Relative contribution of biophysical, oxidative, and inflammatory pathways in the disruption of lung matrix during mechanical ventilation in models of neonatal respiratory distress

Preterm birth is complicated by a number of deficiencies that threaten survival. Life can be sustained in neonates born from around twenty-five weeks on, but at this young gestational age RDS due to surfactant deficiency is eminent and subsequently there is often a need for mechanical ventilation. Mechanical ventilation of preterm infants can result in ventilator induced lung injury (VILI) which often progresses to a chronic disease.;The mechanisms by which conventional mechanical ventilation (CMV) strategies contribute to VILI are three fold; biophysical and oxidative trauma as primary results from respiratory interventions, and inflammatory derived trauma as a secondary response to the respiratory interventions. Ultimately, these forms of trauma may potentially be responsible for interfering with the signaling pathways which guide lung structural development. The overall objective for this project was to identify the relative contribution of these three traumatic pathways on generating injury in the ventilated preterm lung. With the use of three potential respiratory therapies administered to animal models of acute lung injury and neonatal RDS, this study assessed the affects of down regulating proposed pathways to lung injury on parameters indicative of lung structure disruption. Reduction of biophysical trauma by means of perfluorochemical tidal liquid ventilation (PFC TLV) resulted in a much more homogeneous expansion of the lung and thus a more uniform stimulus for matrix protease expression. Reducing oxidative trauma by administration of rhSOD therapy did not provide conclusive evidence that the down regulation of oxidant injury would minimize structural disruption. Attenuating inflammation via rhCC10 augmented surfactant therapy showed a maintenance of lung function and mechanics with a dose of at least 5 mg•kg−1 and provided for a modest improvement in matrix protease profile. This supports the hypothesis that a reduced inflammatory response would foster a preservation of lung structure. In conclusion, down regulating both biophysical and inflammatory pathways to lung injury play significant roles in the maintenance of lung structure. Therapies aimed at addressing these pathways hold the potential to effect long term modeling alterations associated with the development of chronic disease.