Pediatrics and neonatology involves learning more about development and growth through the first stages of life. Early lung development studies investigate the some of the most vulnerable stages of life and must overcome significant experimental challenges when working with small, fragile and uncooperative subjects.
The research targets a range of issues from spontaneously developed disorders to early life exposure and sensitization. Preclinical neonate research typically falls into 1 of 3 categories:
1. Development – Studying how the lungs develop and diseases that impede the proper development such as bronchopulmonary dysplasia (BPD) and congenital diaphragmatic hernia (CDH).
The lungs are one of the last organs to develop in newborns and are dangerously impacted when infants are born prematurely. These infants are ventilated to support life. However, this ventilation process is very damaging to the lung and can cause BPD. In infants with BPD, the development of the alveoli – the principal gas exchange units of the lung – is compromised, with consequences that extend into adulthood.
2. Disease – Exposure to various diseases and their impact on early life such as respiratory syncytial virus (RSV) and asthma.
The development and progression of the disease at early stages of life can have long-lasting impacts on the lung health. Challenges with allergens can lead to asthma and airway hyperresponsiveness, while exposure to viruses can cause an emphysematous phenotype and associated cardiovascular stress (respiratory syncytial virus).
3. In utero exposure – Exposures to the pregnant dams to test susceptibility of the pups such as smoking and allergens.
By challenging the pregnant dam, the stresses can cause impaired development of the fetus at crucial stages of life. The lungs may not be able to account for the stress and can develop abnormally into a diseased lung state.
Early lung development in small animals is very hard to measure. Without detailed respiratory mechanics many changes in the lungs cannot be captured in vivo, even in severe diseases. For diseases such as BPD, the hyperoxia challenge leads to airway remodeling and airway hyperresponsiveness in early adulthood. Changes in the tissue properties of the subject can reflect changes due to the effects of hyperoxia on lung development. The flexiVent measures these detailed respiratory mechanics. An integrated nebulizer has the ability to run a methacholine dose response which is critical in evaluating the respiratory health.
The researchers were studying congenital diaphragmatic hernias (CDH) in embryonic (preterm) rabbits. CDH occurs when the diaphragm doesn’t fuse properly during development, leaving a hole between the thoracic and abdominal cavity. Since breathing is pressure based, this hernia causes the incomplete development of the lung and pulmonary hypertension. In their study, a surgical procedure 5 days before normal birth (E25) induced the hernia. At term (E30), the pups are then measured with the flexiVent to see how their lungs compare to the controls. The lungs responded more like an underdeveloped lung (similar to lungs at E27) with a higher overall stiffness and significantly more resistive lung. This was novel in that it showed at what normal developmental stage the CDH lungs were most similar to, in this case around E27.
This study looked at restricting growth in utero, and the pups associated increased incidence of asthma. The pregnant dams were housed in a hypoxic (low oxygen) environment during gestation. Following births, pups between 2 and 8 weeks were tested with the flexiVent and they found that at baseline the groups did not differ, however the airways became more restrictive during methacholine challenges compared to the controls (sex and age dependent effect), indicative of an asthmatic phenotype. This studied showed that a simple external factor on the dam lead to growth restriction in the pups, who consequently developed an asthmatic phenotype.
The researchers were studying hyperoxia-induced bronchopulmonary dysplasia (BPD) in rats. Following birth, the dam and pups were housed in a chamber with bias-flow and input gas controlled by IOX and the mass flow controllers. Oxygen concentrations varied from 21-100% over the first 19 days of life. The groups given hyperoxia presented higher resistance and stiffness of the airways when measured with the flexiVent. They looked at imaging and cardiovascular effects to show a complete picture of hyperoxia-induced airway remodeling and BPD in a rat model.
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