Pulmonary Pathophysiology Iain MacLeod, Ph.D [email protected] Iain MacLeod 2 November 2009.

Pulmonary Pathophysiology

Iain MacLeod, [email protected]

Iain MacLeod 2 November 2009

Areas of the lungs:

Conducting zones: upper airways, trachea, bronchi, bronchioles

act to filter air of pathogens/dust and to humidify

contains mucous glands, ciliated cells, smooth muscle and cartilage

Transitional zone: respiratory bronchioles

Respiratory zone: alveolar ducts and alveoli

site of gas exchange

synthesizes surfactant

contains type I and II epithelial cells, macrophages and fibroblasts

Anatomy

Alveoli are small, hollow sacs that contain a cell wall that is

usually one cell thick – made up of type I alveolar cells (flat

epithelial cells) – a single cell wall can separate adjacent

alveoli.

In addition to type II alveolar cells, the cell wall can contain

capillaries. A small volume of interstitial fluid can separate

capillaries and the alveolar cell wall, but when fluid is absent,

the capillary and cell wall can fuse – results in an extremely

thin barrier between O2 / CO2 and RBCs.

The thin cell wall coupled with the extensive surface area of

alveoli results in the rapid, bulk movement of gases.

Respiratory Zone

Similar to blood, air move by bulk flow, such that it can be defined as:

F = P / R

Air flow (F) is proportional to the change in pressure, and in this scenario we are thinking in terms of

atmospheric pressure (Patm) and alveolar pressure (Palv):

F = Palv - Patm) / R

During inspiration, Palv is less than Patm so the driving force is negative and air flow moves inward; the

reverse occurs during expiration.

To change Palv the body can vary the volume of the lungs, resulting in a change in pressure (Boyle’s law

– pressure is inversely proportional to the volume)

Mechanics

Two factors determine lung volume: 1.The difference in pressure between the inside and outside of the lungs – the transpulmonary pressure (Ptp)

2.Lung compliance – the amount of expansion that they are capable of

The pressure inside the lungs is equivalent to Palv while the pressure outside equals the pressure of the

intrapleural fluid (Pip). Therefore: Ptp = Palv – Pip

By taking advantage of Boyle’s law, air can flow into the alveoli as a result of decreasing P ip. This is

achieved through the expansion of the chest wall, which as a result increases the volume of the

intrapleural space.

What happens? Pip decreases as a result, making Ptp more positive making the lungs expand. This

expansion results in decreasing Palv allowing air to flow inwards.

Mechanics

Mechanics

Mechanics

0mmHg

-4mmHg -3mmHg

-6mmHg

+3mmHg

-3mmHg

Diaphragm and inspiratory intercostal muscles contract

Thorax Expands

Pip becomes more negative

Transpulmonary pressure increases

Lungs expand

Palv becomes more subatmospheric

Air flows into alveoli

Mechanics

Diaphragm and inspiratory intercostal muscles stop contracting

Chest wall recoils inwards (due to elasticity)

Pip becomes more positive

Transpulmonary pressure decreases back to preinspiration levels

Lungs recoil - elasticity

Palv becomes greater than Patm

Air flows out of lungs

Mechanics

Lung compliance: this can be thought of as the opposite of stiffness

Compliance (CL) is defined as the magnitude of change in lung volume (VL) produced by a

given change in transpulmonary pressure (Ptp): CL = VL / Ptp

Therefore – the greater the compliance, the easier it for the lungs to expand. If compliance

is low, then a greater decrease in Pip must occur so that the lungs can expand sufficiently.

People with low lung compliance tend to have shallow, rapid breathing.

What determines lung compliance?

Mechanics

Lung compliance: this can be thought of as the opposite of stiffness

Compliance (CL) is defined as the magnitude of change in lung volume (VL) produced by a

given change in transpulmonary pressure (Ptp): CL = VL / Ptp

Therefore – the greater the compliance, the easier it for the lungs to expand. If compliance

is low, then a greater decrease in Pip must occur so that the lungs can expand sufficiently.

People with low lung compliance tend to have shallow, rapid breathing.

What determines lung compliance? Elasticity of the connective tissue and surface tension.

Mechanics

Surface Tension:

The surface of alveolar cells is moist creating surface tension (think of two glass slides with

water in between them that are difficult to prise apart). If this attractive force wasn’t

countered, it would require extreme effort to expand the lungs and the would collapse.

Recall that type II alveolar cells are found in the cell wall – these cells release surfactant.

This lipid / protein mixture vastly reduces the attractive forces and increases lung

compliance. Reduces attractive forces of hydrogen bonding by becoming interspersed

between H20 molecules. As alveoli radius decreases, surfactant’s ability to lower surface

tension increases.

Vitally important in premature neonates – infant respiratory distress syndrome

Mechanics

Recall that flow is dependent not only on a change in pressure but also the resistance.

Factors that determine resistance are similar to those of blood flow: tube length, radius and interactions between molecules. Like the circulatory system, airway resistance is inversely proportional to the radius (Poiseuille’s law):

F = ∆P r4 L8

With the main point being that halving the radius results in 16-fold increase in resistance

(decrease in flow).

There is usually little airflow resistance such that small changes in pressure are the main

driving force behind large flows of air - however, it has a detrimental effect when

increased.

what’s the average change in pressure (Palv - Patm) during a normal breath?

Resistance

Recall that flow is dependent not only on a change in pressure but also the resistance.

Factors that determine resistance are similar to those of blood flow: tube length, radius and interactions between molecules. Like the circulatory system, airway resistance is inversely proportional to the radius (Poiseuille’s law):

F = ∆P r4 L8

With the main point being that halving the radius results in 16-fold increase in resistance

(decrease in flow).

There is usually little airflow resistance such that small changes in pressure are the main

driving force behind large flows of air - however, it has a detrimental effect when

increased.

what’s the average change in pressure (Palv - Patm) during a normal breath?

1 mmHg

Resistance

Asthma – how does this disease process help us understand the impact of resistance?

Resistance - Pathologies


A pathology that results from chronic inflammation of the bronchi. Inflammatory mediators

stimulate bronchoconstriction – reduced tube radius = increased restriction.

How is it treated?



A pathology that results from chronic inflammation of the bronchi. Inflammatory mediators

stimulate bronchoconstriction – reduced tube radius = increased restriction.

How is it treated?

Chronic Obstructive Pulmonary Disease – emphysema and chronic bronchitis

Both diseases have the same etiology – they are caused by smoking. Chronic bronchitis is

characterized by excessive mucus production and chronic inflammation of the bronchi.

Emphysema is characterized by an increase in pulmonary compliance – why would this be

an issue?

Similar to chronic bronchitis, toxin-induced inflammation, this time in the alveoli, leads to

cell death.


O2 has to get from the alveoli into the capillaries, from there to metabolically active

tissues, into the extracellular fluid & across the plasma membrane; CO2 does it in reverse

Generally speaking, in a steady state, the volume of O2 added to the blood is the same as

the volume of O2 consumed by tissues, with the reverse being true for CO2.

Gases are usually discussed in terms of partial pressure. For example: at sea level,

atmospheric pressure is 760mmHg, but this accounts for all the gases found in the

atmosphere. If we wish to think about O2 alone then we discuss it’s partial pressure. As

oxygen makes up 21% of the atmosphere then it’s partial pressure (PO2) is 21% of

760mmHg = 160mmHg.

Partial pressures are important for understanding the exchanges of gases

Exchange of Gases

Similar to the bulk movement of air from high to low pressure, dissolved gases in a liquid

behave in a similar manner.

Alveolar gas pressures are PO2 = 105 mmHg and PCO2 = 40 mmHg, whereas the atmospheric

partial pressures are 160 mmHg and 0 mmHg, respectively.

What would lead to a drop in alveolar PAO2?

Exchange of Gases

Similar to the bulk movement of air from high to low pressure, dissolved gases in a liquid

behave in a similar manner.

Alveolar gas pressures are PO2 = 105 mmHg and PCO2 = 40 mmHg, whereas the atmospheric

partial pressures are 160 mmHg and 0 mmHg, respectively.

What would lead to a drop in alveolar PAO2?

High altitude = lower atmospheric PO2

Decreased ventilation

Exercise - Increased demand for O2 from tissues

Exchange of Gases

Exchange of Gases

Venous Blood

Alveoli Arterial Blood

Atmosphere

PO2 40 mmHg 105 mmHg 100 mmHg 160 mmHg

PCO2 46 mmHg 40 mmHg 40 mmHg 0.3 mmHg

You should be able to recognise that as venous blood reaches the pulmonary capillaries,

the differences in partial pressure for O2 and CO2 between the blood and alveoli will result

in an exchange of both gases.

Why isn’t all the CO2 removed?

Review – Pulmonary I - Hypoxemia

Hypoventilation: can result from a defect anywhere in the stimulation of respiratory muscles, from the

controlling centres of the medulla down to the muscles themselves.

occlusion of the upper airway / thoracic cages injuries

hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2

Diffusion Impairment: either a thickening of the alveolar cell well and / or a decrease in surface area leads to

impairment of equilibria between arterial and alveolar PO2

PaCO2 is either normal or reduced (if ventilation is increased to offset hypoxemia)

Shunt: an anatomical abnormality that allowed mixed venous blood to by-pass ventilation and

enter arterial blood.

can also occur when blood passes through alveoli that are unventilated thus the blood in

the capillaries does not become perfused

PaCO2 is normal due to increased ventilation to counteract hypoxemia

Ventilation-Perfusion

Inequality:

most common cause of hypoxemia – found in lung diseases such as COPD – ie. an increase

in dead space. Ventilation is the same but perfusion (gas exchange) is impaired.

PaCO2 is increased or normal if increased ventilation is possible

Primary determinant of partial pressure of arterial CO2 (PaCO2) is alveolar CO2 partial pressure (PACO2), which

in turn is determined by alveolar ventilation.

It should be obvious that alveolar ventilation (VA) is dependent on how much we breathe – how much we

breathe per minute (VE) will rely on the size of the breath (VT) and the number of breaths/min (f):

VE = VT x f

Review – Pulmonary I - Hypercarbia

Primary determinant of partial pressure of arterial CO2 (PaCO2) is alveolar CO2 partial pressure (PACO2), which

in turn is determined by alveolar ventilation.

It should be obvious that alveolar ventilation (VA) is dependent on how much we breathe – how much we

breathe per minute (VE) will rely on the size of the breath (VT) and the number of breaths/min (f):

VE = VT x f

But not all of the air we breathe reaches the gas exchange regions of our lungs, so the dead space (VD) has to

be taken into account when determining VA:

VA = (VT - VD) x f

It is important to realize that PaCO2 = PACO2 thus something that could affect alveolar ventilation will have a

knock-off effect on arterial CO2 levels by altering PACO2, with the primary determinant of hypercarbia being

hypoventilation.


What can cause hypoventilation? (Discuss)



• can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling

centres of the medulla down to the muscles themselves.

• occlusion of the upper airway / thoracic cages injuries

• hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2

Remember: you can still have a high minute ventilation (= tidal volume x freq.) but still be hypoventilating if

the dead space has increased overall this serves to decrease alveolar ventilation

What can cause an increase in dead space? (Discuss)



• can result from a defect anywhere in the stimulation of respiratory muscles, from the controlling

centres of the medulla down to the muscles themselves.

• occlusion of the upper airway / thoracic cages injuries

• hypoxemia by hypoventilation is accompanied by a rise in arterial PCO2

Remember: you can still have a high minute ventilation (= tidal volume x freq.) but still be hypoventilating if

the dead space has increased overall this serves to decrease alveolar ventilation

What can cause an increase in dead space? (Discuss)

• Breathing through a tube

• Pulmonary embolus

• Disease (such as?)


Review – Pulmonary II – Lung Volume

FRC: functional residual capacityTLC: total lung capacityVC: vital capacityRV: residual volumeVT: tidal volume

FRCThe FRC is the volume in your lungs at the end of a breath when you are completely relaxed. It is the point at which the tendency of the chest wall to recoil outwards exactly matches the inward recoil of the lungs. TLCThe TLC is the total amount of air in your lungs at the end of a maximal inspiratory effort. It’s a measure of the overall size of the lungs. TLC increases in emphysema and sometimes in asthma. RVRV is the volume of air in your lungs at the end of a maximal expiratory effort. In diseases such as asthma and emphysema, the airways close at low lung volumes. Air is trapped behind these closed airways and so RV increases. VCVital Capacity is the difference between TLC and RV. It’s primarily determined by overall thoracic size and is influenced by height, age, and gender. It will change whenever RV or TLC changes due to disease.

Review – Pulmonary II - Obstruction

Should be a well-understood concept that when an airway narrows its resistance greatly increases

Airway resistance, and thus obstruction, can be easily measured by determining the FEV1 / FVC ratio - forced

expiratory volume in one second (FEV1) and the forced vital capacity (FVC).

The FVC is measured by having a person take in as much air as they possibly can and then breathe out as

much as they can into a spirometer, until no more air will come out. The total amount of air that they

breathe out is the FVC. The FEV1 is the amount of air that comes out in the first second. The technique has

the advantage of being mostly effort independent.

A value less than 80% indicates that an airway obstruction may be present

Review – Pulmonary II - Asthma


FEV1/FVC is greatly reduced during an attack – why ?



• Bronchoconstriction

- Airway hyperresponsiveness: increased airway narrowing in response to contractile

agonists that have little if any effect in normal subjects

histamine, methacholine, leukotrienes – can be diagnostic using the PD20 (provocative dose)



• Bronchoconstriction

- Airway hyperresponsiveness: increased airway narrowing in response to contractile

agonists that have little if any effect in normal subjects

histamine, methacholine, leukotrienes – can be diagnostic using the PD20 (provocative dose)

• Inflammation

- Mediated mainly by lymphocytes (CD4 and CD8 T cells) and eosinophils.

IL-5 Granules

IgE Diffusion & Contraction

Allergy

Review – Pulmonary II – Asthma & Allergy

Review – Pulmonary II – Asthma Treatment

What do each of these do ?

• Corticosteroids

• -agonists

• Leukotriene Synthesis Inhibitors

• Omalizumab

Review – Pulmonary II – Asthma - Influencing Factors

Nature vs. Nurture

- genetic factors involved in IgE synthesis

- exposure to viruses / allergens / cigarette smoke

Why is asthma on the increase?

- hygiene hypothesis

- obesity

- allergens

- pollution

Review – Pulmonary II - COPD

Emphysema and Chronic Bronchitis

Review – Pulmonary II - COPD

Emphysema and Chronic Bronchitis

• destruction of alveolar wall and capillary bed but without obvious scarring (fibrosis).

• enlarged air spaces

• small airways are narrowed, thin walled, may be reduced in number

• pan acinar - central part of acinus (respiratory bronchioles mainly affected)

• pan lobular whole acinus afflicted‑

• apex of lung most often affected first

• increased pulmonary compliance (elastase)

• hypertrophy of mucus glands

• goblet cell metaplasia

• inflammation in small airways and in glands

• mucus in airways, sometimes occluding airway lumen

• airway wall edema

• thickened epithelium

Review – Pulmonary II – COPD - Emphysema

Inhaled toxins trigger local inflammation

in alveoli

Inflammatory mediators cause the

destruction of alveolar septum – decrease

in surface area available for gas exchange

Additional destruction of capillaries that

serve alveoli.

Ventilation/ Perfusion inequality – some areas of the lung could receive large quantities of air but have

insufficient blood flow (or vice versa).

Lower PaO2 but normal PaCO2 (although PaCO2 will rise once disease becomes extensive)

Review – Pulmonary II – COPD - Emphysema

How does emphysema lead to pulmonary hypertension ?

- as disease progresses and high enough PaO2 cannot be reached, the body compensates through

vasoconstriction.

- the heart tries to provide more blood to the lungs in order for PaO2 to increase, leading to thickening of

the heart muscle. Eventual heart failure ensues.

What role does 1 anti-trypsin play? (Discuss)

Review – Restrictive Lung Diseases

Lung recoil:

The pressure required to fill an air filled lung is much greater than the pressure required to fill a fluid filled lungAt the air/liquid interface, attractive forces between water molecules resist lung expansionSurfactant, a combination of proteins and phospholipids synthesized in Type II epithelial cells, reduces surface tension by interposing itself between water moleculesWith surfactant, pressure required to inflate the lung is still greater than it would be if you were filling it with liquid, but much less than if there was no surfactant

Pulmonary Edema:

Most fluid that gets out of the circulation into the interstitial space is collected into lymphatics and taken back to the circulation.If the fluid flow becomes greater than the lymphatics can handle, it first goes to spaces around the large airways and blood vessels, and then starts accumulating in the interstitial spaces.The epithelium is normally extremely impermeable to water, but if the fluid accumulation in the interstitial spaces gets big enough, it will start to leak across into alveoli.Fluid in the alveolar spaces impairs diffusion across the alveolar capillary membrane. If severe, it can fill up these spaces and form a shunt.Fluid in the airspaces can also interfere with surfactant function and impair lung inflation.


Heart Disease left atrial pressure pressure in pulmonary vein Pcap fluid flux across the endothelium Self-limiting - fluid accumulation in the interstitial space causes the pressure in the intersitial space to rise. As fluid leaks out, the proteins in the capillary become more concentrated, there is an increase in the oncotic pressure, and fluid tends to get pulled back into the capillary.


Heart Disease left atrial pressure pressure in pulmonary vein Pcap fluid flux across the endothelium Self-limiting - fluid accumulation in the interstitial space causes the pressure in the intersitial space to rise. As fluid leaks out, the proteins in the capillary become more concentrated, there is an increase in the oncotic pressure, and fluid tends to get pulled back into the capillary. Increased capillary permeability Toxins - eg: chlorine, nitrogen oxides, SO2, endotoxin, radiation, bacterial or viral pathogens, high O2

concentrations over long periods of time. Integrity of the endothelial barrier is destroyed, and proteins start leaking into the interstitial space; capillary oncotic pressure decreases resulting in increased leak of fluid into the interstitial space. Is not a self limiting process; the fluid that comes out has protein in it, so the oncotic pressure of the interstitium starts to increase, further increasing fluid flux. This kind of edema is extremely dangerous.


If only interstitial edema is present, there is little change in PaO2. Even though the barrier to diffusion is

increased, at rest, O2 uptake across the alveolar-capillary barrier is still complete.

If alveolar edema is present, there is a decrease in PaO2, mainly because of blood flow to fluid filled alveoli

that are not being ventilated (shunt). PaCO2 stays normal or even low, because the patients increase their

ventilation. The reason for the increased ventilation may be the low PaO2, or stimulation of lung receptors

by high transpulmonary pressures (lung is stiffer, so it requires greater pressures for ventilation).

Pulmonary Pathophysiology Iain MacLeod, Ph.D [email protected] Iain MacLeod 2 November 2009.

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