2 left)
3. Bronchioles - no cartilage, walls are smooth muscle
4. Terminal bronchioles - the smallest conducting airways (end of the conducting zone)
5. Respiratory bronchioles - have some alveoli budding from their walls (beginning of the respiratory zone)
6. Alveolar ducts and alveolar sacs - clusters of alveoli where gas exchange occurs

Key Structural Changes Along the Bronchial Tree

As you move from the trachea toward the alveoli, several important structural changes occur:

Two trends to remember: cartilage decreases while smooth muscle increases as airways get smaller. Large airways need cartilage to stay open, but small airways need smooth muscle to regulate airflow distribution. This is why asthma (bronchiolar constriction) affects exhalation so dramatically: the small airways have no cartilage to keep them propped open against the squeeze.

The Lungs

The two lungs are not identical:

• Right lung: 3 lobes (superior, middle, inferior), separated by the horizontal and oblique fissures
• Left lung: 2 lobes (superior, inferior), separated by the oblique fissure; has a cardiac notch - an indentation where the heart sits

The Pleural Membranes

Each lung is enclosed in a double-layered membrane called the pleura:

• Visceral pleura - the inner layer, directly adherent to the lung surface. It dips into the fissures between lobes.
• Parietal pleura - the outer layer, lining the inside of the chest wall and the superior surface of the diaphragm.
• Pleural cavity - the potential space between the two layers, containing a thin film of pleural fluid.

The pleural fluid serves two functions: it lubricates the pleural surfaces so the lungs can slide smoothly during breathing, and it creates surface tension that keeps the lungs adhered to the chest wall (like two wet glass slides stuck together).

Intrapleural Pressure

The pressure within the pleural cavity (intrapleural pressure) is normally negative - about -4 mmHg at rest relative to atmospheric pressure. This negative pressure is critical because it keeps the lungs inflated.

Why is it negative? The lungs have elastic recoil that constantly tries to collapse them inward, while the chest wall has its own elastic tendency to spring outward. These two opposing forces pull the pleural layers slightly apart, creating a suction effect (negative pressure) in the pleural space.

Pneumothorax

A pneumothorax occurs when air enters the pleural space, breaking the negative pressure seal. Without negative intrapleural pressure, the elastic recoil of the lung is no longer opposed, and the lung collapses.

A pneumothorax can result from chest trauma or spontaneous rupture of a small air pocket on the lung surface. The key concept is understanding why loss of negative intrapleural pressure leads to lung collapse.

The Alveoli

The alveoli are the functional units of the lung - tiny, thin-walled sacs where all gas exchange occurs. Each alveolus is wrapped in a dense network of capillaries, and the barrier between alveolar air and capillary blood is extraordinarily thin - only about 0.5 micrometers.

This barrier, called the respiratory membrane, consists of:

1. A thin layer of fluid lining the alveolus (with surfactant)
2. The alveolar epithelium (Type I cells)
3. A fused basement membrane
4. The capillary endothelium

Two types of cells make up the alveolar epithelium:

Alveolar macrophages (dust cells) patrol the alveolar surfaces, engulfing bacteria, dust, and other particles that make it past the mucociliary escalator. They are the last line of defense before the gas exchange surface.

Surfactant

Surfactant is a phospholipid-rich substance (primarily dipalmitoylphosphatidylcholine, or DPPC) secreted by Type II pneumocytes. It reduces surface tension within the alveoli, preventing them from collapsing during exhalation.

Why is this necessary? The alveoli are essentially tiny wet bubbles. Surface tension in a wet sphere naturally tries to collapse it (think of a soap bubble popping). Without surfactant, the smallest alveoli would collapse first (because LaPlace’s law tells us that smaller spheres have higher collapsing pressure for the same surface tension), and each breath would require enormous effort to re-inflate them.

Here is a question that trips up many students: do you actively suck air into your lungs? No. You create a pressure difference, and the atmosphere pushes air in for you. Breathing is entirely about pressure gradients, and the physics behind it is Boyle’s Law - one of the simplest gas laws you will encounter on the MCAT.

Inspiration (Inhalation)

Inspiration is an active process. It requires muscle contraction and energy expenditure. Here is what happens in sequence:

Step 1: Muscle contraction. The diaphragm (the dome-shaped muscle separating the thoracic and abdominal cavities) contracts and flattens downward, increasing the vertical dimension of the thoracic cavity. Simultaneously, the external intercostal muscles contract, pulling the ribs upward and outward (think of a bucket handle lifting), increasing the anteroposterior and lateral dimensions.

Step 2: Volume increases. The thoracic cavity expands in all three dimensions.

Step 3: Pressure drops. Per Boyle’s Law, as volume increases, intrapulmonary pressure (pressure inside the lungs) drops below atmospheric pressure. This creates a negative pressure gradient.

Step 4: Air rushes in. Air always flows from high pressure to low pressure. Since atmospheric pressure (760 mmHg at sea level) is now higher than intrapulmonary pressure, air flows into the lungs until pressures equalize.

Expiration (Exhalation)

Quiet expiration is a passive process. It requires no muscle contraction:

Step 1: Muscles relax. The diaphragm relaxes and domes upward. The external intercostal muscles relax, and the ribs move down and inward due to gravity and elastic recoil of the chest wall.

Step 2: Volume decreases. The thoracic cavity shrinks.

Step 3: Pressure rises. Per Boyle’s Law, decreased volume means increased intrapulmonary pressure, which now exceeds atmospheric pressure.

Step 4: Air is pushed out. Air flows from the higher-pressure lungs to the lower-pressure atmosphere.

The key insight: quiet expiration is driven entirely by elastic recoil of the lungs and chest wall. The lungs are stretched during inspiration like a rubber band, and they snap back passively. No energy required.

Forced Expiration

During exercise, coughing, or any situation requiring rapid, forceful exhalation, forced expiration becomes an active process:

• Internal intercostal muscles contract, pulling the ribs downward and inward
• Abdominal muscles (rectus abdominis, obliques) contract, pushing the abdominal organs upward against the diaphragm

These muscles actively compress the thoracic cavity, rapidly decreasing volume and increasing pressure far above atmospheric pressure, forcing air out quickly.

Pressure Changes During Breathing

Understanding the three pressures involved in breathing is essential:

The critical relationship: intrapleural pressure is always more negative than intrapulmonary pressure during normal breathing. This keeps the lungs inflated. If intrapleural pressure ever equals atmospheric pressure (as in a pneumothorax), the lung collapses.

The Role of the Diaphragm

The diaphragm is the primary muscle of respiration. It is innervated by the phrenic nerve, which arises from cervical spinal cord levels C3, C4, and C5.

Compliance and Elastance

Two opposing properties determine how easily the lungs move:

• Compliance = how easily the lungs stretch. High compliance = inflate easily. Emphysema destroys alveolar walls and elastic tissue, so compliance goes up.
• Elastance = how readily the lungs snap back. High elastance = strong recoil. Pulmonary fibrosis deposits stiff scar tissue, so elastance goes up.

The two trade off: emphysema is easy to inflate but hard to deflate (air trapping). Fibrosis is hard to inflate but easy to deflate (restrictive pattern). Surfactant raises compliance by lowering surface tension, so its absence (preterm RDS) makes the alveoli hard to inflate.

During heavy exercise or respiratory distress, accessory muscles (neck muscles for inspiration, abdominals for forced expiration) join in to help the primary respiratory muscles.

Imagine your lungs as a water bottle. During quiet breathing, you only sip from the top (tidal volume). But you could chug much more if you tried (inspiratory reserve). After a normal sip, you could force out more water by squeezing (expiratory reserve). And no matter how hard you squeeze, some water always stays at the bottom, trapped in the crevices (residual volume). Understanding these volumes - and how they combine into capacities - is essential for MCAT questions about pulmonary function.

The Four Lung Volumes

There are four non-overlapping lung volumes that cannot be subdivided further:

The residual volume exists because the airways and alveoli do not completely collapse during exhalation. RV prevents alveolar collapse and maintains gas exchange even between breaths.

Lung Capacities

Lung capacities are combinations of two or more volumes. There are four:

Spirometry

Spirometry is the clinical test used to measure lung volumes and capacities. The patient breathes into a device that records volume changes over time, producing a spirogram.

Important limitation: spirometry cannot measure residual volume directly. Since RV is the air you cannot blow out, it stays in the lungs during the test. This means spirometry also cannot directly measure FRC or TLC (both include RV).

To measure RV, clinicians use indirect methods such as gas dilution techniques. The key point for the MCAT: spirometry alone cannot give you RV.

Minute Ventilation and Alveolar Ventilation

Minute ventilation is the total volume of air moved per minute:

But minute ventilation overestimates how much air is actually useful, because it includes dead space air. Alveolar ventilation corrects for this:

Why Breathing Pattern Matters

Consider two patients who both have a minute ventilation of 6 L/min:

Patient B has the same minute ventilation but far less alveolar ventilation. Shallow, rapid breathing is inefficient because a larger proportion of each breath is wasted filling dead space. This is why deep, slow breaths are more effective than shallow, fast ones.

Obstructive vs. Restrictive Lung Disease

Pulmonary function tests are used to distinguish two broad categories of lung disease:

Gas exchange is the entire reason the respiratory system exists. Every tube, every muscle, every membrane in the previous sections is designed to get oxygen from the atmosphere into your blood and carbon dioxide from your blood into the atmosphere. The mechanism is simple: diffusion down partial pressure gradients. No pumps, no active transport, no ATP. Just molecules moving from where there are more of them to where there are fewer.

Dalton’s Law of Partial Pressures

The total pressure of a gas mixture equals the sum of the individual partial pressures of each gas. This is the same Dalton’s law from general chemistry - here we apply it to respiration.

The composition of dry atmospheric air:

Alveolar Gas Composition

The air inside alveoli is not the same as atmospheric air. It differs because:

1. Water vapor is added (airways humidify incoming air to 100% humidity), which dilutes all other gas partial pressures
2. Oxygen is continuously being absorbed into the blood
3. Carbon dioxide is continuously being added from the blood

The water vapor pressure at body temperature (37°C) is always 47 mmHg. This must be subtracted when calculating alveolar gas pressures.

Henry’s Law

Henry’s Law governs how much gas dissolves in a liquid (like blood):

Fick’s Law of Diffusion

Fick’s Law describes the rate at which a gas diffuses across a membrane like the respiratory membrane:

How Fick’s Law Applies to Disease

Every factor in Fick’s Law can be disrupted by disease:

The Partial Pressure Gradients Driving Gas Exchange

Gas exchange happens at two locations: the lungs and the tissues.

At the lungs (external respiration):

Oxygen diffuses from the alveolus ($P_{\text{O}_{2}}$ = 104) into the blood ($P_{\text{O}_{2}}$ = 40) because of the 64 mmHg gradient. CO2 diffuses from the blood ($P_{\text{CO}_{2}}$ = 46) into the alveolus ($P_{\text{CO}_{2}}$ = 40) because of the 6 mmHg gradient. Blood leaving the lungs has $P_{\text{O}_{2}}$ of ~100 mmHg and $P_{\text{CO}_{2}}$ of ~40 mmHg.

At the tissues (internal respiration):

The process reverses: oxygen diffuses from blood into tissues, and CO2 diffuses from tissues into blood.

Normal vs. Impaired Gas Exchange

Under normal conditions, blood flowing through the pulmonary capillary has enough time to fully equilibrate with alveolar air - oxygen transfer is very efficient. In diseases that thicken the membrane (fibrosis, edema) or reduce the surface area (emphysema), diffusion slows and blood may not fully equilibrate before leaving the capillary, resulting in hypoxemia.

Oxygen is not very soluble in blood. If you relied on dissolved oxygen alone, your blood could carry only about 3 mL of O2 per liter - nowhere near enough to meet your body’s demand of roughly 250 mL of O2 per minute. The solution? A molecular shuttle bus called hemoglobin, which increases oxygen-carrying capacity by nearly 70-fold.

Hemoglobin Structure

Hemoglobin is a quaternary protein consisting of 4 polypeptide subunits:

• Adult hemoglobin (HbA): 2 alpha chains + 2 beta chains (α2β2)
• Fetal hemoglobin (HbF): 2 alpha chains + 2 gamma chains (α2γ2)

Each subunit contains a heme group - a porphyrin ring with a central iron atom (Fe2+) that can bind one O2 molecule.

Cooperative Binding and the T/R State Model

Hemoglobin exists in two conformational states:

When the first O2 molecule binds to a heme group, it triggers a conformational change that shifts the entire molecule from T-state to R-state, making it easier for the next O2 molecules to bind. This is positive cooperativity - each O2 binding event facilitates the next.

The reverse is also true: when the first O2 is released in the tissues, the remaining O2 molecules are released more easily. This creates a very efficient loading/unloading system.

The Oxygen-Hemoglobin Dissociation Curve

The O2-Hb dissociation curve plots hemoglobin saturation (%) against partial pressure of oxygen ($P_{\text{O}_{2}}$). Because of cooperative binding, the curve is sigmoidal (S-shaped), not linear.

Key points on the curve:

The steep middle portion of the curve ($P_{\text{O}_{2}}$ ~20-60 mmHg) is where small changes in $P_{\text{O}_{2}}$ cause large changes in saturation. This is the tissue range, where hemoglobin efficiently unloads oxygen in response to small drops in $P_{\text{O}_{2}}$.

The flat upper portion ($P_{\text{O}_{2}}$ > 70 mmHg) means that hemoglobin stays nearly saturated even if $P_{\text{O}_{2}}$ drops somewhat. This is a safety buffer - even at altitude, saturation remains high until $P_{\text{O}_{2}}$ drops significantly.

Right Shift - Decreased Affinity (Releases O2 More Easily)

A right shift means hemoglobin releases oxygen more readily at any given $P_{\text{O}_{2}}$. This is beneficial in the tissues where O2 is needed.

Factors causing a right shift:

• Increased CO2 (hypercapnia)
• Decreased pH / increased H+ (acidosis)
• Increased temperature
• Increased 2,3-BPG (2,3-bisphosphoglycerate)

All of these conditions are found in actively metabolizing tissues - muscles during exercise are hot, acidic, and producing CO2. The right shift ensures that hemoglobin dumps oxygen exactly where it is needed most.

Left Shift - Increased Affinity (Holds O2 Tighter)

A left shift means hemoglobin binds oxygen more tightly and is less willing to release it. This is beneficial in the lungs where O2 is being picked up.

Factors causing a left shift:

• Decreased CO2
• Increased pH (alkalosis)
• Decreased temperature
• Decreased 2,3-BPG
• Fetal hemoglobin (HbF)
• Carbon monoxide (CO) binding

The Bohr Effect

The Bohr effect specifically describes how CO2 and H+ concentration affect hemoglobin’s oxygen affinity:

• In the tissues: high CO2 and low pH cause a right shift, promoting O2 release
• In the lungs: low CO2 and high pH cause a left shift, promoting O2 binding

This creates an elegant delivery system: hemoglobin automatically releases more oxygen to tissues that are metabolically active (producing CO2 and acid) and picks up more oxygen in the lungs (where CO2 is being exhaled).

The Haldane Effect

The Haldane effect is the mirror image of the Bohr effect: it describes how oxygenation of hemoglobin affects its ability to carry CO2.

• In the tissues: deoxygenated hemoglobin binds CO2 more readily (forming carbaminohemoglobin)
• In the lungs: oxygenated hemoglobin releases CO2 more readily

The Bohr and Haldane effects work together: the Bohr effect promotes O2 delivery to tissues, and the Haldane effect promotes CO2 pickup from tissues and CO2 release in the lungs.

2,3-BPG (2,3-Bisphosphoglycerate)

2,3-BPG is a molecule produced by red blood cells during glycolysis. It binds to the central cavity of the deoxyhemoglobin tetramer, stabilizing the T-state and reducing oxygen affinity (right shift).

2,3-BPG levels increase in response to chronic hypoxia - for example, at high altitude or in anemia. This is an adaptive response that helps deliver more oxygen to tissues when overall oxygen availability is reduced.

Fetal Hemoglobin (HbF)

Fetal hemoglobin has gamma chains instead of beta chains. The gamma chains do not bind 2,3-BPG as well, so HbF has a higher oxygen affinity than adult HbA (left-shifted curve).

This is essential for fetal survival: at the placenta, fetal blood must “steal” oxygen from maternal hemoglobin. HbF’s higher affinity allows it to grab O2 even at the relatively low $P_{\text{O}_{2}}$ of the placenta.

Myoglobin

Myoglobin is a single-subunit oxygen-binding protein found in muscle tissue. Unlike hemoglobin’s 4 subunits, myoglobin has only one heme group and therefore shows no cooperativity.

Its dissociation curve is hyperbolic (not sigmoidal), and it has a much higher affinity for oxygen than hemoglobin. Myoglobin does not release oxygen until $P_{\text{O}_{2}}$ drops very low.

Function: myoglobin acts as an oxygen reservoir in muscle cells. During intense exercise, when capillary $P_{\text{O}_{2}}$ drops dramatically, myoglobin releases its stored O2 to sustain aerobic metabolism.

Carbon Monoxide Poisoning

Carbon monoxide (CO) binds hemoglobin with approximately 200-250 times greater affinity than oxygen. Even small amounts of CO in inhaled air can occupy a large fraction of heme binding sites, forming carboxyhemoglobin (COHb).

CO poisoning is devastating for two reasons:

1. Reduced carrying capacity - CO occupies heme sites that would otherwise carry O2
2. Left shift - CO binding causes the remaining heme groups to hold onto O2 more tightly (increased affinity), so even the O2 that is loaded cannot be delivered to tissues

If hemoglobin is the bus that carries oxygen, what about the return trip? Carbon dioxide - the waste product of aerobic metabolism - needs to get from the tissues back to the lungs for exhalation. But CO2 does not just hitch a ride on hemoglobin the way oxygen does. Instead, CO2 travels by three different routes, and the dominant one involves a clever chemical conversion that also happens to be your blood’s primary pH buffering system.

The Three Mechanisms of CO2 Transport

The Bicarbonate Buffer System

The bicarbonate pathway is the most important CO2 transport mechanism and the body’s primary blood pH buffer. Here is the complete reaction:

The Process in the Tissues

1. CO2 diffuses from metabolizing tissue cells into the blood and enters red blood cells
2. Carbonic anhydrase (inside RBCs) catalyzes: CO2 + H2O → H2CO3
3. H2CO3 spontaneously dissociates: H2CO3 → H+ + HCO3-
4. H+ binds to hemoglobin (buffered - this is the Bohr effect mechanism)
5. HCO3- is transported out of the RBC into the plasma

The Chloride Shift

When HCO3- exits the RBC into the plasma, it would create a charge imbalance (too much negative charge leaving). To maintain electrical neutrality, chloride ions (Cl-) move into the RBC from the plasma via an antiport protein. This 1:1 exchange - one HCO3- out, one Cl- in - is called the chloride shift.

The Process in the Lungs

Everything reverses:

1. In the pulmonary capillaries, the high $P_{\text{O}_{2}}$ environment promotes oxygen binding to hemoglobin
2. As hemoglobin binds O2 (Haldane effect), it releases H+ and CO2
3. Cl- exits the RBC, HCO3- re-enters (reverse chloride shift)
4. Inside the RBC: H+ + HCO3- → H2CO3 → CO2 + H2O (carbonic anhydrase runs in reverse)
5. CO2 diffuses into the alveolus and is exhaled

Blood pH and the Bicarbonate Buffer

Normal arterial blood pH is 7.35-7.45. The bicarbonate buffer system maintains this narrow range because the two sides of the equilibrium can be independently regulated:

• The lungs control CO2 levels (respiratory component)
• The kidneys control HCO3- levels (metabolic component)

Acid-Base Disturbances

There are four primary acid-base disturbances. Each alters the 20:1 ratio differently:

The body always compensates by adjusting the opposite system: respiratory problems get renal compensation, and metabolic problems get respiratory compensation. Compensation returns the ratio toward 20:1 but rarely fully normalizes pH.

You breathe about 20,000 times a day without thinking about it. You can also hold your breath voluntarily - but only for so long before an overwhelming urge forces you to gasp. And during exercise, your breathing rate and depth increase automatically to match your metabolic demand. All of this happens through a sophisticated control system involving brainstem respiratory centers, chemical sensors in your blood vessels, and feedback loops that adjust ventilation breath by breath.

The Brainstem Respiratory Centers

Breathing rhythm is generated by neurons in the medulla oblongata and modulated by the pons. There are four key centers:

The Normal Breathing Cycle

During quiet breathing:

1. The DRG fires rhythmic signals via the phrenic nerve (to the diaphragm) and intercostal nerves (to the external intercostal muscles)
2. These signals last about 2 seconds, causing inspiration
3. The DRG then stops firing for about 3 seconds, allowing passive expiration through elastic recoil
4. The pneumotaxic center modulates this cycle by controlling when the DRG shuts off

During exercise or forced breathing, the VRG activates and recruits accessory muscles for both active inspiration and active expiration.

Chemical Control of Breathing

The most important regulators of breathing are chemical sensors that detect changes in blood gas levels and pH. There are two types:

Central Chemoreceptors

Located on the ventral surface of the medulla, central chemoreceptors are the primary drive to breathe. They detect changes in H+ concentration in the cerebrospinal fluid (CSF).

Here is the key mechanism: CO2 (but not H+ or HCO3-) can freely cross the blood-brain barrier. Once in the CSF, CO2 combines with water (via carbonic anhydrase) to form H2CO3, which dissociates into H+ and HCO3-. The central chemoreceptors detect this H+ increase and stimulate the respiratory centers to increase ventilation.

So while the central chemoreceptors technically sense H+, they are effectively monitoring blood CO2 levels because CO2 is the source of the H+.

Peripheral Chemoreceptors

Located in the carotid bodies (at the bifurcation of the common carotid arteries) and the aortic bodies (in the aortic arch), peripheral chemoreceptors detect:

1. $P_{\text{O}_{2}}$ - the primary O2 sensor; responds to critically low oxygen ($P_{\text{O}_{2}}$ < 60 mmHg)
2. $P_{\text{CO}_{2}}$ - responds faster than central chemoreceptors but plays a secondary role
3. pH - detects metabolic acidosis directly (since H+ cannot cross the BBB)

The carotid bodies send signals via the glossopharyngeal nerve (CN IX).
The aortic bodies send signals via the vagus nerve (CN X).

CO2 is the Primary Drive to Breathe

This is one of the most important concepts in respiratory physiology: under normal conditions, CO2 (not O2) is the primary stimulus for breathing.

Even small increases in $P_{\text{CO}_{2}}$ (from 40 to 44 mmHg) cause large increases in ventilation. In contrast, $P_{\text{O}_{2}}$ must drop dramatically (below 60 mmHg) before it significantly stimulates breathing. This makes sense evolutionarily - CO2 is constantly produced by metabolism and needs to be continuously eliminated. Oxygen levels in the atmosphere are usually adequate, so fine-tuning breathing based on CO2 is more useful.

Why Hyperventilation is Dangerous

Hyperventilation blows off CO2, reducing $P_{\text{CO}_{2}}$ below normal. This removes the primary drive to breathe. The key concept: without CO2 buildup to trigger breathing, a person can lose consciousness from hypoxia before feeling any urge to breathe.

Oxygen as a Backup Drive: The Hypoxic Drive

If central chemoreceptors become desensitized to chronically elevated CO2, a person may switch to using low O2 as their primary breathing stimulus - this is the hypoxic drive.

Other Inputs to Breathing

Beyond chemical sensors, several other factors influence breathing:

• Hering-Breuer reflex: stretch receptors in the lungs detect overinflation and send signals via the vagus nerve to inhibit further inspiration (prevents over-inflation)
• Irritant receptors: detect smoke, dust, or chemical irritants in the airways, triggering coughing or bronchoconstriction
• Cortical input: you can voluntarily override automatic breathing (holding breath, singing, speaking) - but CO2 buildup eventually overrides voluntary control
• Limbic system: emotions (fear, excitement) can alter breathing patterns
• Temperature: fever increases respiratory rate; hypothermia decreases it

Imagine a factory with workers and raw materials. For maximum efficiency, you need the right number of workers at each station AND the right amount of raw materials delivered to them. Too many workers with no materials? Wasted labor. Materials pouring in but no workers? Wasted resources. In the lungs, ventilation is the “materials delivery” (air) and perfusion is the “workers” (blood flow). The ratio between them - the V/Q ratio - determines how efficiently each region of the lung exchanges gas.

The V/Q Ratio

The ventilation-perfusion ratio (V/Q) compares the amount of air reaching the alveoli (ventilation, V) to the amount of blood flow past those alveoli (perfusion, Q).

The overall V/Q ratio for the entire lung is approximately 0.8 (alveolar ventilation ~4 L/min, cardiac output ~5 L/min).

Dead Space vs. Shunt

Dead space (high V/Q): alveoli are ventilated but not perfused. Air reaches the alveoli, but there is no blood flow to pick up the oxygen. The air is “wasted.” This happens when blood flow is blocked - for example, a pulmonary embolism blocks perfusion to a region while ventilation continues.

There are two types of dead space:

• Anatomical dead space: the conducting airways (~150 mL) - these never participate in gas exchange
• Alveolar dead space: ventilated alveoli with no blood flow
• Physiological dead space = anatomical + alveolar dead space (total wasted ventilation)

Shunt (low V/Q): alveoli are perfused but not ventilated. Blood flows past alveoli that have no fresh air in them, so the blood passes through without picking up oxygen. This results in deoxygenated blood mixing with oxygenated blood. Examples include airway obstruction (mucus plug, tumor), atelectasis (collapsed alveolus), and pneumonia (alveolus filled with fluid).

Gravity and the V/Q Ratio

In an upright person, gravity creates a gradient in both ventilation and perfusion from the apex (top) to the base (bottom) of the lung:

Both ventilation and perfusion are greater at the base due to gravity, but perfusion increases more steeply than ventilation as you move from apex to base. This means:

• The apex is relatively over-ventilated compared to its blood flow (higher V/Q - closer to dead space)
• The base is relatively over-perfused compared to its ventilation (lower V/Q - closer to shunt)

Hypoxic Pulmonary Vasoconstriction

The lungs have a unique response to low oxygen that is the opposite of what systemic blood vessels do:

• Systemic blood vessels: low O2 causes vasodilation (to bring more blood to hypoxic tissue)
• Pulmonary blood vessels: low O2 causes vasoconstriction (to divert blood away from poorly ventilated regions)

This response is called hypoxic pulmonary vasoconstriction (HPV). It is a brilliant matching mechanism: if an alveolus is not receiving enough air (low O2 in that region), the pulmonary arterioles serving that alveolus constrict, redirecting blood to better-ventilated regions. This optimizes V/Q matching.

V/Q Mismatch in Disease

Any condition that disrupts the match between airflow and blood flow impairs gas exchange and leads to hypoxemia.

Everything you have learned about respiratory physiology assumes you are near sea level, breathing normal atmospheric air at 760 mmHg. But what happens when those conditions change? At high altitude, atmospheric pressure drops and oxygen becomes scarce. Underwater, pressure increases and gases dissolve into your tissues in dangerous quantities. Both environments push the respiratory system to its limits and reveal the elegance - and vulnerabilities - of human physiology.

High Altitude Physiology

At high altitude, atmospheric pressure decreases. Since the fraction of oxygen in air remains 21%, the partial pressure of oxygen ($P_{\text{O}_{2}}$) decreases proportionally.

Acute Responses to High Altitude

When you first arrive at high altitude, your body responds immediately:

1. Hyperventilation - peripheral chemoreceptors detect low $P_{\text{O}_{2}}$ and stimulate increased ventilation. This is the most important acute response.
2. Increased heart rate - sympathetic activation increases cardiac output to deliver more blood per minute.
3. Hypocapnia - hyperventilation blows off CO2, causing respiratory alkalosis (pH rises).

The respiratory alkalosis from hyperventilation is actually a problem: the elevated pH shifts the O2-Hb curve to the LEFT, making hemoglobin hold onto oxygen more tightly. This partially counteracts the benefit of hyperventilation.

Acclimatization (Chronic Responses)

Over days to weeks at altitude, the body acclimatizes through several mechanisms:

Renal compensation (days): The kidneys excrete excess HCO3- to compensate for the respiratory alkalosis, bringing pH back toward normal. This allows the O2-Hb curve to shift back toward the right.

Increased 2,3-BPG (hours to days): Red blood cells increase production of 2,3-BPG, which binds to hemoglobin and shifts the curve to the RIGHT. This facilitates oxygen delivery to tissues despite the lower arterial $P_{\text{O}_{2}}$.

Increased EPO and red blood cell production (days to weeks): The kidneys detect hypoxia and release erythropoietin (EPO), which stimulates the bone marrow to produce more red blood cells (polycythemia). More RBCs means more hemoglobin and greater total oxygen-carrying capacity.

Increased capillary density (weeks to months): Tissues develop more capillaries (angiogenesis) to improve oxygen extraction.

Increased mitochondrial density: Muscle cells increase their mitochondrial content to more efficiently utilize available oxygen.

Acute Mountain Sickness (AMS)

Rapid ascent to altitudes above 2,500 m without acclimatization can cause acute mountain sickness, characterized by headache, nausea, fatigue, and dizziness.

Diving Physiology

Underwater, the opposite problem occurs: pressure increases. For every 10 meters (33 feet) of depth, pressure increases by 1 atmosphere (760 mmHg).

According to Henry’s Law (C = k x $P_{\text{gas}}$), the amount of gas dissolved in a liquid increases proportionally with the partial pressure of that gas. At increased depth, more nitrogen and oxygen dissolve in blood and tissues.

Nitrogen Narcosis

At great depths, the high partial pressure of nitrogen causes nitrogen narcosis - impaired judgment and disorientation similar to alcohol intoxication. The effect reverses upon ascent.

Decompression Sickness (The Bends)

If a diver ascends too quickly, the dissolved nitrogen in their tissues comes out of solution as gas bubbles (like opening a carbonated soda - rapidly reducing pressure causes dissolved gas to form bubbles). These nitrogen bubbles can lodge in joints, blood vessels, and tissues, causing:

• Joint and muscle pain (the most common symptom - hence “the bends”)
• Skin rash
• Neurological symptoms (paralysis, confusion)
• Pulmonary embolism (if bubbles reach the lungs)

Prevention: ascend slowly, allowing nitrogen to gradually diffuse out of tissues and be exhaled. The concept to understand is Henry’s Law in reverse - reducing pressure decreases solubility.

Oxygen Toxicity

While O2 is essential, too much is toxic. At very high partial pressures, excess oxygen generates reactive oxygen species (ROS) that damage cells. This is why oxygen concentration must be carefully controlled in clinical settings.

Summary: Altitude vs. Diving