Preterm babies with the lung condition bronchopulmonary dysplasia (BPD) — a risk factor for the development of pulmonary hypertension (PH) — have lower levels of the anti-aging-associated protein Klotho, a study shows.
The results support the potential for Klotho as a biomarker for BPD. Moreover, early Klotho protein supplementation in a rat model of neonatal BPD reduced pulmonary vascular remodeling — the key structural alteration in PH — and improved both pulmonary and cardiac function.
The study, “Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants,” was published in the journal Nature Scientific Reports.
BPD affects premature babies and is characterized by damage to the airway passages, or bronchi. Preterm infants with BPD often have delayed growth and, in the most severe cases, develop PH and heart problems.
The lung condition is known to increase the risk of infant mortality, and BPD survivors often experience cardiovascular complications in adulthood. Estimates from the National Institute of Child Health and Human Development, for the years between 2003 and 2007, indicate that BPD incidence was 42% in infants with less than 29 weeks gestational age.
The klotho gene was identified as an anti-aging gene. It codes for the klotho protein that exists in several forms, including as a protein membrane and as a soluble form in the blood.
Mice engineered to lack the klotho gene show signs of premature aging, accompanied by spontaneous pulmonary fibrosis or scarring, emphysema — a lung disease that causes shortness of breath — and vascular impairment. In turn, above-normal levels of klotho protected animals from cardio-pulmonary injuries and extended their life span.
The role of Klotho in neonatal disease is poorly understood. Previous studies suggested that environmental factors — like intra-amniotic infection and smoking during pregnancy — are associated with reduced maternal levels of the protein. Pre-eclampsia and having babies who are small for their gestational age also are complications linked to lower levels of Klotho in the blood.
Now, researchers at the University of Miami Miller School of Medicine investigated whether lower Klotho levels in preterm infants are associated with an increased risk for BPD–PH. The team also tested whether early protein supplementation could halt lung damage.
First, the levels of Klotho protein were measured in the cord blood of 40 infants. Among these babies, 11 had BPD and 14 had BPD-PH. The remaining 15 infants (controls) had neither BPD nor BPD–PH.
Compared with the control group, the infants with BPD or BPD-PH had significantly lower Klotho levels — a mean 1,306 picograms per milliliter (pg/mL) in the BPD group and a mean 1,529 pg/mL in those with BPD-PH — compared with a mean 2,726 pg/ml in the control group.
The team also measured Klotho levels in a rodent BPD-PH model. In this model, neonatal rat pups were exposed to high levels of oxygen (85%) for different time periods — three, five, 14 and 21 days. The animals developed similar symptoms to human newborns with BPD-PH.
A prolonged exposure to high levels of oxygen (14 to 21 days) led to a significant reduction in Klotho, both at the gene and protein levels. Blood sampling at day 14 and 21 confirmed the lower levels in the BPD-PH model rats compared with rats exposed to normal oxygen.
Next, the researchers tested whether early supplementation with Klotho had an impact on rat lung development. Rat pups either exposed to normal room air or to 85% oxygen were randomly assigned to receive injections of lab-made Klotho or a placebo. The injections were given every other day.
The results showed that these injections improved vascular development in the lungs of rats exposed to high oxygen levels.
The scientists next sought to demonstrate that this improvement was due to a direct effect of the protein on pulmonary vasculature. They treated with Klotho human pulmonary artery endothelial cells exposed to high oxygen. Endothelial cells compose the lining of blood vessels and are affected by BPD.
Treatment with Klotho increased the cells’ viability and the number of capillaries these cells formed, in contrast with non-treated cells exposed to high oxygen.
Using the rodent model, the researchers also found that Klotho supplementation lessened the effects of PH. It also reduced the heart’s right ventricular enlargement, which is a characteristic of PH.
Vascular remodeling — defined by an increased percentage of muscle cells in vessels and greater wall thickness — also was reduced with early administration of Klotho. Tests of cardiac function revealed that the protein supplement improved the heart’s left ventricle function, namely its ejection fraction, or how much blood the heart’s left ventricle pumps out with each contraction.
Moreover, Klotho had a positive effect on lung development, especially in the alveoli, which are the air sacs found at the end of the respiratory tree of the lungs. Compared with high-oxygen-exposed rats given a placebo, the Klotho group showed improved alveolar structure.
At the molecular level, Klotho supplementation was found to decrease oxidative stress in newborn rats exposed to high oxygen. Oxidative stress — caused by an imbalance between the body’s production of potentially harmful reactive oxygen species and its ability to contain them — is associated with increased cellular damage and death.
The researchers also observed that rats exposed to high oxygen and treated with the protein had a slight better survival (69%) compared with the placebo group (44%).
Overall, the results “show that early administration of soluble Klotho improves lung vascular development, attenuates PH, and reduces myocardial dysfunction,” the team wrote.
“Our findings suggest that Klotho deficiency is a potential mediator and biomarker for BPD and PH risk and early interventions, which augment Klotho levels, may be an effective strategy to improve cardiopulmonary outcomes in preterm infants,” the team added.
Further research is needed to evaluate the effects of Klotho on other developing organ systems, the investigators said.
“This will be crucial to translate the findings of our studies to the bedside,” they wrote.
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