Antioxidant Intervention Combined With Inhaled Nitric Oxide In Acute Lung Injury Of Infant Rats Following Meconium Aspiration

BackgroundMeconium aspiration syndrome (MAS) remains a principal cause of morbility and mortality in both term and post-term infants. The pathogenesis of severe acute lung injury (ALI) following meconium aspiration is similar to acute respiratory distress syndrome (ARDS). The pathophysiology of ALI following meconium aspiration is very complex, including early mechanical obstruction of the airways, surfactant inactivation, ventilation / perfusion mismatch and progressively developing lung injury with areas of atelectasis and respiratory failure, PPHN or even death. ALI following meconium aspiration is also characterized by rapidly developing pulmonary inflammation with influx of activated polymorphonuclear cells. A recent in vivo study indicated that moderate and high concentrations of aspirated meconium rapidly activate circulating neutrophils with a resulting oxidative burst contributing to pulmonary tissue injury. Little is known of the effects of antioxidants on the oxidative lung injury of ALI with meconium aspiration.Inhaled nitric oxide (iNO) or pulmonary surfactant (Surf) substitutesare remarkably successful in treating respiratory distress syndrome (RDS) of premature infants, a disease characterized by a deficiency of Surf. Multi-center, randomized trials have shown that iNO or Surf substitutes improve oxygenation and decrease the need for extracorporeal membrane oxygenation (ECMO) in infants with PPHN. However, effects of these therapies are less dramatic when they are used to treat ALI following meconium aspiration because of its complicated pathogenesis. Additional research of the mechanism involved in the pathogenesis and treatment of ALI following meconium aspiration is likely to improve the efficacy of treatment with iNO or Surf.Superoxide dismutases (SODs) are ubiquitous antioxidant enzymes that have been shown in several animal studies to have a role in reducing lung injury caused by exposure to endotoxin, hyperoxia and mechanical ventilation. Previous studies showed that a single intratracheal (IT) dose of recombinant human superoxide dismutase (rhSOD) is well tolerated with significantly increase SOD concentrations and activity in serum, tracheal aspirates and urine within 3 days in premature infants with RDS. Until now, few studies have been reported on the effects of rhSOD on lung injury caused by meconium aspiration. We hypothesized that. IT rhSOD will have antioxidantive and anti-inflammatory effects on ALI with meconium aspiration by an increase SOD concentration and activity.In addition to the effects of selective pulmonary vascular relaxion and potential anti-inflammation, inhaled NO can rapidly combine with superoxide to form the potent oxidant peroxynitrite (ONOO"), which is a highly oxidative species that is capable of nitrating tyrosine residues of numerous proteins, leading to the formation of nitrotyrosine that may result in protein inactivation. By scavenging superoxide, SOD may increase the bioability of iNO while simultaneously reducing ONOO" formation. Potential toxicities of NO and its higher oxides indicate theneed for designing the therapeutic strategies that will allow delivery of the lowest effective iNO concentration. In 2001, Steinhorn reported that IT rhSOD enhanced the effect of inhaled nitric oxide in persistent pulmonary hypertension. On the other hand, Surf as a vehicle may significantly increases uptake and airspace deposition of IT rhSOD. It was reported that antioxidant-surfactant liposomes mitigated hyperoxic lung injury in premature rabbits. In our present studies, we established an infant rat model of ALI following meconium aspiration and examined the effects of a single IT 5-20mg/kg rhSOD alone and 20mg/kg rhSOD combined with 20ppm iNO or 50 mg/kg curosurf. The BAL cell count, pulmonary MPO and SOD activity, formation of pulmonary MDA, endogenous NO (N02-/N03-) and nitrotyrosine, expression of pulmonary IL-1 and MIP-1 mRNA, expression of pulmonary iNOS and SOD protein were all measured to observe the possible pathogenesis of ALI f...