a-mouse-model-neonatal-continuous-positive-airway-pressure

A Mouse Model of Neonatal Continuous Positive Airway Pressure Administration and the Precision Lung Slice Method for Measuring Airway Contractility

Mechanical forces associated with positive-pressure respiratory support used in the intensive care of preterm infants can have both positive and ...

UH Rainbow Babies & Children's Hospital

Case Western Reserve University School of Medicin

Proteolipid protein (Plp) gene mutation in rodents causes severe CNS dysmyelination, early death, and lethal hypoxic ventilatory depression (Miller et al., 2004). To determine if Plp mutation alters neuronal function critical for control of breathing, the nucleus tractus solitarii (nTS) of four rodent strains were studied: myelin deficient rats (MD), myelin synthesis deficient (Plp(msd)), and Plp(null) mice, as well as shiverer (Mbp(shi)) mice, a myelin basic protein mutant. Current-voltage relationships were analyzed using whole-cell patch-clamp in 300 microm brainstem slices. Voltage steps were applied, and inward and outward currents quantified. MD, Plp(msd), and Plp(null), but not Mbp(shi) neurons exhibited reduced outward current in nTS at P21. Apamin blockade of SK calcium-dependent currents and iberiotoxin blockade of BK calcium-dependent currents in the P21 MD rat demonstrated reduced outward current due to dysfunction of these channels. These results provide evidence that Plp mutation specifically alters neuronal excitability through calcium-dependent potassium channels in nTS.

Mutation in the myelin proteolipid protein gene alters BK and SK channel function in the caudal medulla.

Maternal infection is a risk for preterm delivery. Preterm newborns often require supplemental oxygen to treat neonatal respiratory distress. Newborn hyperoxia exposure is associated with airway and vascular hyperreactivity, while the complications of maternal infection are variable. In a mouse model of prenatal maternal intraperitoneal lipopolysaccharide (LPS, embryonic day 18) with subsequent newborn hyperoxia (40% oxygen × 7 days) precision-cut living lung slices were used to measure intrapulmonary airway and vascular reactivity at 21 days of age. Hyperoxia increased airway reactivity to methacholine compared to room air controls. Prenatal maternal LPS did not alter airway reactivity in room air. Combined maternal LPS and hyperoxia exposures increased airway reactivity vs. controls, although maximal responses were diminished compared to hyperoxia alone. Vessel reactivity to serotonin did not significantly differ in hyperoxia or room air; however, prenatal maternal LPS appeared to attenuate vessel reactivity in room air. Following room air recovery, LPS with hyperoxia lungs displayed upregulated inflammatory and fibrosis genes compared to room air saline controls (TNFαR1, iNOS, and TGFβ). In this model, mild newborn hyperoxia increases airway but not vessel reactivity. Prenatal maternal LPS did not further increase hyperoxic airway reactivity. However, inflammatory genes remain upregulated weeks after recovery from maternal LPS and newborn hyperoxia exposures.

Prenatal Maternal Lipopolysaccharide and Mild Newborn Hyperoxia Increase Intrapulmonary Airway but Not Vessel Reactivity in a Mouse Model.

Hyaluronan (HA) is a major component of the extracellular matrix. Increased pulmonary HA concentrations are associated with several respiratory disorders and is a pathophysiological feature of lung disease. We investigated whether elevated urine HA is a biomarker of an unfavorable 40-week respiratory outcome in preterm infants.

Elevated Urine Hyaluronan Concentrations Are Associated with an Unfavorable Respiratory Outcome in Preterm Neonates at 40 Weeks Postmenstrual Age.

Neonatal sepsis results in significant morbidity and mortality, but early detection is clinically challenging. In a neonatal rat model of endotoxic shock, we characterised unique infrared thermographic (IRT) profiles in skin temperature that could identify risk of later mortality. Ten-day old rats were placed in a thermally stable isolette and IRT images of cranial (T), scapula (T) and rump (T) skin temperature were obtained continuously for 8 h following an intraperitoneal injection of lipopolysaccharide (LPS) or saline. LPS resulted in ∼74 % mortality (designated as non-survivors, LPS) between 4.5 and 7.5 h post-injection. LPS and survivors of LPS (LPS) rats displayed hypothermic tendencies with T, T and T decreasing at ∼80-100 min (T) post-injection. Compared to LPS rats, however, the hypothermia of LPS rats occurred slightly earlier (T), was more severe, and failed to recover. The T, T and T of LPS rats fully recovered by 4 h (T) post-injection. In separate rats, hypothalamic microglia and extracellular matrix (ECM) expression at T post-injection were increased in putatively identified LPS rats (but not LPS rats) and negatively correlated with IR temperatures. IRT could be a useful early identifier of infants at risk of death from endotoxic shock, which may be related to early failure of central nervous system (CNS) thermogenic mechanisms mediated by unique hypothalamic changes in inflammatory (microglia) and ECM neurochemistry.

Article	Year
Mutation in the myelin proteolipid protein gene alters BK and SK channel function in the caudal medulla. Respiratory physiology & neurobiology\| PubMed ID: 19808102	2009
Prenatal Maternal Lipopolysaccharide and Mild Newborn Hyperoxia Increase Intrapulmonary Airway but Not Vessel Reactivity in a Mouse Model. Children (Basel, Switzerland)\| PubMed ID: 33807828	2021
Elevated Urine Hyaluronan Concentrations Are Associated with an Unfavorable Respiratory Outcome in Preterm Neonates at 40 Weeks Postmenstrual Age. Neonatology\| PubMed ID: 38484718	2024
Unique infrared thermographic profiles and altered hypothalamic neurochemistry associated with mortality in endotoxic shock. Experimental neurology\| PubMed ID: 39732274	2025

Catherine A. Mayer

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