Table 1.

A Summary of Drugs for the Treatment of BPD and Mechanisms of Action

Drug	Class	Mechanism of Action	Comment
Macrophage Migration Inhibitory Factor	Immune Modulator	A protein involved in innate immunity and appears to be involved in lung development, angiogenesis and host defense	Murine studies have shown MIF to provide some benefit when mice who over-expressed MIF were exposed to conditions that resulted in BPD in wild-type mice
IL-1RA anakinra	Immune Modulator	IL-1RA antagonist that opposes the generation of IL-1β	Some benefit has been shown in anakinra-treated mice in BPD models induced by exposure to LPS and hypoxia, though studies of administration of anakinra at the stages of lung development in which preterm human infants are at greatest risk (late canalicular, early saccular) have not yet been performed
Mesenchymal Stem Cells	Stem Cell Therapy	Reduce lung inflammation via a paracrine effect	Have also been shown to increase bronchoalveolar stem cell growth efficiency and improve angiogenesis; had bactericidal effects
Extracellular Vesicles		Lipid-bilayer enclosed vesicles that are released by cells containing bioactive compounds that play a role in cell-to-cell communication	Murine studies have revealed improvement in pulmonary parenchymal and vascular development.
VEGF, Platelet-derived growth factor A, Hypoxia-inducible factor 1-α, insulin-like growth factor	Growth Factors	Promote alveolar structural development	Various animal models have shown administration of growth factors that are lacking with BPD help protect lung structure and improve lung development
Micro-RNAs (miRs)		Small non-coding RNAs that act to control gene expression of protein encoding genes with	Dysregulation in the expression of miRs contribute to development of lung disorders
iNO	Anti-inflammatory, Pulmonary vasodilator	Relaxes pulmonary arterial vasculature via reducing intracellular calcium levels in pulmonary arterial smooth muscle cells via the cGMP pathway	Improves pulmonary hypertension but may also improve alveolarization and pulmonary vascular growth
Corticosteroids	Anti-inflammatory	Acutely: decrease vasodilation, capillary permeability and leukocyte migration. Long-term: action at the glucocorticoid receptors mediates changes in gene expression that affect many inflammatory cell-signaling molecules, resulting in a broad reduction in inflammation.	Multiple steroid options available; optimal timing and duration of therapy remains unclear
PF543	Anti-inflammatory	Sphingosine Kinase 1 inhibitor	Murine studies demonstrated improved airway remodeling in newborn mice exposed to hyperoxia when treated with PF543. Studies are currently underway to investigate the therapeutic efficacy of PF543 provided at different stages of lung development
Clara Cell 10-kD Protein (CC10)	Anti-inflammatory	Generated by Clara Cells in pulmonary epithelium; results in reduced inflammation	Studies ongoing regarding amelioration of BPD in premature infants
Surfactant	Exogenous surfactant (bovine, porcine, or synthetic)	Reduces inner alveolar surface tension and improves lung compliance	Surfactant therapy often eliminates or reduces the need for aggressive mechanical ventilator support and may therefore reduce its resultant lung injury.
Surfactant + Budesonide	Surfactant + anti-inflammatory	Improved inner alveolar surface tension, anti-inflammatory	Greatest benefit if administered within the first several hours of life (2–8 hours)
Superoxide Dismutase	Antioxidant	An intracellular enzyme that converts toxic superoxide radical into hydrogen peroxide, reducing free radial pulmonary tissue damage	Has been used as an adjunctive therapy to iNO in lamb models to decrease oxidative stress and restore eNOS coupling and shows promise as a future treatment in the neonatal population
Azithromycin and Clarithromycin	Antimicrobial	Inhibits bacterial protein synthesis, has anti-inflammatory properties	A meta-analysis revealed azithromycin to result in reduction of the risk of BPD in extremely premature infants but the quality of evidence was low; the prophylactic use of macrolides is not recommended for the prevention of BPD.
Surfactant Protein D	Immune Modulator	A protein within surfactant that is involved in immune defense	Has important immune functions in protection from oxidative stress; recombinant SP-D that could be administered to patients not currently available
Docosahexaenoic Acid (DHA)	Anti-inflammatory	An omega-3 fatty acid known to have anti-inflammatory properties	A decrease in DHA has been observed in the first few weeks of life despite at birth having similar mean DHA levels to term infants
Furosemide, Bumetanide	Loop Diuretic	Inhibit reabsorption of NaCl in the renal thick ascending loop of Henle, increase generation of prostaglandin E2 in renal parenchyma	May provide benefit in the setting of pulmonary hypertension by reducing right ventricle distension and therefore, avoiding impeding left ventricle filling
Hydrochlorothiazide	Thiazide Diuretic	Inhibit the reabsorption of sodium and chloride in the distal convoluted nephron	As resistance to loop diuretics many develop over time, the addition of a thiazide diuretic may be beneficial if given 30–60 minutes prior to loop diuretic
Spironolactone	Potassium-Sparing Diuretic	An aldosterone antagonist that acts at the cortical tubule to reduce the expression of the sodium-potassium exchange site in the apical membrane of the distal convoluted renal tubule	Through multiple mechanisms, elevated aldosterone levels reduce endothelial NO production and promote abnormal pulmonary extracellular remodeling. May reduced abnormal extracellular matrix remodeling and pulmonary arteriole muscularization
Milrinone	Pulmonary vasodilator	Phosphodiesterase 3 (PDE3) inhibitor; use leads to increased cAMP levels and increased vasodilation	Also has inotropic and lusitropic effects, which may improve the cardiovascular dysfunction often associated with BPD and PH
Sildenafil and Tadalafil	Pulmonary vasodilator	Inhibit phosphodiesterase Type 5, increasing [cGMP] in lungs, therefore increasing endogenous NO and promoting vasodilation	May also promote angiogenesis and alveolar development via the vascular endothelial growth factor-NO-cGMP pathway, decrease lung inflammation, and reduce hyperoxia-induced lung injury
Bosentan	Pulmonary vasodilator	An Endothelin-1 (ET-1) receptor antagonist yielding pulmonary vasodilation	May have a direct anti-fibrotic effect. Often used in infants who failed to respond optimally to Sildenafil. May result in elevated liver transaminases with prolonged use, so levels need to be monitored frequently
Iloprost, Epoprostenol, and Treprostinil	Pulmonary vasodilator	Prostacyclin (PGI2) analogues, which lead to pulmonary vasodilation via increased cAMP	Recent studies have shown it to be safe in infants, with improvement in pulmonary hypertension and decreased respiratory support
Inhaled Prostacyclin	Pulmonary Hypertensive Agent	Prostacyclin analogue resulting in pulmonary vasodilation	Limited data with regards to safety and efficacy particularly with lack of approved administration device but serves as local treatment while avoiding systemic side effects.
L-Citrulline	Pulmonary vasodilator	Results in pulmonary vasodilation via the cGMP cascade	Has been shown to improve pulmonary hypertension in animal models but has not been adequately tested in the human neonatal population.

Notes: Green – Targets pathways involved in early lung development and growth. Pink – Targets prevention of inflammation, infection, and oxidative injury in immature lung during pre-disease state, yellow – Targets prevention of inflammation, infection, and oxidative injury in immature lung during pre-disease state.