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DISEASES OF ALVEOLAR HOMEOSTASIS: RDS and BPD

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

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DISEASES OF ALVEOLAR HOMEOSTASIS: RDS and BPD

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  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 45229-3039

  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 0 20 40 60 80 Weight Group (per 100gm)

  5. Normal Pediatric Lung Immunohistochemistry SP-B proSP-C SP-B and SP-C are synthesized in alveolar Type 2 cells.

  6. Alveolar Structure

  7. PL PG chol protein PC DPPC Surfactant Composition • SP-B • SP-C • SP-A • SP-D

  8. Alveolar macrophage Surfactant homeostasis Type II cell

  9. 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

  10. Measurements to Evaluate Surfactant Metabolism

  11. Surfactant Concentration in Alveoli of Human Lung

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

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

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

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

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

  17. 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

  18. 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

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