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.