Unit 2: Physiology of Respiration in Mammals

1. Mechanism of Respiration and Pulmonary Ventilation

Conceptual Overview

Respiration is the metabolic process by which organisms exchange gases between their internal cells and the external environment. In mammals, respiration encompasses three distinct stages: external respiration (pulmonary ventilation), internal respiration (gas exchange at tissues), and cellular respiration.

Pulmonary Ventilation: The mechanical process of moving air into and out of the lungs to maintain appropriate alveolar concentrations of oxygen and carbon dioxide.

Boyle's Law and Pressure Gradients

Pulmonary ventilation operates strictly on the principles of physics described by Boyle's Law, which states that at a constant temperature, the pressure of a given mass of gas is inversely proportional to its volume.

P = k / V (or P1 * V1 = P2 * V2)

Air always flows from an area of higher pressure to an area of lower pressure. The mammalian lung creates alternating intra-pulmonary pressure gradients relative to atmospheric pressure (760 mmHg at sea level).

Mechanism of Inspiration (Inhalation)

1. Muscle Contraction: The diaphragm contracts and flattens downward. Simultaneously, the external intercostal muscles contract, pulling the ribs upward and outward.
2. Volume Expansion: Contraction increases the thoracic cavity volume in both the antero-posterior and dorso-ventral axes.
3. Pressure Drop: As thoracic volume increases, intra-pleural pressure becomes more negative (-6 mmHg relative to atmospheric) and intra-pulmonary pressure drops to approximately -1 mmHg relative to atmosphere (759 mmHg).
4. Airflow: Atmospheric air flows down the pressure gradient through the respiratory tract into the alveoli until pressures equalize.

Mechanism of Expiration (Exhalation)

1. Muscle Relaxation: Quiet expiration is a passive process. The diaphragm relaxes and arches upward; external intercostal muscles relax, allowing the rib cage to fall downward and inward due to gravity and elastic recoil.
2. Volume Reduction: Thoracic cavity volume decreases back to its resting state.
3. Pressure Rise: Intra-pulmonary pressure rises above atmospheric pressure to approximately +1 mmHg (761 mmHg).
4. Airflow: Air is forced out of the lungs into the environment.

Forced Expiration: An active process requiring internal intercostal muscles and abdominal wall muscles to actively depress the ribs and compress abdominal organs upward against the diaphragm.

Comparison: Inspiration vs. Expiration

2. Respiratory Volumes and Capacities

Respiratory Volumes

Lungs contain specific volumes of air during various phases of breathing. These are measured using a instrument called a spirometer.

• Tidal Volume (TV): The volume of air inspired or expired during a normal, quiet breath. Standard human value is approximately 500 mL.
• Inspiratory Reserve Volume (IRV): The additional volume of air that can be forcibly inspired after a normal tidal inspiration. Standard value is approximately 2500 to 3000 mL.
• Expiratory Reserve Volume (ERV): The extra volume of air that can be forcibly expired after a normal tidal expiration. Standard value is approximately 1000 to 1100 mL.
• Residual Volume (RV): The volume of air remaining in the lungs even after a maximum forceful expiration. Lungs can never be completely emptied. Standard value is approximately 1100 to 1200 mL.

Respiratory Capacities

Pulmonary capacities are combinations of two or more respiratory volumes.

• Inspiratory Capacity (IC): The total volume of air a person can inspire after a normal expiration.

IC = TV + IRV

• Functional Residual Capacity (FRC): The volume of air remaining in the lungs after a normal tidal expiration. FRC acts as a buffer against large fluctuations in blood gas levels.

FRC = ERV + RV

• Vital Capacity (VC): The maximum volume of air a person can expire after a maximum forced inspiration. It measures the total dynamic range of the lung.

VC = TV + IRV + ERV

• Total Lung Capacity (TLC): The total volume of air present in the lungs and respiratory passages after a maximum forced inspiration.

TLC = VC + RV = TV + IRV + ERV + RV

Summary Table of Volumes and Capacities

3. Transport of Oxygen and Carbon Dioxide in Blood

Transport of Oxygen

Oxygen is transported in the blood through two distinct modes:

1. In Dissolved State: Approximately 3% of oxygen is dissolved directly in blood plasma due to low O2 solubility in aqueous solution.
2. Bound to Hemoglobin (Oxyhemoglobin): Approximately 97% of oxygen is carried in combination with hemoglobin inside Red Blood Cells (RBCs).

Hb + 4 O2 <=> Hb(O2)4 (Oxyhemoglobin)

Oxygen binding is cooperative: the binding of the first oxygen molecule increases the affinity of the remaining iron sites for oxygen.

Transport of Carbon Dioxide

Carbon dioxide is produced by tissues and transported back to the lungs through three primary mechanisms:

1. In Dissolved State: About 7% of CO2 is carried dissolved in plasma.
2. As Carbaminohemoglobin: About 23% combines directly with the amino groups of globin proteins in hemoglobin.

Hb-NH2 + CO2 <=> Hb-NHCOOH (Carbaminohemoglobin)

1. As Bicarbonate Ions (HCO3-): About 70% is converted into bicarbonate ions inside RBCs and transported in the plasma.

Step-by-Step Bicarbonate Formation and Chloride Shift

1. Hydration of CO2: CO2 diffuses into RBCs where it reacts with water to form carbonic acid (H2CO3). This reaction is catalyzed at high speeds by the enzyme Carbonic Anhydrase.

CO2 + H2O <= Carbonic Anhydrase => H2CO3 <=> H+ + HCO3-

1. Dissociation: Carbonic acid dissociates into hydrogen ions (H+) and bicarbonate ions (HCO3-).
2. Chloride Shift (Hamburger Phenomenon): As HCO3- accumulates inside RBCs, it diffuses out into plasma along a concentration gradient. To maintain electrical neutrality across the RBC membrane, chloride ions (Cl-) diffuse from the plasma into the RBC.
3. Reverse Action at Lungs: In pulmonary capillaries, the entire process reverses: Cl- moves out of RBCs, HCO3- moves in, forms H2CO3, which breaks down into CO2 and H2O. CO2 then diffuses into the alveoli to be exhaled.

4. Respiratory Pigments and Dissociation Curves

Respiratory Pigments

Respiratory pigments are conjugated proteins containing metal ions that increase the oxygen-carrying capacity of respiratory fluids.

• Hemoglobin (Hb): Found in mammalian erythrocytes. It is a tetrameric protein consisting of 4 globin chains (2 alpha and 2 beta) each attached to a heme group containing an iron ion in the ferrous state (Fe2+). Each molecule of hemoglobin can reversibly bind up to 4 molecules of O2.
• Myoglobin (Mb): Monomeric respiratory pigment present in muscle tissue with a single heme group. It has a much higher oxygen affinity than hemoglobin and stores oxygen for muscle activity.

Oxygen-Hemoglobin Dissociation Curve

The relationship between the partial pressure of oxygen (pO2) and the percentage saturation of hemoglobin with oxygen is represented by a graphic plot called the Oxygen-Hemoglobin Dissociation Curve, which exhibits a characteristic Sigmoid (S-shaped) curve.

This sigmoid shape arises due to cooperative binding: binding of one O2 molecule increases the affinity for subsequent molecules.

P50 Value: The partial pressure of oxygen at which hemoglobin is 50% saturated. Normal P50 for human adult hemoglobin is approximately 26.8 mmHg. An increase in P50 indicates decreased affinity, whereas a lower P50 indicates higher affinity.

Factors Influencing the Dissociation Curve

The dissociation curve can shift right or left depending on physiological conditions:

Right Shift (Decreased Affinity / Increased O2 Unloading)

A right shift means hemoglobin releases oxygen more readily to tissues. It is caused by:

• Increased pCO2: Known as the Bohr Effect. High pCO2 enhances O2 dissociation at tissue level.
• Decreased pH (Increased H+ concentration): Acidity weakens Hb-O2 binding.
• Increased Temperature: Metabolic heat promotes O2 release.
• Increased 2,3-BPG (2,3-Bisphosphoglycerate): Produced during glycolysis in RBCs; stabilizes the deoxygenated state of Hb.

Left Shift (Increased Affinity / Increased O2 Loading)

A left shift means hemoglobin holds onto oxygen more tightly. It is caused by:

• Decreased pCO2
• Increased pH (Alkalosis)
• Decreased Temperature
• Decreased 2,3-BPG
• Presence of Fetal Hemoglobin (HbF has higher affinity than adult HbA)

5. Carbon Monoxide Poisoning

Mechanism

Carbon Monoxide (CO) is a toxic, colorless, odorless gas. Poisoning occurs because hemoglobin has an affinity for carbon monoxide that is approximately 200 to 250 times greater than its affinity for oxygen.

Hb + CO --> HbCO (Carboxyhemoglobin)

Pathophysiological Effects

1. Competitive Inhibition: CO binds strongly to iron in heme, blocking oxygen from binding and forming stable carboxyhemoglobin (HbCO).
2. Allosteric Effect (Left Shift): Binding of CO to even one site increases the affinity of the remaining sites for oxygen, preventing oxygen from releasing into peripheral tissues.
3. Tissue Hypoxia: Tissues suffer severe oxygen starvation despite high blood arterial pO2.

Symptoms and Clinical Significance

• Early symptoms: Headache, dizziness, nausea, confusion, and weakness.
• Severe poisoning: Loss of consciousness, seizures, respiratory failure, cherry-red skin coloration, and death.
• Treatment: Administration of 100% pure oxygen or hyperbaric oxygen therapy to competitively force CO off hemoglobin molecules.

6. Control of Respiration

Respiration is involuntarily regulated to match body metabolic needs through neural and chemical feedback loops.

Neural Control of Respiration

Respiratory centers located in the brainstem (medulla oblongata and pons) generate and regulate the rhythm of breathing.

Medullary Respiratory Centers

• Dorsal Respiratory Group (DRG): Located in the dorsal region of the medulla. It controls quiet, normal inspiration by sending rhythmic signals via the phrenic and intercostal nerves to the diaphragm and external intercostals.
• Ventral Respiratory Group (VRG): Located ventrally in the medulla. Contains both inspiratory and expiratory neurons. Inactive during quiet breathing; activated during forced breathing to excite internal intercostal and abdominal muscles.

Pontine Respiratory Centers

• Pneumotaxic Center: Located in the upper pons (nucleus parabrachialis). Transmits inhibitory impulses to the inspiratory center, limiting the duration of inspiration and controlling respiratory rate.
• Apneustic Center: Located in the lower pons. Sends excitatory signals to the inspiratory center, promoting prolonged deep inspirations. It is overridden by the pneumotaxic center under normal conditions.

Chemical Control of Respiration

Chemoreceptors detect changes in pCO2, pH, and pO2 in blood and body fluids.

1. Central Chemoreceptors

• Located on the ventral surface of the medulla oblongata.
• Highly sensitive to changes in H+ concentration and pCO2 in the cerebrospinal fluid (CSF).
• Note: CO2 easily crosses the blood-brain barrier and forms H+ in CSF. H+ directly stimulates central chemoreceptors, driving hyperventilation to exhale excess CO2.

2. Peripheral Chemoreceptors

• Located in the Carotid Bodies (via Glossopharyngeal nerve IX) and Aortic Bodies (via Vagus nerve X).
• Sensitive primarily to arterial pO2 drops (only when pO2 falls below critical levels, ~60 mmHg), as well as arterial H+ and pCO2 increases.

7. Effect of High Altitude and Deep Sea Diving on Respiration

Effects of High Altitude on Respiration

At high altitudes, atmospheric pressure decreases significantly, leading to a proportional drop in partial pressure of oxygen (pO2), resulting in Hypoxia (low oxygen supply to tissues).

Acute Effects (Mountain Sickness)

Rapid ascent causes Acute Mountain Sickness (AMS) characterized by nausea, dizziness, fatigue, dyspnea, and headache. Severe cases lead to High Altitude Pulmonary Edema (HAPE) or High Altitude Cerebral Edema (HACE).

Physiological Acclimatization

Given time, the body adapts through several physiological mechanisms:

1. Hyperventilation: Decreased arterial pO2 triggers peripheral chemoreceptors to increase breathing rate, improving lung oxygenation.
2. Erythropoietin Release: Kidneys detect hypoxia and release the hormone erythropoietin (EPO), stimulating bone marrow to produce more red blood cells (Polycythemia), raising hemoglobin concentration.
3. Increased 2,3-BPG: RBCs produce higher concentrations of 2,3-BPG, shifting the oxygen dissociation curve to the right to facilitate oxygen unloading into hypoxic tissues.
4. Vascular Changes: Increased systemic capillarization and cardiac output.

Effects of Deep Sea Diving on Respiration

During deep-sea diving, ambient water pressure increases by 1 atmosphere (760 mmHg) for every 10 meters (33 feet) of depth. Divers breathe compressed air at equal pressure to prevent lung collapse, exposing lungs to elevated partial pressures of gases.

1. Nitrogen Narcosis ("Rapture of the Deep")

• At high pressures (depths exceeding 30-40 meters), high partial pressure of nitrogen causes nitrogen to dissolve into lipid-rich neuronal membranes.
• Produces an intoxicating/anesthetic effect similar to alcohol, impairing judgment, motor function, and consciousness.

2. Decompression Sickness ("The Bends")

• When a diver stays at high pressure, large amounts of nitrogen dissolve in body tissues and blood.
• If ascent is too rapid, ambient pressure drops suddenly. Nitrogen comes out of solution and forms gas bubbles in blood vessels and tissues.
• Symptoms: Severe joint pain ("the bends"), paralysis, sensory loss, pulmonary embolism ("chokes"), and potential death.
• Prevention/Treatment: Gradual, staged decompression during ascent or treatment in a hyperbaric oxygen chamber.

3. Oxygen Toxicity

• Breathing high pO2 at depth generates high concentrations of reactive oxygen species (ROS), causing CNS toxicity, muscle twitching, seizures, and lung damage.