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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.

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 Pco2levels (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.