4 | DISCUSSION
In this study, we investigated the therapeutic effect of BUD intratracheally delivered by two (diluted and full strength) concentrations of exogenous surfactant on the ALI in a rat model. The ALI in our model was established by repeated saline lavage, to produce surfactant insufficiency, followed by an intratracheal LPS insult. Our results demonstrated that intratracheal treatments with full-strength surfactant with or without BUD improved post-injury deteriorations of cardiopulmonary variables. Additionally, intratracheal treatments with surfactant (both concentrations) with or without BUD alleviated ALI, with IT-FS-BUD being the most effective treatment, as evidenced by our data of lung injury scores. Furthermore, intratracheal treatments with BUD delivered by normal saline or surfactant (both concentrations) ameliorated lung inflammation, with IT-FS-BUD being the most effective treatment, as evidenced by our data of immunohistochemical analysis. Collectively, among our therapeutic strategies, intratracheal BUD delivered by full-strength surfactant conferred the optimal protection against LPS-induced ALI in surfactant-insufficiency rat lungs.
Preterm infants may concurrently have surfactant deficiency and Gram-negative bacterial infections of the lungs, which are major causes of PARDS.4,5,7 To avoid the side effects of systemic steroid,10-12 several investigators advocated the use of intratracheal steroid for the treatment of ALI or PARDS.13-18 However, surfactant deficiency may lead to alveolar collapse and diffuse lung atelectasis, 7,19which hinders the uniform distribution of drug within the lungs and reduces the efficacy of local steroid treatment. Surfactant is a surface tension-lowering agent that has been widely used to treat surfactant-deficiency lung diseases or PARDS.8,19 When instilled into the trachea, the surfactant may spread throughout the lungs, driven by the surface tension gradient.20 For this reason, surfactant has been proposed as a vehicle for intratracheal steroid administration.20 This notion is supported by the stable biophysical and chemical properties of the surfactant/steroid mixtures under ex vivo condition21-23 and enhanced pulmonary distribution of steroid in vivo when using a surfactant as the vehicle.21-24 In our study, IT-FS provided certain benefits against ALI but was ineffective in reducing lung inflammation. On the other hand, IT-NS-BUD was ineffective in alleviating ALI but had a slight effect on the reduction of lung inflammation. Our findings regarding the superiority of IT-FS-BUD combined therapy in alleviating ALI and lung inflammation in our model provide a strong evidence for using full-strength surfactant as a vehicle for intratracheal steroid therapy.
The use of surfactant as a vehicle to deliver steroids to the lungs of premature infants has been the subject of increasing clinical interest.20 Several clinical studies have investigated the efficacy of this steroid delivery mode in preventing BPD32 and chronic respiratory diseases33 or in treating neonatal ARDS34,35 in premature infants. Two recent meta-analysis studies reported that intratracheal instillation of steroid‐surfactant combination was an effective therapy for preventing BPD in preterm infants with neonatal ARDS, but its benefit in reducing mortality was inconsistent.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,23,25MAS,26 hyperoxia27, 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 ALI23,25-29 and reduce lung inflammation.23,26-28 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.
This study exhibited several limitations. First, we did not use preterm rats as our animal model for lung surfactant deficiency because preterm rats have a high mortality rate in response to the insult of LPS when they are mechanically ventilated. Second, our observation period was 4 h, and thus, we cannot be certain about the changes that might have occurred after that time. Third, the concentration of BUD in the systemic circulation was not measured, and thus, further studies targeting this topic are required.
In conclusion, intratracheal BUD delivered by full-strength surfactant effectively alleviates ALI and lung inflammation in surfactant-insufficiency rat lungs with LPS insult. This intratracheal steroid-surfactant treatment may be considered a potential therapy for preterm infants with Gram-negative bacteria lung infections.