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Mulrooney, et al., unpublished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