Small Molecule Inhibitor Adjuvant Surfactant Therapy Attenuates Ventilator- and Hyperoxia-Induced Lung Injury in...

Area of Science:

• Neonatal research
• Pulmonary medicine
• Pharmacology

Background:

• Invasive mechanical ventilation (IMV) is crucial for premature infant survival but can cause lung inflammation and injury.
• Small molecule inhibitors (siRNAs, miRNAs) are emerging therapeutics for lung injury.
• CHOP, Ang2, and miR34a are upregulated in experimental lung injury models.

Purpose of the Study:

• To evaluate the efficacy of CHOP siRNA, Ang2 siRNA, and miR34a antagomir as treatments for ventilation and hyperoxia-induced lung injury.
• To determine if surfactant (Curosurf®) can serve as an effective vehicle for delivering these small molecule inhibitors.
• To assess the adjuvant effects of surfactant combined with small molecule inhibitors.

Main Methods:

• Preterm rabbits underwent intratracheal instillation of small molecule inhibitors with or without Curosurf® before IMV and hyperoxia.
• Proof-of-concept studies involved transfecting inhibitors into mouse lung cells and intranasal delivery to neonatal mice.
• Outcomes measured included survival, pulmonary function, histopathology, and molecular markers.

Main Results:

• Curosurf® effectively facilitated small molecule transfection in lung cells, comparable to Lipofectamine.
• Surfactant, alone or with inhibitors, improved survival rates in preterm rabbits.
• Combined therapy reduced inflammation, improved pulmonary function, and decreased lung injury scores.

Conclusions:

• Curosurf® is a successful adjuvant for delivering small molecule inhibitors (CHOP/Ang2/miR34a) in treating lung injury.
• The miR34a inhibitor demonstrated the most significant potential in mitigating ventilation and hyperoxia-induced lung injury.