Fisiología Respiratoria

I. Mecánica de la respiración A. Anatomía B. Ventilación

1. Músculos respiratorios2. Flujo del aire3. Presión Intrapleural4. Volúmenes pulmonares5. Trabajo respiratorio6. Compliance pulmonar7. Tensión superficial alveolar8. Resistencia de vías aéreas9. Compresión dinámica de vías aéreas10. Espacio muerto11. Factores determinantes de pCO2 y pO2

A. AnatomyA. Anatomy

(Thoracic Cavity)

Intrapleural space

Surface area

2.5 cm2

> 1 x 106 cm2

300 millones de alvéolos0,3 mm dam.85 m2! (en 5-6 litros)

Problemas: -humo de cigarrillo-fibrosis quística

Structure of lung lobuleEach cluster of alveoli is surrounded by elastic fibers and a network of capillaries.

B. Ventilation (how we breathe)B. Ventilation (how we breathe)

descent of diaphragm

elevation of rib cage

V1V2

VaVb

V1 < V2

Va < Vb

Normal Lung at rest

lung collapses to unstretched

size

Pneumothorax

Pleural membranes

Flow (F) of airFlow (F) of air

RespirometerRespirometer

F = k(P1 - P2) = (P1 - P2)/RP = pressure; k = conductance = 1/R; R = resistance

P1 P2

F

Lung VolumesLung Volumes

VT = Tidal volume

ERV = expiratory reserve vol

IRV = inspiratory reserve vol

RV = residual vol

FRC = functional residual capacity

Vital capacity

Total lung capacity

Minute Volume = V = VT x resp. ratee.g., 0.5 L/breath x 12 breaths/min = 6 L/min

Functional residual capacity

Vital capacity (sum total of all except RV)

Work of BreathingWork of Breathing

Compliance Work: force to expand lung against its elastic properties

Force to overcome viscosity of lung & chest wall

Airway Resistance Work: force to move air through airways

Compliance Work: force to expand lung against its elastic properties

Force to overcome viscosity of lung & chest wall

Airway Resistance Work: force to move air through airways

The ability of the lung to stretch is measured as the COMPLIANCE, C

C = ∆V/∆P

where V is lung volume and P is pressure

Vo

lum

e, l

iter

s

3

2

1

0

TLC

MV

RV

FRC

∆P = 6.5 cm H2O

∆V = 1.8 L

∆V/∆P = 1.8 L/6.5 cm H2O

= 0.28 L/cm H2O

Compliance Work: Compliance of lung & chest wallCompliance Work: Compliance of lung & chest wall

For comparison:

vein = 0.04 and artery = 0.002 L/cm H2O

lun

g v

olu

me

(%

TL

C)

insp

irat

ion

expi

ratio

n

Translung pressure (cm H2O)

2. Difference between inspiratory & expiratory curves called hysteresis

1. Curves are not linear

air air air

What is surface tension?

x x

P

T

x x

A major component of lung surfactant is dipalmitoylphosphatidylcholine (DPPC). DPPC has typical phospholipid structure: two fatty acid residues are water insoluble, hydrophobic; phosphocholine at other end is charged and water soluble, hydrophilic.

x x

What is the origin and composition of Lung Surfactant?

Approximate composition of surfactant

Dipalmitoylphosphatidylcholine 62

Other phospholipids 15

Neutral lipids 13

Proteins 8

Carbohydrates 2

Component percent composition

Importance of Surfactant:Importance of Surfactant:

1. Reduces surface tension, therefore increases compliance

2. Stability of alveoli; LaPlace

3. Helps keep alveoli dry; helps prevent pulmonary edema

4. Expansion of lungs at birth

1. Reduces surface tension, therefore increases compliance

2. Stability of alveoli; LaPlace

3. Helps keep alveoli dry; helps prevent pulmonary edema

4. Expansion of lungs at birth

Like Poiseuille flow in blood vessels, i.e., inversely to r4

Agents that constrict vessels (bronchioles) or accumulate debris (e.g., mucus) increase resistance (makes airflow difficult).

Remember: ∆P = Raw x Flow

Conductive Airway Resistance.

One might think that because the terminal bronchioles are very narrow they would represent very high resistance. However, because there are so many (>106) and because they are in parallel they represent a relatively small portion of the total Raw.

Resistance Work:Resistance Work:

Raw = (Palv - Patm)/ Flow

Bronchiolar smooth muscle is under neurohumoral controlSympathetic stimulation (adrenaline): bronchiole dilationParasympathetic stimulation (Ach): bronchiole constrictionHistamine release from mast cells -- allergic/asthmatic response bronchiole constriction

R =8lr4

Dead Space

Volumen corriente = 500 mlEspacio muerto = 150 mlLlegan al alvéolo = 350 ml

Ventilación pulmonar = volumen corriente x frec.ventilatoria

Ventilación alveolar = (volumen corriente-espacio muerto) x frec.ventilatoria

¿Conviene modificar volumen corriente o frecuencia ventilatoria?

Does Dead Space Matter? How?Does Dead Space Matter? How?

VT = VA + VT

It is necessary to correct for dead space to effectively measure ventilation rate

We have already been introduced to the respiratory minute volume, V

V = freq x VT

A more important “minute volume” is the alveolar ventilation rate

Alveolar vent. rate = total volume of "new air" entering alveoli each minute, VA

VA = freq x (VT - VD)Think about and Do homework questions from readerThink about and Do homework questions from reader

Calculate some VD’s

Is it more efficient to change VA by frequency or by VT?

What are the consequences of breathing through a long tube?

What is an absolute upper limit for the length of the tube?

II. PHYSICAL PRINCIPLES OF GAS EXCHANGE A. Properties of GASES

II. PHYSICAL PRINCIPLES OF GAS EXCHANGE A. Properties of GASES

General Gas Law: PV = nRT

Accounting for water

Dry atm. air Partial pressure vapor pressure = 47mmHg

% mm Hg mm Hg

O2 20.9 160 149

CO2 0.04 0.3 0.3

N2 & other 79 600 564

total 100 760 713

Partial Pressure = pressure exerted by any one gas in a mixture

Partial Pressure = total pressure x fraction of total represented by the gas (Dalton’s law), i. e.,

Pgas = Ptotal x fgas

What is the composition of the room air that we breathe? (in percent & in partial pressure)

What is the composition of the room air that we breathe? (in percent & in partial pressure)

STPD BTPS ATPS

(0.21x760)

(0.0004x760)

(0.79x760)

How do we deal with gases in solution?

Henry’s Law:

Conc. of gas in solution = partial pressure of gas X solubility coefficient

e.g., [O2] in moles/L: [O2] = PO2 x SO2

Therefore [Gas] depends on both Pgas and Sgas

SCO2 is 20x higher than SO2

SCO2 = 0.03 mmol/L / mm Hg

SO2 = 1.37 µmol/L / mm Hg

How fast is DIFFUSION?How fast is DIFFUSION?

What is DIFFUSION?What is DIFFUSION?

Diffusion distance (µm)Diffusion distance (µm)

Time required for diffusionTime required for diffusion

1

10

100

1,000 (1 mm)

10,000 (1 cm)

1

10

100

1,000 (1 mm)

10,000 (1 cm)

0.5 msec

50 msec

5 seconds

8.3 minutes

14 hours

0.5 msec

50 msec

5 seconds

8.3 minutes

14 hours

startstart equilibriumequilibrium

CONCLUSION?CONCLUSION?

intermediateintermediate

Fick's 1st Law of Diffusion

Rate of diffusion = dm/dt = D · A ·

D = the diffusion coefficient

C = concentration of the substance

A = area available for diffusion

x = the distance for the diffusion

Rate of Diffusion Distance

Area x Concentration

What is the strategy in the evolution of the respiratory apparatus?

available surface area

distance required for diffusion

dC dx

(i.e., thickness)

O2

CO2

P1

P2

thickness

Area

FACTORES QUE INFLUYEN SOBRE EL TRANSPORTE DE GASES

1. Gradientes de presión parcialOxígeno:105 100 40 40 15 5-2 alvéolos arterias capilares intersticio citosol mitocondrias

2. Superficie de intercambio

3. Distancia de difusión

Total AREA available for diffusion of gases is large

in human ~50-100 m2

Diffusion PATH LENGTH is very small, <1 µm

Enfisema!

Edema!

Characteristics of the Pulmonary Circulation

“Special” Characteristics of the Pulmonary Circulation

Systemic Circ. Pulmonary Circ.

C.O. (L/min) 6.0 ≈ 5.9

Arterial B.P. (mm Hg) 100 >> 15

Venous B.P. (mm Hg) 2 “≈” 5

Vascular resistance (∆P/flow) 100-2/6=16.3 > 15-5/5.9=1.7

Vascular compliance (∆V/∆P) Csystemic << Cpulm

Ability to promote a decrease in resistance as blood pressure rises

Special Characteristics of the Pulmonary Circulation: high compliance

R =8lr4

Remember that resistance to Flow =

viscosity length

radius

Pulmonary blood vessels are much more compliant than systemic blood vessels. Also the system has a remarkable ability to promote a decrease in resistance as the blood pressure rises.

Two reasons are responsible:

Recruitment: opening up of previously closed vessels

Distension: increase in caliber of vessels

Special characteristic of blood vessels surrounding alveoli: hypoxic vasoconstriction

When PO2 within the alveoli decreases there is a decrease in blood flow to that alveolus

This is called hypoxic vasoconstriction

Thought to be the result of O2-sensitive K+ channels in the smooth muscle membrane. At low O2 the K+ channels close, the Em rises, and the cell

reaches threshold and depolarizes and contracts.

smooth muscle cell

This phenomenon is just the opposite the response to hypoxia you get with arteriole smooth muscle in the systemic circulation, but it is an important feature of the pulmonary circulation that helps to match perfusion with ventilation

Normal Emphysema AsthmaPulm. Circ.

Exercise Capillary enlargement (e.g., Mitral Stenosis)

Longer paths for diffusion

Pathological Examples of Altered Respiratory Mechanics

Carriage of blood gasesHow are gases carried by the blood??

Carriage of blood gasesHow are gases carried by the blood??

all values are in ml of gas/100 ml solution

H2O or plasma (pH = 7.4) Whole blood (Hct = 0.45)

dissolved combined dissolved combined

O2 (at a PO2 = 100 mm Hg) 0.3 0 0.3 19.5

CO2 (at a PCO2 = 40 mm Hg) 2.6 43.8 2.6 46.4

SCO2 = 0.03 mmol/L / mm Hg

SO2 = 1.37 µmol/L / mm Hg

note the difference

in units

Carriage of blood gasesHow are gases carried by the blood??

Carriage of blood gasesHow are gases carried by the blood??

all values are in ml of gas/100 ml solution

H2O or plasma (pH = 7.4) Whole blood (Hct = 0.45)

dissolved combined dissolved combined

O2 (at a PO2 = 100 mm Hg) 0.3 0 0.3 19.5

CO2 (at a PCO2 = 40 mm Hg) 2.6 43.8 2.6 46.4

SCO2 = 30.0 µmol/L / mm Hg = 0.65 ml/L / mm Hg

SO2 = 1.37 µmol/L / mm Hg = 0.03 ml/L / mm Hg

O2: 99% como oxihemoglobina, 1% disueltoCO2: 67% como bicarbonato, 24% como carboxihemoglobina, 9 % disuelto

The oxygen-binding site of oxyhemoglobin, space filling model (a) and stick model (b). The Fe2+ ion is bound to oxygen. The Fe2+ ion lies almost in the heme plane. Valine E11 and phenylalanine CD1 provide a hydrophobic environment at the oxygen-binding site.

Myoglobin molecule heme + globin monomer

Hemoglobin molecule

tetramer, 22

Oxygenation: Hb (deep red to bluish) + O2 HbO2 (oxyhemoglobin; red)

readily reversible

in fact, since Hb is a tetramer the reaction is really

Hb + 4O2 Hb(O2)4

Oxidation: Hb(Fe2+) Hb(Fe3+) (methemoglobin; brownish) difficult to reduce

CO reaction: Hb + CO HbCO (carboxyhemoglobin; bright red, pink) very high affinity (230X greater than for O2)

Spectral characteristics of Hemoglobin:

color changes with reaction of iron heme

(deoxyhemoglobin)

hemoglobin

myoglobin

Active cell

ml

O2/

100

ml

blo

od

0

5

10

15

20

Tissues

3 ml/100 ml O2 released to tissues

17 ml/100 ml

Let’s compare Hemoglobin and Myoglobin

Effect of pHEffect of PCO2

Effect of temperature

PCO2 effect is the same as the pH effect

CO2 + H2O H2CO 3 H+ + HCO3-

(Bohr Effect)

Why is Hb-O2 association “S-shaped”?

% saturation

100

0 25 50 75 100

tissue PO2 lung PO2

hyperbolic curve with lowest K

hyperbolic curve with highest K

PO2, mm Hg

y

100

0[O2]

1

23

4

Conformational change induced by the movement of the iron atom on oxygenation are transmitted to parts of the molecule that are far away

ml

O2/

100

ml

blo

od

0

5

10

15

20

High affinity onlyCan’t release much O2 to tissues

Low affinity onlyDoesn’t hold on to But can’t pick up much O2 at tissues much O2 at lungs

S-shaped hemoglobin curveReleases much Becomes saturated

O2 at tissues with O2 at lungs

Advantages of “S-shaped” curve for Hb-O2 association

Active cell

100

0

pH 7.4

pH 7.2

100 mm Hg

% saturation

PO2

R - CH2 - C — NH

HC CHN

Fe

O2

H+

R - CH2 - C — NH

HC CH

NH+

Fe

O2

H+

Advantages & Mechanistic Basis of the Bohr effect (change in pH or PCO2)

Effect of pH

Protonic association alters O2 affinity

PCO2 effect is the same as the pH effect

CO2 + H2O H2CO 3 H+ + HCO3-

Bohr Effect: Release of O2 by HbO2 into tissue is enhanced when:

pH is lowered

PCO2 is increased

Adequately oxygenated tissue

Normal pH

PCO2 ~ 46 mm Hg

PO2 ~ 40 mm Hg

adenosine normal

Inadequately oxygenated tissue

Low pH

PCO2 > 46 mm Hg

PO2 < 40 mm Hg

adenosine high

As noted by Prof. Machen: Local regulation (H+, CO2, adenosine, myogenic autoregulation) increases blood flow to inadequately oxygenated tissue

A second physiologic process, the Bohr effect, simultaneously increases unloading of O2 by Hb to the poorly oxygenated tissue (right shift in HbO2 curve)

% saturation

100

0

PO2 , mm Hg

25 50 75 100

Hb + add back 2,3 BPG

tissue PO2 lung PO2

Hb "stripped"of 2,3 BPG

2,3-Bisphosphoglyceric acid has important physiological consequences

2,3 BPG alters O2 affinity

2,3-Bisphosphoglycerate (BPG) [2,3-Diphosphoglyceric acid (DPG)]

Glucose 6-PO4

3-Phosphogyceraldehyde

1,3-Diphosphoglycerate

Phospho-glycerate kinase

Pyruvic acid

3-Phosphoglyceric acid

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

2,3-DPG mutase

2,3-DPG phosphatase

2,3-Bisphosphoglyceric acid:

Where does it come from & what does it do to Hb?

Normal RBC glycolysis

How 2,3 BPG is produced

Biochemical & functional differences of Fetal Hemoglobin

advantage

Expression of Hb differs during development

CO2

Tissues

C.A.CO2 + H2O H2CO3 H+ + HCO3

-

HCO3-

slow

HbO2 Hb.H + O2+

O2

Arterial blood Venous blood CO2(%)

Total CO2 49 52.7 100

CO2 in solution 2.6 3.0 11

H2CO3 negligible negligible 0

HCO3- 43.8 46.3 67

Carbamino compounds 2.6 3.4 21

How is CO2 carried by the blood??

Hb + CO2 Hb.CO2 (carbamino cmpd.)

Tis

sues

Lu

ngs