Tantalizing Therapeutics in Bronchopulmonary Dysplasia

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Tantalizing Therapeutics in Bronchopulmonary Dysplasia
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Dedication
Contributors
Preface
Section 1: Current therapeutics: State of the art
1 - Systemic and topical glucocorticoids to prevent BPD
	Introduction
	Dexamethasone
	Dexamethasone and hydrocortisone in the brain: different actions, different outcomes?
	Hydrocortisone
	Other systemic steroids
	Topical steroids (inhaled and instilled)
	Conclusion
	References
2 - Use of caffeine for prevention of bronchopulmonary dysplasia
	Brief history of caffeine use in premature neonates
	Epidemiology of caffeine use
	Pharmacology of caffeine in premature neonates
	Cellular mechanism of action of caffeine
	Mechanism of action of caffeine for prevention of BPD
	Dosing and route of caffeine administration
	Drug interactions with caffeine
	Serum drug monitoring for caffeine
	Timing of caffeine use – early vs. late
	Evidence for the use of late caffeine for prevention of BPD
	Evidence for the use of early caffeine for prevention of BPD
	Adverse effects of caffeine
	Caffeine and neurodevelopmental outcomes
	Caffeine controversies
		What is the optimal duration of caffeine?
		Is it safe to discharge babies home on caffeine?
	Conclusions
	Recommendations
	References
3 - Next generation ventilation strategies to prevent and manage bronchopulmonary dysplasia
	Introduction
	Pathophysiology of ventilator-associated lung injury
	General strategies to prevent PBD
	Respiratory support at birth and lung injury
	Positive end-expiratory pressure in the delivery room
	Sustained inflation (SI)
	Non-invasive respiratory support
	Less invasive surfactant administration
	Lung-protective strategies of mechanical ventilation
	Volume-controlled and volume-targeted ventilation
	Volume-controlled versus volume-targeted ventilation
	How does VTV work?
	Documented benefits of volume-controlled and volume-targeted ventilation
	General guidelines for clinical application of VTV in preterm infants
	Importance of the open lung strategy
	High-frequency ventilation
	Neurally adjusted ventilatory assist (NAVA)
	Airway pressure release ventilation (APRV)
	Respiratory support of infants with established BPD
	Conclusion
	References
Section 2: Ongoing therapeutic studies with translational potential
4 - End points for therapeutic trials for BPD: lessons learned from clinical trials
	Introduction
	Limitations of common BPD definitions as clinical trials endpoints
	Does a BPD diagnosis predict important long-term outcomes with high sensitivity and specificity?
	Is 36 weeks PMA the optimal timing for a BPD endpoint?
	Is 40 weeks PMA a better endpoint than 36 weeks?
	Should a diagnosis of BPD be based on respiratory status on a single day of a protracted hospital stay?
	Should BPD be based on use of oxygen, positive pressure or both?
	Are there advantages to a graded severity score over a dichotomous BPD endpoint?
		Incorporating pulmonary function tests (PFTs) as endpoints in clinical trials of BPD
	Respiratory death as an outcome
	Considerations when defining clinical trials endpoints after NICU discharge
	Long-term clinical trials endpoints; how long is too long?
	Conclusions
	References
5 - What can exogenous surfactant provide in the fight against BPD?
	Introduction
	Conventional surfactant therapy and BPD
	Late surfactant therapy and BPD
	New modes of exogenous surfactant administration
	Anti-inflammatory and immunomodulatory effects of surfactant
		Exogenous surfactant preparations in clinical use
		Newer synthetic surfactant preparations
	Surfactant proteins A and D
	Surfactant as a vehicle for anti-inflammatory therapy
		Exogenous surfactant therapy as a vehicle – right place, right time, right patient
		The biophysical advantage of surfactant as a delivery vehicle
		Known effects of relevant additives on the biophysical profile of surfactant
	Known effects of surfactant on the potency/bioactivity of therapies targeting BPD
		Specific therapies partnered with surfactant
	Conclusion
	References
6 - Stem cells in the treatment of bronchopulmonary dysplasia
	Introduction
	Prospects and challenges for successful clinical translation
		The right cells
			Sources
			Allogenic versus autologous MSCs
			Standardization of MSCs
			Paracrine potency assay
			Preconditioning of MSCs
			Genetic engineering of MSCs
		The right patients
		The right route
		The right timing
		The right dose
	Long-term outcomes and safety of MSCs transplantation
	Conclusions
	References
Section 3: Future therapeutic directions
7 - Extracellular vesicles in the therapy of BPD
	Bronchopulmonary dysplasia (BPD) and the rationale for stem cell-based therapies
	EVs: Intro and nomenclature
	EV isolation methods
	EV characterization methods
	EVs as therapeutic vectors
	EVs in BPD
	Acknowledgment
	References
8 - Growth factors in the therapy of bronchopulmonary dyplasia
	Introduction
		IGF-1
		VEGF
		HIF
		PDGF
		PEDF
		EMAP II
		TGFα
		TGFβ
		Connective tissue growth factor (CTGF)
		Epidermal growth factor (EGF)
		Hepatocyte growth factor (HGF)
		KGF
		MIF
	Summary and conclusions
	References
9 - Antenatal approaches in the therapy of BPD
	Introduction
	Antenatal treatment to prevent BPD
		Antenatal treatment targets to decrease BPD
	Maternal factors influencing lung fetal lung development
		Pre-existing maternal conditions
			Pre-existing maternal condition: risk of preterm birth
			Pre-existing maternal condition: hypertension
			Pre-existing maternal condition: maternal body mass index (BMI)
		Maternal toxin exposure
			Maternal toxin exposure: smoking
			Maternal toxin exposure: alcohol consumption
			Maternal toxin exposure: air pollution
		Maternal nutrition
			Maternal nutrition: Vitamin A
			Maternal nutrition: Vitamin D
			Maternal nutrition: Vitamin E
		Placental factors influencing fetal lung development
			Placental factors: inflammatory
			Placental factors: inflammatory-anti-microbial agents
			Placental factors: anti-inflammatory micronutrients
			Placental factors inflammatory: interleukin 1 (IL-1) antagonists
			Placental factors: abnormal placentation
			Placental factors: abnormal placentation-VEGF
		Fetal growth restriction (FGR)
			Fetal growth restriction: phosphodiesterase-5 inhibitor
	The fetal environment
		Intra-amniotic therapy
			Intra-amniotic therapy: vascular endothelial growth factor (VEGF)
			Intra-amniotic therapy: epidermal growth factor
			Intra-amniotic therapy: thyroxine
			Intra-amniotic therapy: stem cells
			Intra-amniotic therapy: surfactant
		Antenatal therapy to advance lung maturation
			Antenatal steroid therapy
			Ambroxol-trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol hydrochloride
			Antenatal leptin to advance fetal lung maturity
		The fetal environment-intra-uterine surgical procedures
			Fetal tracheal occlusion
			Fetal intra-tracheal drug delivery
			Placental replacement
	Conclusions
	References
10 - miRs – Mere hype or master regulators in the therapy of BPD?
	Introduction
	MicroRNA and early lung development
	MicroRNA and late lung development
	MicroRNAs for BPD risk prediction and therapeutic targets
	miRs and BPD sex predilection
	miRs and the lung microbiome
	Conclusions
	Funding
	References
11 - Immune modulators for the therapy of BPD
	Introduction
	Antenatal corticosteroids
	Macrophage migration inhibitory factor (MIF)
	MIF and BPD
	Complexity of MIF signaling pathways
	Development of MIF modulating agents
	Future possibilities for MIF research in BPD
	IL-1β
	Impact of IL-1β and the NLRP3 inflammasome on lung development
	Use of the recombinant IL-1RA anakinra in BPD
	NLRP3 inflammasome as a potential therapeutic target in BPD
	Surfactant protein D in the treatment of neonatal lung disease
	Conclusion
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	K
	L
	M
	N
	O
	P
	R
	S
	T
	U
	V
	W
	Z
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