Every year in the US, up to 10,000 infants are diagnosed with Bronchopulmonary dysplasia (BPD), a chronic respiratory disease that causes damage to the bronchi, or airway passages. This condition often results in delayed development, long-term lung problems, and a heightened risk of infant mortality. BPD occurs most often in low-weight or premature infants who require supplemental oxygen or have received respiratory assistance in the form of mechanical ventilation. It can also occur among older infants displaying abnormal lung development or those that suffered an infection before birth or abnormalities in the placenta, such as preeclampsia. Many researchers believe that BPD cases represent an underlying abnormality that negatively impacts lung development and could be relieved through the use of protein therapy..
The majority of infants with BPD will fully recover, but this condition can produce serious complications and may require hospitalization and other forms of intensive medical care. Even after an infant has successfully recovered from BPD, this disease can produce sustained abnormalities in the function and structure of their lungs that continue into adolescence and adulthood. Infants with BPD demonstrate heightened risk for developing severe cardiovascular complications, such as pulmonary hypertension (PH), defined as high blood pressure within the lung’s main artery, as well as dysfunction of the heart’s right side. As they age, these infants are more likely to experience respiratory infections, asthma, and pneumonia.
Promising Research Concerning BPD and Klotho
To improve cardiac and pulmonary function in preterm infants and reduce the risk of BPD-PH, one avenue researchers are currently exploring is attempting to understand the influence of the Klotho protein on vascular health. This protein is coded by the anti-aging Klotho gene, which was first discovered in 1997. Klotho exists as both a protein membrane and as a soluble form within the infant’s blood, primarily found in the kidneys and choroid plexus, but also expressed in the lungs, heart, placenta, and parathyroid glands. Published by the Nature Scientific Reports journal in July 2020, a study by the University of Miami’s Miller School of Medicine was conducted, entitled “Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants.”
In this study, researchers attempted to determine if Klotho protein levels influence the risk for preterm infants of developing bronchopulmonary dysplasia and whether the presence of Klotho can alleviate lung damage. First, they verified the connection between protein therapy and BPD in human infants, then conducted two separate experiments on rats and on human cells to uncover the details of this connection. They began by measuring the levels of Klotho protein within the cord blood of a sample size of 40 infants. Eleven of the subjects had BPD, fourteen had PBD-PH, and the control group of fifteen had neither of these conditions. When compared to the control group, infants suffering from BPD or PBD-PH showed significantly lower levels of the Klotho protein.
To discover how the Klotho protein impacts lung health in infants, researchers examined the Klotho genes of rat populations and developed a rat model. Rats with homozygous Klotho deficient genes demonstrated premature aging, vascular dysfunction, pulmonary emphysema, and fibrosis. In contrast, mice over-expressing Klotho genes benefited from protection against cardiopulmonary injury and extended life spans. To determine if supplemental Klotho protein exposure provides the same effects, researchers exposed neonatal rat pups to high oxygen levels over the course of different time periods (three days, five days, fourteen days, and 21 days), then randomly assigned the rat pups to receive injections every other day of lab-created soluble Klotho or a placebo.
The infant rats developed symptoms similar to human infants with BPD-PH, with higher oxygen levels causing a substantial reduction in Klotho genes and Klotho protein levels. They found that the Klotho injections following exposure to high oxygen levels resulted in improved cardiac function and healthier vascular development of the lung structure, especially in the alveoli, the lung’s air sacs. This treatment also decreased oxidative stress, which is associated with heightened cellular damage and death, and resulted in higher survival rates (69%) compared to the control group (44%).
The final experiment was conducted to examine whether this improvement was the direct consequence of the Klotho protein levels on pulmonary vasculature. Researchers treated a sample of human pulmonary artery endothelial cells, which form the lining of blood vessels and are impacted by BPD. In contrast with a control group exposed to high oxygen levels, the cells treated with Klotho showed enhanced viability and an increase in the number of capillaries they were able to form. Early supplementation of the Klotho protein therapy also reduced the enlargement of the heart’s right ventricle, a characteristic aspect of PH. It also resulted in reduced vascular remodeling, or an increase of muscle cells within blood vessels and greater thickness of the cell walls. The Klotho protein improved the function of the heart’s left ventricle by increasing its ejection fraction, or the amount of blood that can be pumped out with every contraction.
Where Klotho Treatment Is Headed
Klotho protein treatment holds the potential to be an effective strategy for improving cardiopulmonary development in human infants and reducing the likelihood of negative health outcomes later in life. Because Klotho is expressed in other organ systems, this type of protein therapy may be diversified in the future to expand its therapeutic effectiveness. Researchers are currently studying the application of Klotho protein in slowing the progression of kidney disease, reducing blood glucose levels in patients with diabetes, and shrinking cancerous tumors.
