Blood Flow & Metabolism

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

• Analyze the pathophysiology of respiratory disorders that affect pulmonary blood flow and gas exchange, such as pulmonary embolism, pulmonary hypertension, and acute respiratory distress syndrome (ARDS).

• Textbook of Medical Physiology, Guyton and Hall, 12th edition:

  • Chapter 38, Pg 477 - 484 (already in the AIRWAYS AND AIRFLOW SET) 

• Physiology, Costanzo, 6th edition:

  • Chapter 5, Pg 216 - 224

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

I. OVERVIEW: What Determines Pulmonary Blood Flow?

Pulmonary blood flow (Q) depends on:

1. Ventilation (V) — air reaching alveoli

2. Gravity — affects regional perfusion

3. Pulmonary Vascular Resistance (PVR) — resistance of pulmonary vessels

4. Right ventricular output

5. Local alveolar oxygen levels (hypoxic vasoconstriction)

Because the pulmonary circulation is low pressure and highly compliant, small changes in these factors greatly alter perfusion.

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

II. EFFECT OF VENTILATION ON BLOOD FLOW

Ventilation regulates blood flow primarily through alveolar oxygen levels.

1. Alveolar Hypoxia → Hypoxic Pulmonary Vasoconstriction

If a region of the lung is poorly ventilated (low PO₂):

↓ PAO₂ → local pulmonary arteriole constriction

This is opposite of systemic circulation, where hypoxia causes dilation.

Physiologic purpose

• Diverts blood AWAY from poorly ventilated alveoli

• Sends blood to better-ventilated areas

• Optimizes V/Q matching

• Pneumonia

• Mucus plugging

• Atelectasis
  Poor ventilation → hypoxic vasoconstriction → ↓ blood flow to that region.

2. Global Hypoxia → Generalized Vasoconstriction

Global Hypoxia occurs in:

• High altitude

• Advanced COPD (due to to emphysema and chronic bronchitis)

In COPD, especially emphysema and chronic bronchitis (airways are fully constricted in chronic bronchitis):

• Many alveoli are destroyed

• Many have mucus plugging

• Many have very low PAO₂

• Hypoxia is diffuse, not isolated

• Neonatal persistent pulmonary hypertension (PPHN)

Result:

• Marked increase in PVR

• Right ventricular strain → co rpulmonale

• cor → Latin “heart”

• pulmonale → Latin “pulmo/pulmonis” = lung

Literal meaning: “Heart condition caused by the lungs”

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

effect of gravity on pulmonary blood flow

III. EFFECT OF GRAVITY ON PULMONARY BLOOD FLOW

Gravity causes a vertical gradient in perfusion.

Apex (top) of lung

• Lowest blood flow AND lowest pressure lowest pressure

• V/Q ratio high (more ventilation than perfusion)

Base (bottom) of lung

• Highest blood flow

• Vessels distend under hydrostatic pressure

• V/Q ratio low (more perfusion than ventilation)

Why this happens

Hydrostatic pressure in pulmonary vessels is lower than systemic, so gravity dramatically affects perfusion

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

what is the PVR at low and high volume

what is the PVR at FRC?

IV. PULMONARY VASCULAR RESISTANCE (PVR)

PVR is the resistance offered by the pulmonary vasculature to blood flow.

PVR is LOW at the Functional Residual Capacity (FRC).

FRC = the volume of air remaining in the lungs after a normal, passive exhalation.

1. Effect of Lung Volume on PVR High Lung Volumes (inspiration)

• Alveoli enlarge → stretch alveolar vessels

• Capillaries are compressed
  → PVR increases

1. Alveoli expand

2. Their walls stretch outward

3. This stretches—and compresses—capillaries embedded in alveolar walls

4. Capillary diameter decreases → capillary resistance ↑

5. Therefore: PVR increases

Low Lung Volumes (forced expiration)

• Extra-alveolar vessels collapse
  → PVR increases

• Elastic recoil decreases

• Radial traction decreases

• Extra-alveolar vessels become floppy

• Their diameter decreases

• PVR increases

Lowest PVR occurs at FRC

(where alveolar and extra-alveolar vessel diameters are both optimal)

3. At FRC (end of normal tidal expiration) (this is an explanation for what happens above)

The FRC is the sweet spot where:

A. Alveolar capillaries are not over-stretched

• Alveoli are moderately inflated

• Capillaries are open but not compressed

• Alveolar vessel resistance is low

B. Extra-alveolar vessels receive enough radial traction

• Lung elastic recoil is present

• Surrounding parenchyma gently pulls vessels open

• Extra-alveolar resistance is also low

C. The two opposing resistances cancel each other out

• Alveolar capillaries: lowest resistance at moderate volume

• Extra-alveolar vessels: lowest resistance at moderate volume

→ Total PVR = minimal at the midpoint between the extremes

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

sympathetic nervous system

SYMPATHETIC NERVOUS SYSTEM → TENDS TO DECREASE PVR

…but with some nuance.

Receptors involved β₂ receptors (dominant)

• Located on pulmonary vascular smooth muscle

• Activated by circulating epinephrine

• Effect: Vasodilation → PVR ↓

epinephrine binds to b2 receptors

α₁ receptors (minor role)

• Located on large pulmonary arteries

• Activated by norepinephrine from sympathetic nerves

• Effect: Vasoconstriction → PVR ↑ (small effect)

norepinephrine binds to a1 receptors to cause vasoconstriction.

Net effect Because the lung vasculature is thin-walled, compliant, and has low resting tone, β₂-mediated dilation dominates (fight or flight means you need more oxygen so vasodilation occurs)

Overall: sympathetic activation tends to ↓ PVR.

When does sympathetic tone really matter?

• Exercise → CO ↑ → recruitment + β₂ dilation → prevents pulmonary hypertension

• Shock → sympathetic drive ↑, but pulmonary vessels are relatively protected

• Asthma medications (β₂ agonists) → small pulmonary vasodilatory effect

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

PARASYMPATHETIC NERVOUS SYSTEM → INCREASES PVR

PARASYMPATHETIC NERVOUS SYSTEM → INCREASES PVR

Vagus nerve → acetylcholine (ACh)→ M3 receptors → vasoconstriction.

Mechanisms M₃ receptors

• Cause pulmonary vasoconstriction

• Increase intracellular Ca²⁺ in vascular smooth muscle

• Effect: PVR ↑

Secondary effects

• Parasympathetic activation → bronchoconstriction

• Increases airway resistance → hypoventilation of some units

• Regional alveolar hypoxia → hypoxic pulmonary vasoconstriction
  → PVR increases even more (indirect mechanism)

Parasympathetic activation increases PVR.

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

thromboxane A2, Prostacyclin, Leukotrienes

Thromboxane A2 is a powerful local vasoconstrictor of both arterioles and veins.

TXA₂ is made by platelets → designed for hemostasis

Platelets synthesize TXA₂ during vascular injury.
Its biological purpose is to stop bleeding, and the fastest way to do that is:

• constrict the vessel to reduce blood loss

• aggregate platelets to plug the hole

TXA₂ therefore evolved to be a potent constrictor.

If a vessel is cut or injured: you want both arteries and veins squeezed shut.

Prostacyclin (prostaglandin I2), also a product of arachidonic acid metabolism via the cyclooxygenase pathway, is a potent local vasodilator. It is produced by lung endothelial cells.

WHY DOES THE LUNG ENDOTHELIUM PRODUCE PGI₂?

Because prostacyclin is the lung’s “anti-clotting, keep-flowing” molecule.

Pulmonary circulation has special needs:

• extremely low-resistance

• receives the entire cardiac output

• cannot tolerate microthrombi (or the alveoli lose perfusion)

• must prevent platelet aggregation on delicate capillaries

So lung endothelial cells use PGI₂ as a protective mechanism.

Endothelium expresses prostacyclin synthase

Arachidonic acid → COX → PGH₂ → PGI₂
Lung endothelial cells have high PGI₂ synthase → they make PGI₂ constantly.

leukotrienes, another product of arachidonic acid metabolism (via the lipoxygenase pathway), cause airway constriction.

1) Leukotrienes are made by the cells that mediate inflammation in the airways

Produced by:

• Mast cells

• Eosinophils

• Basophils

• Macrophages

These immune cells sit in the airway mucosa and are activated during:

• Asthma

• Allergies

• Infections

• Anaphylaxis

So leukotrienes are released directly into the airway environment, right where smooth muscle is.

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

recruitment and distension (during exercise)

3. Recruitment & Distension (during exercise)

The pulmonary bed is compliant:

Recruitment: Previously unperfused capillaries open

Distension: Perfused capillaries widen as pressure rises

Both decrease PVR, allowing pulmonary blood flow to increase during exercise without increasing pulmonary artery pressure significantly.

• Explain the factors that regulate pulmonary blood flow, including the effects of ventilation, gravity, and pulmonary vascular resistance.

V. SUMMARY TABLE (Exam-Ready)

Factor	Effect on Pulmonary Blood Flow	Mechanism
Ventilation (alveolar O₂)	↓ PO₂ → ↓ blood flow	Hypoxic pulmonary vasoconstriction
Gravity	↑ Blood flow at base; ↓ at apex	Hydrostatic pressure gradient
Lung Volume	↑ PVR at high & low volumes	Alveolar vs. extra-alveolar vessel compression
Chemical Factors	Hypoxia, hypercapnia → ↑ PVR; NO/PGI₂ → ↓ PVR	Smooth muscle contraction/relaxation
Exercise	↑ Flow with ↓ PVR	Recruitment & distension

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

what are the characteristics of the respiratory membrane?

what is the structure of the respiratory membrane?

I. OVERVIEW OF GAS EXCHANGE

Gas exchange = the movement of O₂ from alveoli → blood and CO₂ from blood → alveoli, driven entirely by passive diffusion (no ATP required).

It occurs across the respiratory membrane, which is extremely:

• Thin (~0.5 μm)

• Large in surface area (~70 m²)

• Highly perfused

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

II. STRUCTURE OF THE RESPIRATORY MEMBRANE

Gas must cross:

1) fluid surfactant layer

2) Alveolar epithelium (Type I pneumocytes)

3) epithelial basement membrane

4) interstitial space

5) capillary basement membrane

6) capillary endothelium

7) red blood cell

epithelium “epi”: top, the “layer that lies on top of the surface”

IMPORTANT NOTE: Basement membranes are usually fused

In ~90% of the alveolar surface:

• the alveolar epithelial basement membrane

• is fused with the capillary endothelial basement membrane

→ making the diffusion barrier extremely thin (~0.2–0.6 μm)
This is why diffusion is so fast in healthy lungs.

Thin membrane + large surface area = rapid diffusion

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

principles of diffusion

III. PRINCIPLES OF DIFFUSION

Gas exchange follows Fick’s Law of Diffusion:

Rate of diffusion ∝ (Surface Area × Pressure Gradient × Solubility) ÷ Membrane Thickness

1. Pressure gradients drive the exchange Oxygen

• Alveolar PO₂ ≈ 104 mmHg

• Pulmonary capillary PO₂ ≈ 40 mmHg
  → O₂ diffuses from alveoli into blood until capillary PO₂ ≈ 100 mmHg

Carbon Dioxide

• Pulmonary capillary PCO₂ ≈ 45 mmHg

• Alveolar PCO₂ ≈ 40 mmHg
  → CO₂ diffuses from blood into alveoli

2. Solubility differences

CO₂ is 20× more soluble than O₂ → diffuses easily despite smaller pressure gradient.

3. Diffusion limitations

Diffusion slows down if:

• Membrane thickens (fibrosis, edema, pneumonia)

• Surface area is lost (emphysema)

• Blood transit time is shortened (exercise + diffusion impairment)

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

principles of perfusion

IV. PRINCIPLES OF PERFUSION

Perfusion = blood flow through pulmonary capillaries.

Adequate gas exchange requires:

1. Sufficient blood flow

2. Proper matching of ventilation (V) and perfusion (Q)

1. V/Q Matching

Optimal gas exchange happens when:

Ventilation (V) ≈ Perfusion (Q)

Low V/Q (shunt physiology)

Perfusion but poor ventilation
→ pneumonia, airway obstruction, atelectasis
→ blood leaves poorly oxygenated

High V/Q (dead space)

Ventilation but poor perfusion
→ pulmonary embolism
→ wasted ventilation, no oxygen uptake

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

gas exchange process

V. GAS EXCHANGE PROCESS (Step-by-Step)

1. Fresh air enters alveolus

PO₂ rises; PCO₂ falls.

2. Large pressure gradient for O₂

• High PO₂ in alveolus

• Low PO₂ in venous blood
  → rapid O₂ diffusion into blood

3. O₂ dissolves in plasma, then binds hemoglobin

• Hb greatly increases O₂ carrying capacity

• O₂ content rises until equilibrium is reached

4. CO₂ moves in opposite direction

• Higher PCO₂ in venous blood

• Lower PCO₂ in alveolus
  → CO₂ diffuses into alveoli

5. Blood becomes oxygenated

Capillary blood leaves alveoli with:

• PO₂ ~100 mmHg

• PCO₂ ~40 mmHg

6. Gas exchange completes in ~0.25 seconds

Even though RBCs remain in the capillary for 0.75 seconds.

• Describe the process of gas exchange between the alveoli and the pulmonary capillaries, including the principles of diffusion and perfusion.

what is the difference between perfusion-limited and diffusion-limited for O2?

does CO2 ever problems with exchange?

VI. KEY POINT: Diffusion vs. Perfusion Limitations O₂

• Normally perfusion-limited (limited by blood flow, not diffusion), it’s in the name.

• Can become diffusion-limited in disease: fibrosis, edema, pneumonia

CO₂

• Diffusion is so efficient that CO₂ is rarely diffusion-limited

• Even with thick membranes, CO₂ exchange is usually preserved.  

Analyze the pathophysiology of respiratory disorders that affect pulmonary blood flow and gas exchange, such as pulmonary embolism, pulmonary hypertension, and acute respiratory distress syndrome (ARDS)

pulmonary embolism

1. Pulmonary Embolism (PE)

“embolism: a plug”

pulmonary embolism: A plug thrown into (and blocking) the lung’s blood vessels

Primary problem: obstruction of pulmonary arteries → impaired perfusion (Q)

pulmonary artery: carries blood from the right ventricle to the lungs (only deoxygenated artery in the body) 

Pathophysiology

• A blood clot (usually from a Deep Vein Thrombosis) travels to the pulmonary arterial tree.

DVT = a blood clot in one of the deep veins, usually of the legs or pelvis.

• Embolus blocks blood flow to part of the lung.

• Ventilation continues normally, but perfusion is absent (because there is blocked blood flow)

Effects on Gas Exchange

A. V/Q Mismatch — Dead Space

• Ventilation without perfusion → V/Q → ∞

• Called physiologic dead space

• O₂ cannot enter blood because no blood is present to receive it.

dead space → hypoxia (because no tissue is receiving the oxygen)

B. Hypoxemia Mechanisms

• Loss of perfused capillaries → ↓ diffusion surface area

• Reflex bronchoconstriction → worsens V/Q mismatch

• Hyperventilation → ↓ CO₂ (respiratory alkalosis)

C. Hemodynamic Effects

Large Pulmonary Embolism → severe:

• ↑ Pulmonary vascular resistance

• Acute right ventricular strain → right sided heart failure. 

A large PE blocks the pulmonary artery, so the Right Ventricle suddenly has to pump against a massively increased resistance.

• Shock if obstruction is massive

• PE = perfusion failure → dead space → hypoxemia → RV strain.

Analyze the pathophysiology of respiratory disorders that affect pulmonary blood flow and gas exchange, such as pulmonary embolism, pulmonary hypertension, and acute respiratory distress syndrome (ARDS)

Pulmonary Hypertension (PH)

2. Pulmonary Hypertension (PH)

hypertension: a lot of pressure

pulmonary hypertension has NOTHING to do with hypertension of heart, it’s hypertension of lungs due to high PVR. 

Primary problem: increased pulmonary vascular resistance (PVR)

hypertension= lots of vascular resistance. 

Pathophysiology

• Chronic (constant) vasoconstriction, vascular remodeling, or obstruction → ↑ PVR

• Causes include:

  • Left heart disease

  Left heart disease → backward transmission of pressure into the pulmonary circulation → pulmonary venous hypertension → pulmonary arterial hypertension → right heart strain.

  This is the most common cause of pulmonary hypertension.

  • Chronic lung disease (COPD, ILD)

  • Recurrent PE

  • Idiopathic pulmonary arterial hypertension

  • Hypoxia (high altitude)

Vascular Changes

• Medial hypertrophy (smooth muscle thickening)

• Intimal fibrosis

• In severe disease → plexiform lesions

Effects on Blood Flow & Gas Exchange (compensation)

A. Decreased Perfusion (Q)

• Capillaries narrow → ↓ blood flow through well-ventilated alveoli

Capillaries narrow in pulmonary hypertension because the pulmonary vascular system remodels in response to chronically elevated pressure.

• This produces high V/Q ratio (dead space–like physiology)

B. V/Q Mismatch

• Some lung units are ventilated but underperfused

• Creates wasted ventilation

• ↓ O₂ uptake

C. Right Ventricular Failure

• Chronic pressure overload → RV hypertrophy → cor pulmonale

D. Hypoxemia mechanisms

• Reduced perfusion

• Destruction of capillary bed (e.g., in emphysema)

• Consequence of increased dead space

• PH = high PVR → perfusion deficits → V/Q mismatch → progressive hypoxemia → RV failure.

Analyze the pathophysiology of respiratory disorders that affect pulmonary blood flow and gas exchange, such as pulmonary embolism, pulmonary hypertension, and acute respiratory distress syndrome (ARDS)

Acute Respiratory Distress Syndrome (ARDS)

hyaline membrane formation

3. Acute Respiratory Distress Syndrome (ARDS)

acute: sudden

respiratory: respiratory

distress: Severe difficulty (in this case, difficulty breathing or oxygenating).

syndrome: a group of symptoms

ARDS occurs when diffuse inflammation and injury to the alveolar–capillary membrane cause increased permeability → protein-rich pulmonary edema → loss of surfactant → alveolar collapse → severe V/Q mismatch and shunt.

ARDS is not one disease — it is a final common pathway of many insults:

Direct lung injury

• Pneumonia (most common)

• Aspiration

• Inhalational injury

• Near-drowning

• Lung contusion

Indirect injury (systemic inflammatory states)

• Sepsis (most common overall)

• Trauma

• Pancreatitis

• Massive transfusion

• Burns

All of these trigger massive inflammatory activation.

Mechanism

1. Inflammatory mediators cause:

   • Damage to alveolar epithelium (Type I and II cells)

   • Capillary endothelial injury

2. Protein-rich fluid floods alveoli → noncardiogenic pulmonary edema

3. Surfactant is lost → alveolar collapse

type II pneumocytes that produce surfactant are injured, destroyed, or functionally shut down by the inflammatory damage to the alveolar–capillary membrane.

1. Hyaline membranes form

leak into the alveoli and then organize into a glassy (hyaline) layer.

1. Severe ↓ compliance (stiff lungs)

Effects on Gas Exchange

A. Diffusion Limitation

• Thickened respiratory membrane

• Fluid + protein-filled alveoli

• ↓ O₂ diffusion capacity

• CO₂ diffusion is often preserved early

B. Severe V/Q Mismatch 1. Shunt physiology (Q > V)

• Blood flows past unventilated or collapsed alveoli

• Does NOT improve with supplemental oxygen (key clinical sign)

C. Decreased Compliance

• Stiff lungs require high pressures to inflate

• ↓ tidal volumes → ↓ ventilation

D. Hypoxemia

• Profound

• Due to shunt + diffusion barrier + V/Q mismatch

Summary

ARDS = alveolar flooding + collapse → shunt → refractory hypoxemia + low compliance.

• Physiology, Costanzo, 6th edition:

  • Chapter 5, Pg 216 - 224 

put the flashcards from the book here, you need everything, and the stuff highlighted.