LUNG DEVELOPMENT OLEKSANDR KUDIN

STAGES OF DEVELOPMENT

¡  Embrionic period

¡  Pseudoglandular stage

¡  Canalicular stage

¡  Sacular and Alveolar stages

EMBRYONIC PERIOD

¡  2-7 weeks

¡  Appears as ventral bud to esophagus ~26 days

¡  Branches into two lungs at 33 days

¡  Lobar airways formed at 37 days

¡  Segmental airways at 42 days and subsegmental bronchi by 48 days

¡  Factors: Thyroid transcription factor-1, FGF-7, FGF-10, EGF. Fibronectin, Laminin, Collagen IV, PDGF.

PSEUDOGLANDULAR STAGE

¡  5-18 weeks

¡  15-20 generation of airway branching

¡  Epithelial development

¡  Growth of pulmonary vasculature

CANALICULAR STAGE

¡  16-25 weeks

¡  Previable lung Potentially viable lung

¡  Formation of acinus, Development of potential air-blood barrier, beginning of surfactant synthesis

SACCULAR AND ALVEOLAR STAGES

¡  24 weeks – term

¡  Further development of terminal sac

¡  Alveolarization ~32 weeks (at term 50-150 mln, continue to form well into adulthood)

MODULATORS OF ALVEOLARIZATION

¡  Negative effect

¡  Mechanical ventilation

¡  Ante- and postnatal corticosteroids

¡  Pro-inflammatory mediators

¡  Chorioamnionitis

¡  Hyperoxia or hypoxia

¡  Poor nutrition

¡  Positive ¡  Retinoids

¡  Thyroxin

FETAL LUNG FLUID

¡  Volume at term ~ 40 ml/kg

¡  Contains little protein

¡  Formation – active transport of Cl from interstitium into lumen

¡  Production rate 4-5 ml/kg/hr ~400 ml/day at term

¡  Some outflow into esophagus and some into amniotic fluid

¡  Both production and clearance important for lung development

PROTEINS OF SURFACTANT

¡  SP-A:

¡  Forms multimeric protein

¡  Serves as innate host defense protein and regulates inflammation

¡  Binds to pathogens, facilitates phagocytosis

SP-B: §  Contained in lamellar bodies §  Facilitates absorption of surface lipids and development of low surface tension

SP-C: §  Associated with lipids in lamellar bodies §  Deficiency Interstitial lung disease

SP-D: §  Host defense molecule §  Binds pathogens and facilitates their elimination

PRODUCTION OF SURFACTANT

¡  Type II cells

¡  Glucose, Ph, fatty acids – substrates for synthesis

¡  Lipoprotein complex condensed in lamellar bodies

¡  Stimulators of secretion:

¡  β-agonists

¡  ATP

¡  Mechanical stretch

SURFACTANT POOLS

¡  Term infant – 100 mg/kg. Preterm infants 5-10 mg/kg

¡  Infants with RDS normalize their surfactant pool by 4-5 days of life

¡  Secretion of surfactant takes longer than synthesis

¡  Half life of surfactant – few days

¡  90% of phospholipids are recycled in neonates (Adults ~50%)

SURFACTANT POOLS AFTER EXOGENOUS ADMINISTRATION

¡  Increases both alveolar and tissue pools

¡  Function of administered surfactant improves within hours (transformation by lung)

¡  No feedback inhibition of native surfactant production

¡  Slow catabolic rate

SURFACTANT IN ALVEOLI

¡  Lamellar bodies Tubular myelin(reserve pool)

¡  New surfactant is squeezed out of this structure

¡  Old surfactant forms small vesicles that are cleared from airways

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