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 45229-3039

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

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

BPD Based on Birth Weight - NICHD Network - 2003 0 20 40 60 80 % Survivors with BPD Weight Group (per 100gm)

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.

Alveolar Structure

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

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

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

Measurements to Evaluate Surfactant Metabolism

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? ?

Adapted from Mulrooney et al., AJRCCM, 2005

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

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)

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

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