1 | INTRODUCTION
Pediatric pneumonia is a major cause of mortality and morbidity in children under 5 years old, especially in developing countries.1,2 Among the cases of pediatric pneumonia, 21.7% occur during the neonatal stage.3 Preterm infants who have pneumonia may develop acute lung injury (ALI) and its severe form—acute respiratory distress syndrome (ARDS).4,5 One major presentation of this form of ALI is lung inflammation mainly induced by lipopolysaccharide (LPS), a major pathogenic component of Gram-negative bacilli.6 In particular, the inflammatory effect of the LPS insult accompanies the injurious impact of surfactant deficiency in the lungs, a situation that generally occurs in preterm infants.7,8 Thus, surfactant deficiency and the lack of ability to cope with inflammation are the major disadvantages of these infants against LPS-induced ALI.4,5,7,8 The therapy options for ALI or pediatric ARDS (PARDS) in this vulnerable population are currently limited.5,9 Thus, investigations of effective therapeutic strategies to alleviate LPS-induced ALI in surfactant-insufficiency lungs are warranted.
Steroid has been long considered a classical therapy for neonatal ARDS due to its anti-inflammatory effect; however, the side effects of systemic steroids remain a major concern.10-12 For the prevention of side effects, several animal or clinical studies used intratracheal instillation13,14 or inhalation15-18 of steroids for the treatment of meconium aspiration syndrome (MAS) or prevention of bronchopulmonary dysplasia (BPD) and other respiratory morbidities. However, the local treatment with steroids remains challenging particularly in surfactant-deficiency lungs with alveolar collapse and diffuse atelectasis, which is a common problem in preterm infants7,19. To this end, intratracheal administration of surfactant is an effective treatment for surfactant-deficiency lung diseases or PARDS.19,20 Additionally, growing evidence suggests that surfactants can be used as a vehicle for intratracheal steroid administration.20 This delivery mode distributes the steroid well in the lungs without changing the biophysical and chemical properties of the drug.21-24In animal studies, this steroid delivery mode has been used to investigate its efficacy in reducing ALI in animal models of surfactant-depleted lung diseases,23,25MAS,26 hyperoxia27, and injurious mechanical ventilation.28,29 In clinical studies, this steroid delivery mode has been used to prevent BPD30-32 and chronic diseases33 or to treat neonatal ARDS34,35 in premature infants. However, no study has been conducted to investigate the therapeutic effect of this steroid delivery approach on LPS-induced ALI in surfactant-insufficiency lungs.
This study aimed to investigate the therapeutic effects of intratracheally instilled budesonide (BUD) delivered by two concentrations of exogenous surfactant on LPS-induced ALI in surfactant-insufficiency rat lungs. Our ALI model was established by repeated saline lavage to produce surfactant insufficiency, followed by an intratracheal LPS insult.