Intratracheal budesonide/surfactant attenuates hyperoxia-induced lung injury in preterm rabbits

Abstract

Recent clinical trials have shown improvements in neonatal outcomes after intratracheal administration of combination budesonide/surfactant (ITBS)in infants at risk of bronchopulmonary dysplasia. However, the effect of ITBSon lung function and alveolar structure is not known. We aimed to determine the effect of ITBSon lung function, parenchymal structure and inflammatory cytokine expression in a relevant preterm animal model for bronchopulmonary dysplasia. Premature neonatal rabbits were administered a single dose of ITBSon the day of delivery and exposed to 95% oxygen. Following seven days of hyperoxia,in vivoforced oscillation and pressure-volume maneuvers were performed to examine pulmonary function. Histological and molecular analysis was performed to assess alveolar and extracellular matrix (ECM) morphology, along with gene expression of connective tissue growth factor (CTGF), IL-8 and CCL-2. ITBS attenuated the functional effect of hyperoxia-induced lung injury and limited the change to respiratory system impedance, measured using the forced oscillation technique. Treatment effects were most obvious in the small airways, with significant effects on small airway resistance and reactance. Additionally, ITBS mitigated the decrease of inspiratory capacity and static compliance. ITBS restricted alveolar septal thickening without altering the mean linear intercept and mitigated hyperoxia-induced remodeling of the ECM. These structural changes were associated with improved inspiratory capacity and lung compliance. Gene expression of CTGF IL-8 and CCL-2 were significantly down regulated in the lung. Treatment with ITBS shortly after delivery attenuated the functional and structural consequences of hyperoxia-induced lung injury to day 7 of life in the preterm rabbit.

Efficacy of Intratracheal Budesonide-Surfactant Combined Therapy in Surfactant-Insufficient Rat Lungs with Lipopolysaccharide Insult

“…30,31 Given the diverse etiology of PARDS, 5,7 several animal studies have investigated the efficacy of using a surfactant as a vehicle for intratracheal steroids in reducing ALI in animal models of surfactant-depleted lung diseases, 23,25 MAS, 26 hyperoxia 27 , and injurious mechanical ventilation. 28,29 Regardless of the type of insult to induce ALI, these studies reported that intratracheal instillation of steroid-surfactant combination can alleviate ALI 23,[25][26][27][28][29] and reduce lung inflammation. 23,[26][27][28] Our model is a type of ALI in surfactant-insufficiency lungs, particularly with lung inflammation induced by LPS.…”

“…28,29 Regardless of the type of insult to induce ALI, these studies reported that intratracheal instillation of steroid-surfactant combination can alleviate ALI 23,[25][26][27][28][29] and reduce lung inflammation. 23,[26][27][28] Our model is a type of ALI in surfactant-insufficiency lungs, particularly with lung inflammation induced by LPS. Our results demonstrated for the first time that intratracheal steroid-surfactant therapy is promising in this particular setting.…”

Recent advances in understanding NARDS, and the effect of the budesonide on the prevention of NARDS

“…52,53 It has been reported that intratracheal administration of budesonide with PS on the day of birth limited hyperoxia-associated disruption of lung function and structure in preterm rabbits. 54 In an observational study of 2 premature infants diagnosed with ARDS and receiving ventilator-assisted ventilation, Burak Deliloglu et al found that intratracheal administration of budesonide with PS can effectively improve pulmonary ventilation function and oxygenation index. 27 In a case-control study, T. Brett Kothe et al found that compared with the use of PS alone, the intratracheal administration of budesonide with PS can shorten the duration of mechanical ventilation.…”

The Miracles of Surfactant: Less Invasive Surfactant Administration, Nebulization, and Carrier of Topical Drugs

“…Biophysical and chemical stability of surfactant/ budesonide has been evaluated in a number of experimental studies confirming pulmonary and systemic antiinflammatory effects of this strategy in adult rabbits [95], mechanically ventilated preterm lambs [96], and rats [97]. In preterm neonatal rabbits, the combined administration attenuated hyperoxia-induced lung injury [98]. Moreover, pulmonary distribution of 2 natural surfactant preparations was recently tested, and both were shown to be effective vehicles for budesonide delivery [99].…”