Adverse Effects of Neonatal CPAP on Lung Development

Supplemental O2 therapy and non-invasive ventilation such as continuous positive pressure support (CPAP) are two common life-saving modalities of respiratory care for the treatment of preterm infants with respiratory distress. However, most methods of respiratory care contribute to major life-long unintended consequences such as airway hyperreactivity (AHR) disorders associated with wheezing and asthma. Supplemental O2 therapy and invasive mechanical ventilation have long been recognized as primary contributors to the pathogenesis of wheezing in former preterm infants – these observations have driven efforts to titrate and minimize the usage of O2 in the NICU setting while favoring the use of non-invasive positive pressure support such as CPAP. As a result, there is a growing number of preterm infants who receive CPAP and many without supplemental O2. Although CPAP is on the gentler end of the spectrum of positive pressure modalities, know very little is known about its effects on lung development. Emerging clinical evidence, however, implicates CPAP in poor respiratory outcomes associated with restrictions in airflow and also wheezing in former preterm infants into childhood. We have corroborated these findings using a novel mouse model of neonatal CPAP which is sufficient, without hyperoxia exposure, to elicit AHR via a mechanism involving airway smooth muscle proliferation – a phenotype functionally analogous to that seen with neonatal supplemental O2. We have also demonstrated a role of airway smooth muscle (ASM) proliferation, Ca2+ signaling, and the extracellular matrix, specifically low molecular weight hyaluronan (HALMW) in CPAP effects. Together with the limited clinical data, these observations are at the forefront of identifying the potential adverse effects of CPAP and how it could be a significant contributor to poor respiratory system development seen in former preterm infants. In this application, we utilize the same in vivo mouse (CPAP) model, complemented with a human fetal ASM (fASM) in vitro stretch model which mimics CPAP, to test the overall hypotheses that stretch-induced effects on ASM proliferation and hyperreactivity are initiated by multiple mechanosensitive pathways involving: 1) the newly identified piezo (PZ) family of mechanosensors; 2) extracellular matrix and stretch sensitive HALMW; and 3) plasma membrane caveolae. A novel feature of this proposal is the identification of an apparent feedforward mechanism by all three pathways, while distinctly different, converge and reinforce each other’s effects to cause the persistent AHR. Therefore, this proposal will reveal novel mechanosensitive pathways as a primary mechanistic feature of the unintended consequences of CPAP on airway hyperreactivity, with will be crucial in guiding the clinical care of preterm infants in a way that minimizes the adverse effects of these respiratory interventions and maximizing their benefits. Project Number: 1R01HL177837-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Peter MacFarlane (+1 co-PI) | Institution: CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OH | Award Amount: $740,196 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-M (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17783701