Lung mechanics, airway reactivity, and muscularization are altered in former mechanically ventilated preterm lambs

Background: Ventilated preterm infants may have respiratory morbidities early in life and later at school age and adulthood (Clemm HH, 2014). Modeling with large animals is needed to identify mechanisms Aim: Use a new former preterm (FPT) lamb model to evaluate lung mechanics, airway reactivity, and airway smooth muscle (ASM) thickness. Methods: 6 preterm lambs (128d; term ~150d; ~28w gestation in humans) were resuscitated and supported by mechanical ventilation for 3-6d before weaning from respiratory support (FPT lambs). They lived for ~6m (~5m corrected postnatal age; ≈6y in humans). Control lambs (n=20), born at term, lived 5m. We measured respiratory mechanics monthly by forced oscillation technique (FOT; 11Hz) and airway reactivity by changes in FOT variables after increased doses of nebulized methacholine (MCh; 0.06-4.00 mg; ATS guideline, 1999). We used quantitative histology to measure ASM thickness in terminal bronchioles. Results: FPT lambs had increased airway reactivity during the first 2m of life (figure). ASM thickness was significantly greater in FPT lambs (6.7±1.1vs 3.1±0.5 mm control lambs). Conclusions: The new FPT lamb model recapitulates altered lung mechanics and airway reactivity in FPT humans. Interestingly, airway muscularization persists at 5m when lung mechanics and airway reactivity are no longer impaired. This model provides opportunity to identify pathogenic mechanisms.