Rashmin C Savani

• MBChB
• Head of Department at University of Florida

Lung development is a tightly regulated process that progresses through five distinct stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar. Each stage is characterized by coordinated cellular interactions and structural changes driven by signals from epithelial, endothelial, and mesenchymal cells. The extracellular matrix (ECM) p...

The challenges of present-day healthcare are urgent; there is a shortage of clinicians, patient care is increasingly complex, resources are limited, clinician turnover seems ever-increasing, and the expectations of providers and patients are monumental. To transform problems into innovative opportunities, diverse perspectives and a sense of possibi...

Increased hyaluronan deposition (HA) in various cancer tissues, including sarcomas, correlates with disease progression. The receptor for hyaluronic acid-mediated motility (RHAMM) expression is elevated in most human cancers. β-catenin is a critical downstream mediator of the Wnt signaling pathways, facilitating carcinogenic events characterized by...

Background: Many aspects of care for fetuses and neonates with congenital heart disease (CHD) fall outside standard practice guidelines, leading to the potential for significant variation in clinical care for this vulnerable population. Methods: We conducted a cross-sectional survey of site sponsors of the Children's Hospitals Neonatal Consortiu...

The extracellular matrix (ECM) is an active and dynamic feature of tissues that not only provides gross structure but also plays key roles in cellular responses. The ever-changing microenvironment responds dynamically to cellular and external signals, and in turn influences cell fate, tissue development and response to environmental injury or micro...

Background: The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammator...

Objective: To describe characteristics, outcomes, and risk factors for death or tracheostomy with home mechanical ventilation in full-term infants with chronic lung disease (CLD) admitted to regional neonatal intensive care units. Study design: This was a multicenter, retrospective cohort study of infants born > 37 weeks of gestation in the Chil...

Neonates who present in high output heart failure secondary to vein of Galen aneurysmal malformation can be difficult to manage medically due to the complex physiology that results from the large shunt through the malformation. Though the cardiac function is often normal, right ventricular dilation, severe pulmonary hypertension, and systemic steal...

To predict pulmonary hypertension (PH) therapy at discharge in a large multicenter cohort of infants with congenital diaphragmatic hernia (CDH). Six-year linked records from Children’s Hospitals Neonatal Database and Pediatric Health Information System were used; patients whose diaphragmatic hernia was repaired before admission or referral, who wer...

The pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induced inflammatory cytokines and chemokines...

Background The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. Objective To describe potential indications to pur...

Background and objectives: Many preterm infants stabilized on continuous positive airway pressure (CPAP) at birth require mechanical ventilation (MV) during the first 72 hours of life, which is defined as CPAP failure. Our objective was to decrease CPAP failure in infants ≤29 weeks' gestational age (GA). Methods: A quality improvement bundle nam...

Background The use of telemedicine to provide care for critically ill newborn infants has significantly evolved over the last two decades. Children's Health System of Texas and University of Texas Southwestern Medical Center established TeleNICU, the first teleneonatology program in Texas. Objective To evaluate the effectiveness of Tele Neonatal I...

Objective To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. Study design Data from the Children’s Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between B...

Our hypothesis was that among infants with hypoxic-ischemic encephalopathy (HIE), venoarterial (VA), compared to venovenous (VV), extracorporeal membrane oxygenation (ECMO) is associated with an increased risk of mortality or intracranial hemorrhage (ICH). Retrospective cohort analysis of infants in the Children’s Hospitals Neonatal Database from 2...

Objective To evaluate the association between the time of first systemic corticosteroid initiation and bronchopulmonary dysplasia (BPD) in preterm infants. Study design A multi-center retrospective cohort study from January 2010 to December 2016 using the Children's Hospitals Neonatal Database and Pediatric Health Information System database was c...

To examine characteristics and outcomes of T18 and T13 infants receiving intensive surgical and medical treatment compared to those receiving non-intensive treatment in NICUs. Retrospective cohort of infants in the Children’s Hospitals National Consortium (CHNC) from 2010 to 2016 categorized into three groups by treatment received: surgical, intens...

Teleneonatology, encompassing all telemedicine applications in neonatal medicine, is evolving with innovative applications for use in all aspects of neonatal care. In this chapter, we discuss the key components of and a framework for the development, implementation and evaluation of a program based on existing literature and our own program. We als...

Over a century of innovations in technology and medical care have led to the current day capabilities in telemedicine. In this chapter, we discuss the evolution of telemedicine over the last century and highlight various applications in neonatal care. We hope this chapter demonstrates the exponential adoption of telemedicine, particularly in neonat...

The development, growth, and function of the cardiac, pulmonary, and vascular systems are closely intertwined during both fetal and postnatal life. In utero, placental, environmental, and genetic insults may contribute to abnormal pulmonary alveolarization and vascularization that increase susceptibility to the development of bronchopulmonary dyspl...

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines inc...

Introduction: A patent ductus arteriosus (PDA) in a preterm infant can lead to respiratory insufficiency and chronic lung disease as well as necrotizing enterocolitis due to systemic hypoperfusion. Recently, catheter-based PDA closure has emerged as an appealing alternative to invasive surgical ligation in preterm infants; however, evidence to supp...

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving our understanding...

Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS). However, few studies have examined the mechanisms involved. We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exp...

We present a preterm infant who developed a fever and mild respiratory disease on the second day of life. Infant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal testing was positive at 24 and 48 hours of life. Placenta histopathology revealed SARS-CoV-2 infection by electron microscopy and immunohistochemistry. Further u...

Nitric oxide (NO) has critical roles in a wide variety of key biologic functions and has intricate transport mechanisms for delivery to key distal tissues under normal conditions. However, NO also plays important roles during disease processes, such as hypoxia–ischemia, asphyxia, neuro-inflammation, and retinopathy of prematurity. The effects of ex...

Apart from its known actions as a pulmonary vasodilator, nitric oxide (NO) is a key signal mediator in the neonatal brain. Despite the extensive use of NO for pulmonary artery hypertension (PAH), its actions in the setting of brain hypoxia and ischemia, which co-exists with PAH in 20–30% of affected infants, are not well established. This review fo...

Background: The hyaluronan (HA) receptors CD44 and RHAMM (CD168) are involved in cellular proliferation, differentiation, and motility. As previously investigated, HA and RHAMM expression in human neonatal lungs correlates to gestational age (GA) and air content. Methods: CD44 immunofluorescence was analyzed in post-mortem lung samples from infant...

Objective To determine the relationship between interventricular septal position (SP) and right ventricular systolic pressure (RVSP) and mortality in infants with severe BPD (sBPD). Study design Infants with sBPD in the Children’s Hospitals Neonatal Database who had echocardiograms 34–44 weeks’ postmenstrual age (PMA) were included. SP and RVSP we...

Background/Objective Over 75% of newborns admitted to the neonatal intensive care unit (NICU) receive antibiotics with no proven infection (empiric) at birth. Empiric antibiotic use in the NICU increases susceptibility to late onset sepsis, but the mechanisms are poorly understood. Methods Neonatal mice were exposed to broad-spectrum antibiotics t...

Cell-matrix interactions are fundamental to many developmental, homeostatic, immune and pathologic processes. Hyaluronan (HA), a critical component of the extracellular matrix (ECM) that regulates normal structural integrity and development, also regulates tissue responses during injury, repair, and regeneration. Though simple in its primary struct...

The first breath taken by newborns after birth initiates the transition from fetal to neonatal life. Successful transition is dependent on the establishment of effective gas exchange in the lungs. This exchange takes place in the alveoli, the terminal units of the lung. The embryonic lung undergoes branching morphogenesis to form a vast network of...

Introduction: Hyaluronan (HA) and the receptor for hyaluronan-mediated motility (RHAMM) may play an important role in lung development. We examined the expression of HA content and RHAMM during postnatal lung development by analyzing human lung specimens from newborn infants with a variety of lung diseases at different gestational (GA) and postnata...

Maternal obesity and a high-fat diet (HFD) during the perinatal period have documented short- and long-term adverse outcomes for offspring. However, the mechanisms of maternal HFD effects on neonatal offspring are unclear. While the effects of maternal HFD exposure during pregnancy on the offspring are increasingly being appreciated, we do not know...

Over 50 years after its first description, Bronchopulmonary Dysplasia (BPD) remains a devastating pulmonary complication in preterm infants with respiratory failure and develops in 30–50% of infants less than 1000-gram birth weight. It is thought to involve ventilator- and oxygen-induced damage to an immature lung that results in an inflammatory re...

Acute lung injury results in early inflammation and respiratory distress, and later fibrosis. The glycosaminoglycan hyaluronan (HA) and the Receptor for Hyaluronan-Mediated Motility (RHAMM, CD168) have been implicated in the response to acute lung injury. We hypothesized that, compared to wild type (WT) mice, RHAMM knockout (KO) mice would be prote...

Objectives: To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. Study design: This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation...

Background: Cytokines modulate fetal well-being and contribute to parturition. Their origin in fetal blood, whether maternal, placental or fetal, at the time of parturition remains unclear. Objective: To determine fetal and placental contributions to circulating fetal cytokines by measuring umbilical arterial (UmA) and venous (UmV) concentration...

Objective: To evaluate the impact of the Neonatal Resuscitation Program (NRP)-recommended low oxygen strategy (LOX) on neonatal morbidities, mortality, and neurodevelopmental outcomes in neonates born preterm. Study design: In March 2011, Parkland Hospital changed from a high oxygen strategy (HOX) of resuscitation with initial 100% oxygen and ta...

INTRODUCTION The receptor for hyaluronan-mediated motility (RHAMM) is expressed in endothelial cells, fibroblasts, smooth muscle cells, and immune cells. It regulates signaling pathways that influence cell motility, and proliferation in inflammatory and tumorigenic responses. The role of RHAMM in fetal lung development is not well established. The...

Objective: To estimate the presence and sources of inter-center variation (ICV) in the risk of death or tracheostomy placement (D/T) among infants with severe bronchopulmonary dysplasia (sBPD)Study design:We analyzed the Children's Hospitals Neonatal Database between 2010 and 2013 to identify referred infants born <32 weeks' gestation with sBPD. T...

RHAMM (Receptor for Hyaluronan‐Mediated Motility) is necessary for endothelial cell (EC) migration in vitro and angiogenesis in vivo , but the mechanisms are incompletely understood. Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) involves a signaling cascade through Src kinase and Akt, and results in eNOS phosphorylation....

The last two decades have seen enormous progress in vascular endothelial cell biology with significant advances in our understanding of the regulation of endothelial cell functions, the discovery and extensive study of endothelial cell relaxation and constriction factors, in particular nitric oxide, and the biology of nitric oxide synthases. Physio...

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation,...

Objective: Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia. Approach and results: Neointimal hyperplas...

Pulmonary arterial hypertension (PAH) worsens clinical outcomes in former preterm infants with bronchopulmonary dysplasia (BPD). Oxidant stress disrupts alveolar and vascular development in models of BPD. Bleomycin causes oxidative stress and induces BPD and PAH in neonatal rats. Disruption in the VEGF and nitric oxide signaling pathways contribute...

Maternal nutrition has a profound long-term impact on infant health. Poor maternal nutrition influences placental development and fetal growth resulting in low-birth-weight which is strongly associated with the risk of developing chronic diseases, including heart disease, hypertension, asthma, and type 2 diabetes later in life. Few studies have del...

Objective: To estimate the risk of death or tracheostomy placement (D/T) in infants with severe bronchopulmonary dysplasia (sBPD) born < 32 weeks' gestation referred to regional neonatal intensive care units. Study design: We conducted a retrospective cohort study in infants born < 32 weeks' gestation with sBPD in 2010-2011, using the Children's...

Objective: To determine whether a limited oxygen strategy (LOX) versus a high oxygen strategy (HOX) during delivery room resuscitation decreases oxidative stress in preterm neonates. Methods: A randomized trial of neonates of 24 to 34 weeks' gestational age (GA) who received resuscitation was performed. LOX neonates received room air as the init...

Purpose -Blood vessel formation and distal alveolar structure are closely linked. The expression of EMAP II- a potent antiangiogenic and proinflammatory factor, decreases during periods of vasculogenesis in fetal lung development, and is elevated in lung dysplasias such as BPD and emphysema. EMAP II levels in murine lungs are elevated in hyperoxia....

In Utero Exposure to Maternal High Fat Diet Increases Fetal Lung Inflammation Impairing Lung Development. Purpose: Maternal nutrition has a long-term impact on infant and adult health. Western diets containing high fat (HFD) are associated with maternal obesity and a pro-inflammatory state. Chorioamnionitis and antenatal inflammation increase t...

The intestinal microbiota changes dynamically from birth to adulthood. In this study we identified γ-Proteobacteria as a dominant phylum present in newborn mice that is suppressed in normal adult microbiota. The transition from a neonatal to a mature microbiota was in part regulated by induction of a γ-Proteobacteria-specific IgA response. Neocolon...

Rationale: Alveolar growth abnormalities and severe respiratory dysfunction, are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged poorly septated airspaces is essential to develop new therapies for lung disease. The membrane bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet, in contrast t...

Aims: Pulmonary hypertension (PH) is characterized by an oxidant/antioxidant imbalance that promotes abnormal vascular responses. Reactive oxygen species, such as superoxide (O(2)(•-)), contribute to the pathogenesis of PH and vascular responses, including vascular remodeling and inflammation. This study sought to investigate the protective role o...

The innate immune system protects the host from bacterial and viral invasion. Surfactant Protein A (SPA), a lung-specific collectin, stimulates macrophage chemotaxis. However, the mechanisms regulating this function are unknown. Hyaluronan (HA) and its receptors RHAMM (Receptor for HA-Mediated Motility, CD168) and CD44 also regulate cell migration...

Hyaluronan is activated by fragmentation and controls inflammation and fibroplasia during wound repair and diseases (eg, cancer). Hyaluronan-binding peptides were identified that modify fibrogenesis during skin wound repair. Peptides were selected from 7- to 15mer phage display libraries by panning with hyaluronan-Sepharose beads and assayed for th...

Objective: Magnesium historically has been used for treatment and/or prevention of eclampsia or preterm labor. More recently, antepartum magnesium sulfate has been suggested for prevention of cerebral palsy in preterm infants. Although adverse effects and toxicity of magnesium in pregnant women are well known, the fetal-neonatal effects of magnesi...

Background Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxid...

Traditionally, type 1 diabetes (T1D) has been thought of as a disease of cellular immunity, but there is increasing evidence that components of the innate immune system, controlled largely by Toll-like receptors (TLRs), play a significant role in T1D development. TLRs are pattern-recognition molecules on immune cells that recognize pathogens, leadi...

An increase in hyaluronan (HA) synthesis, cellular uptake, and metabolism occurs during the remodeling of tissue microenvironments following injury and during disease processes such as cancer. We hypothesized that multimodality HA-based probes selectively target and detectably accumulate at sites of high HA metabolism, thus providing a flexible ima...

Oesophageal cancer is a highly aggressive tumour entity with at present poor prognosis. Therefore, novel treatment options are urgently needed. Hyaluronan (HA) is a polysaccharide present in the matrix of human oesophageal squamous cell carcinoma (ESCC). Importantly, in vitro ESCC cells critically depend on HA synthesis to maintain the proliferativ...

Hyaluronan (HA) is a polysaccharide component in the parenchyma and stroma of human esophageal squamous cell carcinoma (ESCC). Clinically, esophageal cancer represents a highly aggressive tumor type with poor prognosis resulting in a 5-year survival rate of 5%. The aim of the present study was the detailed analysis of the role of HA synthesis for E...

Mice with targeted deletion of the lipid transporter ABCA3 have surfactant deficiency and develop lethal neonatal respiratory failure. In contrast heterozygous ABCA3 +/− mice have altered lamellar bodies, but no respiratory difficulties and survive the perinatal period. Since subtle lamellar body abnormalities might precipitate surfactant deficienc...

Acute lung injury results in inflammation, Surfactant Protein B (SPB) deficiency and respiratory distress. Hyaluronan (HA) and its receptor RHAMM have been implicated in the inflammatory response to lung injury. We hypothesized that RHAMM KO mice would be protected from bleomycin‐induced lung injury. Littermate wild type (WT) and RHAMM KO mice were...

Impaired neonatal vascular and alveolar development, and elevated TGFβ contribute to pulmonary hypertension (PH) and bronchopulmonary dysplasia (BPD). Since the hyaluronan receptor CD44 regulates TGFβ signaling, we examined the effects of hypoxia (12% vs. 21% O 2 ) from birth to postnatal day (PN) 14 in neonatal CD44 +/+ (WT) and CD44 −/− mice. At...

A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as...

The pharmacodynamics and elimination kinetics of escalating doses (1.5-12 mg/kg) of hyaluronan (HA) infusions were studied in healthy human volunteers. Metabolic breakdown of serum HA and associated adverse events were monitored throughout the study. The HA-binding capacities of circulating CD4+ and CD8+ T lymphocytes, CD19+ B-lymphocytes and CD14+...

TLR2 recognizes gram‐positive organisms and yeast, and promotes leukocyte recruitment. TGF β stimulates macrophage chemotaxis. Hyaluronan (HA), a glycosaminoglycan, also stimulates cell migration using Receptor for HA‐Mediated Motility (RHAMM). We hypothesized that TLR2 ligation leads to increased production of TGF β, which in turn stimulates macro...

Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced bronchoconstriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that...

The pulmonary collectins, surfactant proteins A and D (SP-A and SP-D) have been implicated in the regulation of the innate immune system within the lung. In particular, SP-D appears to have both pro- and anti-inflammatory signaling functions. At present, the molecular mechanisms involved in switching between these functions remain unclear. SP-D dif...

Adhesion molecules known to be important for neutrophil recruitment in many other organs are not involved in recruitment of neutrophils into the sinusoids of the liver. The prevailing view is that neutrophils become physically trapped in inflamed liver sinusoids. In this study, we used a biopanning approach to identify hyaluronan (HA) as disproport...

Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3–/– knock-out mice died soon after birth, whereas most of the wild type, Abca3+/+, and heterozygous, Abca3+/–, neonate...

LPS from bacteria is ubiquitous in the environment and can cause airway disease and modify allergic asthma. Identification of gene products that modulate the biologic response to inhaled LPS will improve our understanding of inflammatory airways disease. Previous work has identified quantitative trait loci for the response to inhaled LPS on chromos...

Hyaluronan (HA) is synthesized in high-molecular-weight form at the apical pole of airway epithelial cells, covering the luminal surface. When human airway epithelial cells grown and redifferentiated at the air-liquid interface (ALI) were exposed to xanthine/xanthine oxidase (X/XO), ciliary beat frequency (CBF) increased. This effect was blocked by...

Surfactant protein D (SP-D), a member of the collectin superfamily, modulates pulmonary inflammatory responses and innate immunity. Disruption of the SP-D gene in mice induces peribronchiolar inflammation, accumulation of large, foamy macrophages, increased bronchoalveolar lavage (BAL) phospholipid, and pulmonary emphysema. We hypothesized that abs...

We compared serial measurements of inflammatory mediators and markers in infants treated with inhaled nitric oxide or placebo to assess the effects of inhaled nitric oxide therapy on lung inflammation during bronchopulmonary dysplasia. We investigated relationships between respiratory severity scores and airway concentrations of inflammatory marker...

The correct formation of new blood vessels from existing vasculature (angiogenesis) is essential for embryogenesis and the effective repair of damaged or wounded tissues. However, excessive and detrimental vascularization also occurs in neoplasia, promoting tumour growth and metastasis, as well as in proliferative diabetic retinopathy and atheroscl...

In the fetal lung, endogenous transforming growth factor (TGF)-beta inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-beta inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-beta. Epithelial cells wer...