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
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