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DISEASES OF ALVEOLAR DISEASES OF ALVEOLAR HOMEOSTASIS:HOMEOSTASIS:RDS and BPDRDS and BPD
Jeffrey A. Whitsett, M.D.Jeffrey A. Whitsett, M.D.Cincinnati Children’s Hospital Medical CenterCincinnati Children’s Hospital Medical Center
Divisions of Neonatology and Pulmonary BiologyDivisions of Neonatology and Pulmonary Biology3333 Burnet Avenue3333 Burnet Avenue
Cincinnati, OH 45229-3039Cincinnati, OH 45229-3039
Burden of Disease Related to Burden of Disease Related to Pulmonary Immaturity in USAPulmonary Immaturity in USA
4,000,000 Births4,000,000 Births
11% Preterm < 37 weeks11% Preterm < 37 weeks 440,000440,000
1.3% <1500g1.3% <1500g 52,00052,000
0.75% <1 kg0.75% <1 kg 32,00032,000
66%66%RDSRDS
24%24%BPDBPD
Major Lung Diseases of the Premature
• RDS - Surfactant deficiency
• BPD - Injury/disrupted lung development/dysplastic repair
4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15
02
04
06
08
0
Weight Group (per 100gm)
Oxy
ge
n a
t 3
6 w
ee
ks (
%)
Bar Plot of BPD Rate by Weight GroupBPD Based on Birth Weight - NICHD Network - 2003
0
20
40
60
8
0
% S
urv
ivo
rs w
ith
BP
D
Weight Group (per 100gm)
Normal Pediatric LungNormal Pediatric LungImmunohistochemistryImmunohistochemistry
proSP-CproSP-CSP-BSP-B
SP-B and SP-C are synthesized in alveolar Type 2 cells.SP-B and SP-C are synthesized in alveolar Type 2 cells.
Alveolar Alveolar StructureStructure
Surfactant CompositionSurfactant Composition
•SP-B•SP-C•SP-A•SP-D
cholPLPL
PGPG
PCPC
DPPC
protein
Surfactant homeostasisSurfactant homeostasis
Alveolar macrophage
Type II cell
Surfactant Treatment
Surfactant Pool
Recycling
Surfactant Function
Lung Structure Tissue Function
Leaky Epithelial and Endothelial Barriers
Surfactant Inactivation
Pulmonary EdemaSeverity of RDS
Lung Development•Gestational Age
•Prenatal Stress
•Corticosteroids
Pathophysiology of RDS
Measurements to Evaluate Surfactant Metabolism
Surfactant Concentration in Alveoli Surfactant Concentration in Alveoli of Human Lungof Human Lung
Surfactant Surfactant (mg/kg)(mg/kg)
Alveolar Fluid Alveolar Fluid (ml/kg)(ml/kg)
Surfactant Surfactant concentration concentration
(mg/ml)(mg/ml)
AdultAdult
Term newbornTerm newborn
Preterm newbornPreterm newborn
44
Assume 100Assume 100
0-100-10
0.40.4
Assume 0.4Assume 0.4
? High? High
10 mg/ml10 mg/ml
250 mg/ml?250 mg/ml?
??
Gestational Ages
Surfactant Pool Sizes in Preterm Lambs and Pco2 Valuesat 2h of Age
Mulrooney, et al., unpublished
0 2 4 6 8 10 12 14 16 18 20
0
50
100
150
200
250
Alveolar Wash Sat PC (mol/kg)
pC
O2
(mm
Hg
) 132-133 d134-136 d
130-131 d
Adapted from Mulrooney et al., AJRCCM, 2005
Term Lambs Preterm Lambs
Preterm Baboons Preterm Infants
Sp
eci
fic
Ac
tiv
ity
of
PC
C13
Ato
m %
Ex
ces
s in
PC
Hours Hours
0 24 48 72 96 120 144
0.00
0.05
0.10
0.15
0 24 48 72 96 120 144
0.00
0.05
0.10
0 10 20 30 50
0.0
0.5
1.0
1.5
5 100 10 20 30 40 50
0.0
0.3
0.6
0.9
1.2
Appearance of Labeled Surfactant PC in Airway Samples
Data from Multiple Sources
Hours
Hours Hours
Ato
m %
Exc
es
s%
Re
cove
ry
% R
ec
ov
ery
Hours Hours
A Preterm Lambs B Preterm Lambs -
E
Sp
ecif
ic A
cti
vit
y
C Preterm Baboons
D Surfactant Treated PretermHumans withRDS
Preterm Humans After 2nd Surfactant Treatment
0 24 48 72 96 120 144
0.0
0.5
1.0
1.5 Surfactant Treated
0 5 10 15 20 25
0
25
50
75
100
0 24 48 72 96 120 144
0.01
0.1
1
0 12 24 36 48
0.1
1
0 5 10 15 20 25
0
25
50
75
100
Clearance of Labeled Surfactant PC from Airspaces
Data from Multiple Sources
Persistent Effects of Surfactant Depend on Metabolic Characteristics of Surfactant in the Preterm Lung
Surfactant Labeling and Secretion in Ventilated Infants with RDS (13C-glucose labeling of PC)
CV(N=11)
HFOV(N=8)
Birth Weight
Time to peak labeling (Hr)
Half-life after peak (hr)
Fract. Syn. Rate (%/d)
779125
7024
7918
4.72.7
726175
8722
7623
4.23.1
Merchak, et al., J . Pediatr. 140:693, 2002
Metabolic Characteristics of Surfactant in the Preterm with RDS
• Endogenous pool sizes are small (0-10 mg/kg)• Synthesis/secretion of new surfactant is slow (70h)• Catabolism and lung clearance is slow (days)
Surfactant lipid and protein components are substrate for the metabolic pathways are recycled as intact components.
A treatment dose is large and its chemical components persist for days
Chorioamnionitis Resuscitation Mechanical Oxygen Nosocomial Ventilation
Infection
Preterm Fetal Lung
Transitional Lung
Preterm Postnatal Lung
Altered Lung Development
and BPD
Antenatal Corticosteroids Indomethacin Postnatal Corticosteroids
Pro- and Anti-inflammatory Influences on Preterm Lung
Anti-inflammatory
Nn