Interleukin-37 Attenuates Lipopolysaccharide (LPS)-Induced Neonatal Acute Respiratory Distress Syndrome in Young Mice via Inhibition of Inflammation and Cell Apoptosis.

BACKGROUND Neonatal acute respiratory distress syndrome (ARDS) is a common clinical syndrome caused by lung immaturity and the abnormal synthesis of pulmonary surfactant in preterm newborns, and it has high morbidity and mortality rates. The present study investigated the roles of interleukin-37 (IL-37) in the pathogenesis of neonatal ARDS and the underlying biochemical mechanism. MATERIAL AND METHODS We used 6-day-old neonatal C57BL/6 mice to establish the ARDS model. Inflammatory cytokines levels were measured with enzyme-linked immunosorbent assay (ELISA) Kits. The pathological morphology of lung tissues was observed by hematoxylin-eosin (HE) staining. The expression levels of proteins were assessed by Western blotting and apoptotic cells were detected via TUNEL assay. Further, the expression of nucleotide-bound oligomerization domain (Nod)-like receptor P3 (NLRP3) was detected with immunohistochemistry and Western blotting. RESULTS IL-37 attenuated lipopolysaccharide (LPS)-induced cell apoptosis and excessive inflammatory cytokines levels, including IL-1ß, IL-8, TNF-alpha, and MCP-1, and ameliorated lung pathological manifestations in an LPS-induced neonatal ARDS model. Moreover, IL-37 suppressed the abnormal expression of proteins related to the CXCR4/SDF-1 chemokine axis and NLRP3 inflammasome pathway. CONCLUSIONS The present results suggest that IL-37 protect against LPS-induced lung injury through inhibition of inflammation and apoptosis in lung tissue in an LPS-induced neonatal ARDS model. Hence, IL-37 may be considered as a potential therapeutic agent for neonatal ARDS.

Safety and pharmacokinetics of recombinant human superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVE: As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied. METHODS: Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period. RESULTS: Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups. CONCLUSIONS: Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.