The Effect of Stem Cells on Bronchopulmonary Dysplasia

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The Effect of Stem Cells on Bronchopulmonary Dysplasia

   

Keeghan Andrews and Vincent S. Gallicchio*

Department of Biological Sciences, College of Science, Clemson University, Clemson, SC 29636

*Corresponding author: Vincent S. Gallicchio, Department of Biological Sciences, College of Science, Clemson University, Clemson, SC 29636

Citation: Andrews K , Gallicchio VS. (2022) The Effect of Stem Cells on Bronchopulmonary Dysplasia.  J Stem Cell Res. 3(1):1-20.

Received: February 04, 2022 | Published: February 22, 2022

Copyright© 2022 by Andrews K. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.52793/JSCR.2022.3(1)-28

Abstract

Bronchopulmonary dysplasia (BPD) affects over 15,000 infant births per year in the United States and is one of the major causes of mortality in preterm infants. BPD is one of the most common long-term adverse effects from premature infant birth. Unlike other medical complications related to premature infant birth, the incidence of BPD is not declining. Approximately 15 million infants are born prematurely each year. One million infants worldwide are reported to die each year as a result of medical complications due to premature birth. Therapeutic interventions for BPD include: maternal progesterone, antenatal steroids, surgical cerclage, decreased ventilation levels, caffeine/methylxanthines, diuretics, bronchodilators, postnatal steroids, vitamin A, and inhaled nitric oxide. These interventions have demonstrated limited effectiveness. Mesenchymal stem cells (MSCs) are the preferred source for therapy for infants with BPD as they differentiate into various cell types including: muscles, bones, fat, and cartilage. Stem cell transplantation has shown to improve lung function and repair, decrease pulmonary hypertension, decrease risk for neurodevelopmental disorders, decrease BPD severity, and increase survival rates. Researchers believe the use of stem cells may offer alternative options for patients with BPD to improve lung function and decrease complications related to premature birth. 

Keywords

Bronchopulmonary dysplasia; Stem cells; Treatment

Introduction

Bronchopulmonary dysplasia (BPD) affects over 15,000 infant births per year in the United States and is one of the major causes of mortality in preterm infants [1-5]. BPD is one of the most common long-term adverse effects from premature infant delivery. Infants born with very low birth weight (VLBW) develop BPD at a rate of 30% - 40%, while infants born with extremely low birth weight (ELBW) develop BPD at a rate of 54.1% [6-11]. Many infants with BPD are readmitted to the hospital for lower respiratory infections within the first two years of life. Single hospital readmission rates for infants with BPD are reported to be 73% and multiple readmission rates (3 or more hospital readmissions) are reported to be 27% [3,12,13]. The overall mortality rate for infants with BPD is 15% and increases to 41% for infants with severe BPD [12,14]. Unlike other medical complications related to premature infant birth, the incidence of BPD is not declining [15].

The World Health Organization (WHO) defines preterm birth as an infant born before 37 weeks of pregnancy. Premature birth is a medically complex diagnosis and a substantial global public health problem. Approximately 15 million infants are born prematurely each year, accounting for 11% of all live births worldwide. The incidence of premature birth for infants in North America is at 12.5% and increasing. Severe medical complications related premature birth include: periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), hypoxic-ischemic encephalopathy (HIE), and bronchopulmonary dysplasia (BPD) [16-19]. One million infants worldwide are reported to die each year as a result of medical complications due to premature birth [5,15-17,20]. Survival rates for infants improves as gestational age increases. Premature infants born at 28 weeks gestation had a 92% chance of survival while infants born at 22 weeks gestation had a 6% chance of survival [21].

Northway first described BPD as a syndrome of chronic disease occurring in preterm infants that are treated for respiratory distress syndrome with mechanical ventilation and supplemental oxygen [4,17,22-26].  National Institute of Child Health and Human Development (NICHD) defined BPD as a condition in which the infant requires treatment with supplemental oxygen for more than 28 days and additional details are outlined for infants at 36 weeks post-menstrual age indicating severity based on the level of respiratory support required by the infant [9,27]. During the early stages of BPD, patients usually require ventilator or supplemental oxygen support. Most patients gradually withdraw from the ventilator or stop supplemental oxygen treatment based upon BPD level of severity and medical complications [12]. 

NIDCD BPD Severity Scale

Improvements in perinatal medicine have led to an increased rate of survival for extremely premature and low birth weight infants. Improved survival rates for premature infants has led to increased rates of BPD. Patients with BPD are less mature and have lower birthweights than described over 50 years ago [5,14,15,21,22,29-31]. Infants are now surviving at earlier gestational ages. Medical care provided in the Neonatal Intensive Care Unit (NICU) for patients with BPD has adapted to meet the changing needs of these medically complex patients [24] (Table 1). 

  • gestational age <32 weeks
  • timing of assessment: 36 weeks post menstrual age (PMA) or discharge home, whichever comes first
  • therapy with oxygen > 21% for at least 28 days+

mild BPD

breathing room air

moderate BPD

need for <30% oxygen

severe BPD

need for > 30% oxygen and/or positive pressure ventilation (PPV) or continuous pressure airway pressure (CPAP)

Table 1: Lists severity levels of BPD based on NIDCD criteria [4,28].

Prematurity Levels

Lung development includes several stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar. Preterm infant lungs must demonstrate continued alveolar growth and differentiation after birth. Infant preterm birth can lead to impaired alveolarization and abnormal lung growth, even without introducing mechanical ventilation or supplemental oxygen (Table 2). An infant breathing room air results in oxygen exposure that is at least five times higher than oxygen concentration of the amniotic fluid the infant encountered in utero. Infants born before 30 weeks gestation are usually exposed to supplemental oxygen during the late canalicular or saccular lung development stages. Additional perinatal risk factors are show in (Figure 2) [2,3,23,24,27,33-35].

late preterm

34-36 weeks gestation

moderate preterm

32-34 weeks gestation

very preterm

<32 weeks gestation

extremely preterm

<25 weeks gestation

Table 2: Lists prematurity severity levels based upon weeks gestation [32].

Anatomical Stages of Infant Lung Development

Figure 1: Outlines anatomical infant lung development stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar [36].

Figure 2: Outlines multifactorial etiology of BPD: antenatal and postnatal factors that contribute to BPD [27].

Advances in perinatal medical care over the past several years have improved survival rates for preterm infants from 34 weeks gestation to 24 weeks gestation. Preterm infants are now born with more immature lungs and the pathology of BPD has changed. Today, BPD is characterized by impaired alveolar development, decreased pulmonary microvascular growth, and less pulmonary inflammation compared to the original characteristics of BPD several years ago [3,4,9,17,24,28,31,37].

Preterm infants born between 24 and 28 weeks have a higher risk of developing BPD due to interruption of the canalicular and saccular stages of lung development. Differentiation of epithelial cells begins during canalicular stage. This stage is important for surfactant phospholipid and protein development that support immunological protection and lung stability. During the saccular stage, the interstitial space of the saccular walls decreases. Secondary crests are formed and cylindrical saccules develop double capillary layer. Alveolar stage continues after birth and through childhood. During alveolar stage, secondary crest is extended and thinned which leads to fusion of capillaries to help form alveoli in the lungs [6,11,24,28,34,38].

Pathogenesis of BPD

 Risk factors for BPD include: maternal smoking and hypertension, low birth weight, premature birth, intrauterine growth restriction (IUGR), genetic factors including SPOK2 gene, prenatal and postnatal infections, mechanical ventilation, and poor infant nutrition after birth [3,6,11,25,39].