Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia remain the leading causes of preterm infant morbidity, mortality, and lifelong disability. Research to improve outcomes requires translational large animal models for RDS. Preterm pigs delivered by caesarian section at gestation days (GD) 98, 100, 102, and 104 were provided 24 h of neonatal intensive care, monitoring (pulse oximetry, blood gases, serum biomarkers, radiography), and nutritional support, with or without intubation and mechanical ventilation (MV; pressure control ventilation with volume guarantee). Spontaneous development of RDS and mortality without MV are inversely related with GD at delivery and correspond with inadequacy of tidal volume and gas exchange. GD 98 and 100 pigs have consolidated lungs, immature alveolar architecture, and minimal surfactant protein-B expression, and MV is essential at GD 98. Although GD 102 pigs had some alveoli lined by pneumocytes and surfactant was released in response to MV, blood gases and radiography revealed limited recruitment 1-2 h after delivery, and mortality at 24 h was 66% (35/53) with supplemental oxygen provided by a mask and 69% (9/13) with bubble continuous positive airway pressure (8-9 cmH2O). The lungs at GD 104 had higher densities of thin-walled alveoli that secreted surfactant, and MV was not essential. Between GD 98 and 102, preterm pigs have ventilation inadequacies and risks of RDS that mimic those of preterm infants born during the saccular phase of lung development, are compatible with standards of neonatal intensive care, and are alternative to fetal nonhuman primates and lambs.
A translational preterm pig model analogous to infants born at 28 wk of gestation revealed that continuous positive airway pressure results in limited lung recruitment but does not prevent respiratory distress syndrome, whereas assist-control + volume guarantee (AC+VG) ventilation improves recruitment but can cause injury, highlighting the need for improved ventilation strategies. We determined whether airway pressure release ventilation (APRV) can be used to recruit the immature lungs of preterm pigs without injury. Spontaneously breathing pigs delivered at 89% of term (model for 28-wk infants) were randomized to 24 h of APRV (n = 9) vs. AC+VG with a tidal volume of 5 ml/kg (n = 10). Control pigs (n = 36) were provided with supplemental oxygen by an open mask. Nutrition and fluid support was provided throughout the 24-h period. All pigs supported with APRV and AC+VG survived 24 h, compared with 62% of control pigs. APRV resulted in improved lung volume recruitment compared with AC+VG based on radiographs, lower Pco2 levels (44 ± 2.9 vs. 53 ± 2.7 mmHg, P = 0.009) and lower inspired oxygen fraction requirements (36 ± 6 vs. 44 ± 11%, P < 0.001), and higher oxygenation index (5.1 ± 1.5 vs. 2.9 ± 1.1, P = 0.001). There were no differences between APRV and AC+VG pigs for heart rate, ratio of wet to dry lung mass, proinflammatory cytokines, or histopathological markers of lung injury. Lung protective ventilation with APRV improved recruitment of alveoli of preterm lungs, enhanced development and maintenance of functional residual capacity without injury, and improved clinical outcomes relative to AC+VG. Long-term consequences of lung volume recruitment by using APRV should be evaluated.
Bronchopulmonary dysplasia (BPD) is a devastating disease of prematurity that is associated with mechanical ventilation and hyperoxia. We used preterm pigs delivered at gestational day 102 as a translational model for 26–28-week infants to test the hypothesis administering recombinant human keratinocyte growth factor (rhKGF) at initiation of mechanical ventilation will stimulate type II cell proliferation and surfactant production, mitigate ventilator induced lung injury, and reduce epithelial to mesenchymal transition considered as a precursor to BPD. Newborn preterm pigs were intubated and randomized to receive intratracheal rhKGF (20 μg/kg; n = 6) or saline (0.5 ml 0.9% saline; control; n = 6) before initiating 24 h of ventilation followed by extubation to nasal oxygen for 12 h before euthanasia and collection of lungs for histopathology and immunohistochemistry to assess expression of surfactant protein B and markers of epithelial to mesenchymal transition. rhKGF pigs required less oxygen during mechanical ventilation, had higher tidal volumes at similar peak pressures indicative of improved lung compliance, and survival was higher after extubation (83% vs. 16%). rhKGF increased surfactant protein B expression (p < 0.05) and reduced TGF-1β (p < 0.05), that inhibits surfactant production and is a prominent marker for epithelial to mesenchymal transition. Our findings suggest intratracheal administration of rhKGF at initiation of mechanical ventilation enhances surfactant production, reduces ventilator induced lung injury, and attenuates epithelial-mesenchymal transition while improving pulmonary functions. rhKGF is a potential therapeutic strategy to mitigate pulmonary responses of preterm infants that require mechanical ventilation and thereby reduce the incidence and severity of bronchopulmonary dysplasia.
Background: Bronchopulmonary dysplasia is a devastating disease of the premature newborn with high morbidity and mortality. Surfactant deficient preterm lungs are susceptible to ventilator induced lung injury, thereby developing bronchopulmonary dysplasia. Despite surfactant therapy and newer ventilation strategies, associated morbidity and mortality remains unchanged. Enhancing surfactant production and reducing ventilator induced lung injury in premature infants are critical. Recombinant keratinocyte growth factor previously been studied to treat adult respiratory distress syndrome. We hypothesized that administering recombinant human keratinocyte growth factor when initiating mechanical ventilation would help stimulate type II cell proliferation and surfactant production. Recombinant human keratinocyte growth factor may also help mitigate ventilator induced lung injury hereby reducing epithelial to mesenchymal transition, a possible precursor to later development of bronchopulmonary dysplasia. Methods: To test our hypothesis, we delivered preterm pigs via cesarean section on day 102. We performed intubation and ventilation for 24 hr. using intermittent positive pressure ventilation. After ventilation began, pigs randomly received intratracheal recombinant human keratinocyte growth factor (20 µg/kg; n=6) or sham treatment (0.5 ml 0.9% saline; n= 6). We recorded physiology data and arterial blood gases during ventilation. After 24 hr. pigs were extubated and received oxygen via nasal cannulation 12 hr. before euthanasia to collect lungs for histopathology and immunohistochemistry. Immunohistochemistry staining was graded and analyzed for surfactant protein B and epithelial to mesenchymal transition markers. Data were analyzed using t-test and Fisher’s exact test. Continuous variables analyzed using ANOVA.Results: Compared with control pigs, recombinant human keratinocyte growth factor pretreated pigs had improved ventilation with higher tidal volumes and required less oxygen (FiO2) during mechanical ventilation for similar peak pressures demonstrating improved lung compliance. Recombinant human keratinocyte growth factor pretreated pig lungs showed increased surfactant protein B expression (p< 0.05) and significantly reduced TGF-β (p< 0.05), a prominent marker for epithelial to mesenchymal transition.Conclusions: Intratracheal recombinant human keratinocyte growth factor administered at initiation of mechanical ventilation enhances surfactant production, reduce lung injury by mitigation of the changes by epithelial mesenchymal transition, thereby improving outcomes. Thus, recombinant human keratinocyte growth factor may represent a potential therapeutic strategy to prevent bronchopulmonary dysplasia.
Respiratory distresssyndrome and the more severe sequel bronchopulmonary dysplasia remain the leading causes of morbidity, mortality, and lifelong disability after preterm birth, with inadequate surfactant secretion a key contributor. We present the preterm pig as a translational model for lung disease after preterm birth. Preterm pigs were delivered by caesarian section at gestation days (GD) 98, 100, 102,and 104 (comparable to human fetuses delivered at 25, 28, 30, and 32 wks) and were provided intensive care following newborn neonatal intensive care procedures, including mechanical ventilation (MV) or supplemental oxygen and nutritional support. Expression of Surfactant Protein B (SP‐B),a surfactant‐associated protein absolutely required for postnatal lung function, was determined by western analysis using lung tissue harvested 24 h after delivery or earlier for pigs that became moribund. Pigs delivered at GD 98 and 100, had low SP‐B and MV is required for survival. SP‐B increases with gestational age. Moreover, provision of MV to preterm piglets delivered at GD 102 causes a dramatic increase in SP‐B expression and suggests MV can induce SP‐B secretion and reduce dependency on surfactant administration.Based on SP‐B expression, lung histology and pathology, and the responses to MV, the preterm pig is a translational large animal model for studying acute lung disease after preterm birth and for preclinical trials to evaluate interventions and improve MV protocols. The large litters of pigs reduce the numbers of pregnant animals needed, the attributes of the preterm pig allow investigators to refine experimental approaches, and the preterm pig replaces the baboon as a large animal model to study acute lung disease and injury after preterm birth.
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