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Updated: Nov 6, 2025
Assessment of Respiratory Function in Conscious Mice by Double-chamber Plethysmography
Published on: July 10, 2018
Calcium-sensing receptor and CPAP-induced neonatal airway hyperreactivity in mice
Catherine A Mayer1, Benjamin Roos2,3, Jacob Teske2,3
1Department of Pediatrics, Division of Neonatology, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
Insights
Continuous positive airway pressure (CPAP) may increase airway reactivity in infants by affecting the calcium-sensing receptor (CaSR). This finding suggests a link between CPAP use and wheezing disorders in former preterm infants.
Area of Science:
- Neonatal respiratory support
- Airway smooth muscle physiology
- Extracellular receptor signaling
Background:
- Continuous positive airway pressure (CPAP) is vital for preterm infants but may have long-term airway consequences.
- Animal models suggest CPAP can lead to detrimental airway effects, potentially contributing to asthma development.
- The role of the extracellular calcium-sensing receptor (CaSR) in these CPAP-induced airway changes is not well understood.
Purpose of the Study:
- To investigate the role of CaSR in the airway effects of neonatal CPAP.
- To examine how CPAP influences airway reactivity and CaSR expression in a mouse model.
- To analyze the impact of CPAP on human fetal airway smooth muscle cells and CaSR signaling.
Main Methods:
- Utilized a neonatal CPAP mouse model and human fetal airway smooth muscle (ASM) cells.
- Administered CPAP to wild-type and CaSR-deficient mice, followed by airway reactivity testing.
- Investigated CaSR inhibition and knockdown effects, and analyzed intracellular calcium ([Ca2+]i) responses and signaling cascades in ASM cells.
Main Results:
- CPAP increased airway reactivity in wild-type mice but not in CaSR-deficient mice.
- CPAP administration led to increased ASM CaSR expression, which was reversed by CaSR inhibition or knockdown.
- CPAP elevated intracellular calcium in fetal ASM cells, activating ERK1/2 and RhoA signaling pathways.
Conclusions:
- The extracellular calcium-sensing receptor (CaSR) plays a significant role in mediating the airway effects of neonatal CPAP.
- These findings implicate CaSR in CPAP-induced airway hyperresponsiveness and suggest a mechanism for wheezing disorders in former preterm infants.
- Targeting CaSR may offer a therapeutic strategy to mitigate long-term airway complications associated with CPAP treatment.
Background:
Continuous positive airway pressure (CPAP) in preterm infants is initially beneficial, but animal models suggest longer term detrimental airway effects towards asthma. We used a neonatal CPAP mouse model and human fetal airway smooth muscle (ASM) to investigate the role of extracellular calcium-sensing receptor (CaSR) in these effects.
Methods:
Newborn wild type and smooth muscle-specific CaSR-/- mice were given CPAP for 7 days via a custom device (mimicking CPAP in premature infants), and recovered in normoxia for another 14 days (representing infants at 3-4 years). Airway reactivity was tested using lung slices, and airway CaSR quantified. Role of CaSR was tested using NPS2143 (inhibitor) or siRNA in WT mice. Fetal ASM cells stretched cyclically with/without static stretch mimicking breathing and CPAP were analyzed for intracellular Ca2+ ([Ca2+]i) responses, role of CaSR, and signaling cascades.
Results:
CPAP increased airway reactivity in WT but not CaSR-/- mice, increasing ASM CaSR. NPS2143 or CaSR siRNA reversed CPAP effects in WT mice. CPAP increased fetal ASM [Ca2+]I, blocked by NPS2143, and increased ERK1/2 and RhoA suggesting two mechanisms by which stretch increases CaSR.
Conclusions:
These data implicate CaSR in CPAP effects on airway function with implications for wheezing in former preterm infants.
Impact:
Neonatal CPAP increases airway reactivity to bronchoconstrictor agonist. CPAP increases smooth muscle expression of the extracellular calcium-sensing receptor (CaSR). Inhibition or absence of CaSR blunts CPAP effects on contractility. These data suggest a causal/contributory role for CaSR in stretch effects on the developing airway. These data may impact clinical recognition of the ways that CPAP may contribute to wheezing disorders of former preterm infants.
