1. DISEASES OF ALVEOLAR HOMEOSTASIS: RDS and BPD
Jeffrey A. Whitsett, M.D.
Cincinnati Children’s Hospital Medical Center
Divisions of Neonatology and Pulmonary Biology
3333 Burnet Avenue
Cincinnati, OH

2. Burden of Disease Related to Pulmonary Immaturity in USA
4,000,000 Births
11% Preterm < 37 weeks 440,000
1.3% <1500g 52,000
0.75% <1 kg 32,000
66%RDS
24%BPD

3. Major Lung Diseases of the Premature
RDS - Surfactant deficiency
BPD - Injury/disrupted lung development/dysplastic repair

4. BPD Based on Birth Weight - NICHD Network - 2003
% Survivors with BPD
Weight Group (per 100gm)

7. Immunohistochemistry
Normal Pediatric Lung
Immunohistochemistry
SP-B
proSP-C
SP-B and SP-C are small hydrophobic proteins that enhance the surface tension lowering properties of surfactant lipids. Both of these proteins are initially synthesized as large, hydrophilic, precursor proteins, that are then proteolytically cleaved to their final, mature, hydrophobic forms. Immunolocalization has shown that SP-B and SP-C are components of lamellar bodies, the LB being the storage form of surfactant found in Type II cells.
SP-B and SP-C are synthesized in alveolar Type 2 cells.

10. Alveolar Structure

11. Surfactant Composition
chol PL PG PC
DPPC
protein
SP-B
SP-C
SP-A
SP-D
Surfactant is about 90% lipid by weight with carbohydrate and protein making up the balance. Most of the lipid is in the form of phospholipid (80% of total weight) with DPPC being the most abundant species.
DPPC can lower surface tension to very low levels and is the primary surface tension lowering component of surfactant (DPPC forms films that resist collapse at high surface pressures- 70mN/m); however, DPPC alone is a lousy surfactant because it adsorbs very poorly to the air-liquid interface and respreads very poorly following compression.
Rapid adsorption, film stability and respreading are properties of the other components of surfactant, principally unsaturated lipids and the protein components. Unsaturated lipids fluidize the film allowing for faster adsorption and respreading following compression.
Surfactant replacement mixtures consisting of lipids with either SP-B or SP-C are very effective treatments for RDS.
SP-B and SP-C make up 1-2% of surfactant.
Blue- free fatty acids
Brown- glycerides

13. Surfactant homeostasis
Alveolar macrophage
Signal for secretion is stretch which results in mobilization of intracellular Ca
Type II cell

14. Pathophysiology of RDS
Surfactant Treatment
Recycling
Surfactant Pool
Surfactant Function
Lung Development
Gestational Age
Prenatal Stress
Corticosteroids
Surfactant Inactivation
Leaky Epithelial and Endothelial Barriers
Severity of RDS
Pulmonary Edema
Lung Structure
Tissue Function

17. Measurements to Evaluate Surfactant Metabolism

18. Surfactant Concentration in Alveoli of Human Lung
Surfactant (mg/kg)
Alveolar Fluid (ml/kg)
Surfactant concentration (mg/ml)
Adult
Term newborn
Preterm newborn 4
Assume 100
0-10
0.4
Assume 0.4
? High
10 mg/ml
250 mg/ml? ?

19. Adapted from Mulrooney et al., AJRCCM, 2005

20. Appearance of Labeled Surfactant PC in Airway Samples
Data from Multiple Sources

21. Clearance of Labeled Surfactant PC from Airspaces
Data from Multiple Sources

22. Persistent Effects of Surfactant Depend on Metabolic Characteristics of Surfactant in the Preterm Lung

23. Surfactant Labeling and Secretion in Ventilated Infants with RDS (13C-glucose labeling of PC)

24. 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

25. Altered Lung Development and BPD Preterm Postnatal Lung
Pro- and Anti-inflammatory Influences on Preterm Lung
Chorioamnionitis Resuscitation Mechanical Oxygen Nosocomial Ventilation Infection
Altered Lung Development and BPD
Preterm Fetal Lung
Transitional Lung
Preterm Postnatal Lung Nn
Antenatal Corticosteroids Indomethacin Postnatal Corticosteroids
Anti-inflammatory