Timothy JM MossMonash University (Australia) · Department of Obstetrics and Gynaecology
Timothy JM Moss
PhD
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229
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Introduction
Skills and Expertise
Publications
Publications (229)
Background:
Lung inflammation and impaired alveolarization precede bronchopulmonary dysplasia (BPD). Glucocorticoids are anti-inflammatory and reduce ventilator requirements in preterm infants. However, high-dose glucocorticoids inhibit alveolarization. The effect of glucocorticoids on lung function and structure in preterm newborns exposed to ant...
Bacille-Calmette Guérin (BCG) modulates atherosclerosis development in experimental animals, but it remains unclear whether neonatal BCG vaccination is pro- or anti-atherogenic. Many animal models differ fundamentally from BCG administration to human infants in terms of age, vaccine preparation, dosing schedule, and route of administration. We aime...
Background
Antenatal conditions that are linked with preterm birth, such as intrauterine inflammation, can influence fetal cardiac development thereby rendering the heart more vulnerable to the effects of prematurity. We aimed to investigate the effect of intrauterine inflammation, consequent to lipopolysaccharide exposure, on postnatal cardiac gro...
Background
Neurovascular coupling leads to an increase in local cerebral blood flow and oxygenation in response to increased neural activity. Reduced cerebral functional responses may predispose to tissue hypoxia when neural activity is increased. Intrauterine inflammation, identified clinically as chorioamnionitis, is a major contributor to the ne...
Background
Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS...
Background and aims: Preterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis which complicate pregnancies delivering preterm, or recurrent early-life infections, which are common in preterm infants. We previously reported that experimental chorioam...
Background
Lung inflammation and impaired alveolarization are hallmarks of bronchopulmonary dysplasia (BPD). We hypothesize that human amnion epithelial cells (hAECs) are anti-inflammatory and reduce lung injury in preterm lambs born after antenatal exposure to inflammation.
Methods
Pregnant ewes received either intra-amniotic lipopolysaccharide (...
Background and aims
Preterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis, that complicate pregnancies delivering preterm, or recurrent early-life infections, common in preterm infants. We previously reported that experimental chorioamnionitis fo...
Background
Increased systemic and tissue levels of interleukin(IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration can attenuate neuroinflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). M...
Maternal asthma is known to impact intrauterine growth outcomes, whic*h may be mediated, in part, by altered androgen signalling. Our aim was to explore whether the sheep placenta expresses androgen receptor (AR) isoforms and determine if the differential expression of AR protein isoforms is altered by maternal asthma. Four known AR isoforms were d...
Mechanical ventilation of preterm neonates is associated with neuroinflammation and an increased risk of adverse neurological outcomes. Human amnion epithelial cells (hAECs) have anti-inflammatory and regenerative properties. We aimed to determine if intravenous administration of hAECs to preterm lambs would reduce neuroinflammation and injury at 2...
Key points
Experimental maternal allergic asthma in sheep provides an experimental model in which to test impacts on progeny.
Fetuses from allergic asthmatic ewes had fewer surfactant‐producing cells in lungs.
A greater proportion of lymphocytes from thymus were CD44 positive in fetuses from allergic asthmatic ewes than in controls.
These changes t...
Maternal asthma increases the risk of adverse pregnancy outcomes and may affect fetal growth and placental function by differential effects on the expression of glucocorticoid receptor (GR) isoforms, leading to altered glucocorticoid signalling. Our aim was to examine the effect of maternal asthma on placental GR profiles using a pregnant sheep mod...
Atherosclerosis is a chronic inflammatory disease that has its origins in early life. Postnatal inflammation exacerbates atherosclerosis, but the possible effect of intrauterine inflammation is largely unexplored. Exposure to inflammation in utero is common, especially in infants born preterm, who have increased cardiovascular risk in adulthood. We...
Background:
Chorioamnionitis and fetal inflammation are principal causes of neuropathology detected after birth, particularly in very preterm infants. Preclinical studies show that umbilical cord blood (UCB) cells are neuroprotective, but it is uncertain if allogeneic UCB cells are a feasible early intervention for preterm infants. In contrast, me...
Background:
Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs.
Method:
Ventilation was ini...
Background: Delaying umbilical cord clamping until after aeration of the lung (physiological-based cord clamping; PBCC) maintains cardiac output and oxygenation in preterm lambs at birth, however, its efficacy after intrauterine inflammation is not known. Given the high incidence of chorioamnionitis in preterm infants, we investigated whether PBCC...
Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made sig...
Background:
Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised t...
Inflammation of the preterm lungs is key to the pathogenesis of bronchopulmonary dysplasia (BPD), whether it arises as a consequence of intrauterine inflammation or postnatal respiratory management. This review explores steroidal and non-steroidal therapies for reducing neonatal pulmonary inflammation, aimed at treating or preventing BPD.
Background
In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP) is recommended. There is limited information about PEEP delivery in vivo, using different models of self-inflating bag (SIB) at different inflation rates and PEEP settings.
Methods
We compared PEEP delivery to intubated preterm lambs using...
Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus. Human amnion epithelial cells (hAECs) moderate the effect of IA LPS on fetal development, but their influence on the acute inflammatory response to IA LPS is unknown. We aimed to determine the effects of hAECs on the acute fetal inflammatory response...
Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential life-long consequences. Inert 50-nm polystyrene nanoparticles (PS50G) reduce allergic inflammation in the lungs of adult mice. We aimed to confirm the anti-inflammatory effects of PS50G in a sheep asthma model, and investigate the effects of prophylactic...
Purpose
The aim of this study is to examine whether advanced magnetic resonance imaging (MRI) techniques can detect early brain injury caused by intrauterine inflammation and inappropriate initial respiratory support in preterm lambs.
Hypothesis
Neuropathology caused by intrauterine inflammation is exacerbated by mechanical ventilation at birth an...
Diffusion tensor imaging-colour maps of the frontal white matter (FWM); lipopolysaccharide (LPS) groups. Voxel diffusivity intensities falling below the low threshold are shown as red for axial diffusivity (AD) and radial diffusivity (RD) measurements for all lambs exposed to intrauterine inflammation (LPS). All low-diffusion maps are overlaid on d...
SD of diffusion tensor imaging measurements. The SD of the distribution of voxel intensities within each region of interest (ROI) for each animal was calculated for fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity measurements in the LPS + INJ and LPS + PROT groups. The means of the SDs were tested for differences...
Diffusion tensor imaging-colour maps of the periventricular white matter (PVWM); lipopolysaccharide (LPS) groups. Voxel diffusivity intensities falling below the low threshold are shown as red for axial diffusivity, radial diffusivity, and mean diffusivity measurements for all lambs exposed to intrauterine inflammation (LPS). All low-diffusion maps...
Diffusion tensor imaging-colour maps of the periventricular white matter (PVWM); control groups. Voxel diffusivity intensities falling below the low threshold are shown as red for axial diffusivity (AD) and radial diffusivity (RD) measurements for all control lambs not exposed to intrauterine inflammation (lipopolysaccharide). All low-diffusion map...
Diffusion tensor imaging-colour maps of the thalamus; lipopolysaccharide (LPS) groups. Voxel diffusivity intensities falling below the low threshold are shown as red for axial diffusivity (AD) and radial diffusivity (RD) measurements for all lambs exposed to intrauterine inflammation (LPS). All low-diffusion maps are overlaid on diffusion images fo...
Diffusion tensor imaging-colour maps of the mean diffusivity (MD) in the thalamus; lipopolysaccharide (LPS) groups. Voxel diffusivity intensities falling below the low threshold are shown as red for MD, measurements for all lambs exposed to intrauterine inflammation (LPS). All low-diffusion maps are overlaid on diffusion images for a slice passing...
Diffusion tensor imaging-colour maps of the frontal white matter (FWM); control groups. Voxel diffusivity intensities falling below the low threshold are shown as red for axial diffusivity (AD) and radial diffusivity (RD) measurements for all control lambs not exposed to intrauterine inflammation (lipopolysaccharide). All low-diffusion maps are ove...
Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in prete...
Cell proliferation.
(DOCX)
Plasma TNF and IL-6 concentrations.
(DOCX)
Epidemiology formed the basis of 'the Barker hypothesis', the concept of 'developmental programming' and today's discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHa...
Intrauterine inflammation, or chorioamnionitis, is a major contributor to preterm birth. Prematurity per se is associated with considerable morbidity and mortality resulting from lung immaturity but exposure to chorioamnionitis reduces the risk of neonatal respiratory distress syndrome (RDS) in preterm infants. Animal experiments have identified th...
Background: Lung inflammation is central to the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. Lung inflammation impairs alveolarisation, which is a characteristic pathological feature of BPD. Glucocorticoids are anti-inflammatory, improve lung function, and reduce ventilator requirements in preterm inf...
Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV)...
The surge in uptake of nasal continuous positive airway pressure (CPAP) for respiratory support in preterm infants has occurred in the absence of an authentic animal model. Such a model would allow investigation of research questions of physiological and therapeutic importance. We therefore aimed to develop a preterm lamb model of the non-intubated...
The initiation of ventilation in the delivery room is one of the most important but least controlled interventions a preterm infant will face. Tidal volumes (V
T) used in the neonatal intensive care unit are carefully measured and adjusted. However, the V
Ts that an infant receives during resuscitation are usually unmonitored and highly variable. I...
Cardiovascular disease continues to be the leading cause of global morbidity and mortality. Traditional risk factors account for only part of the attributable risk. The origins of atherosclerosis are in early life, a potential albeit largely unrecognized window of opportunity for early detection and treatment of subclinical cardiovascular disease....
BACKGROUND:
Inadvertently injurious ventilation of preterm neonates in the delivery room can cause cerebral white matter (WM) inflammation and injury. We investigated the impact of an early high dose of recombinant human erythropoietin (EPO) on ventilation-induced WM changes in preterm lambs.
METHODS:
Injurious ventilation, targeting a VT of 15 ml...
Maternal asthma during pregnancy adversely affects pregnancy outcomes but identification of the cause/s, and the ability to evaluate interventions, is limited by the lack of an appropriate animal model. We therefore aimed to characterise maternal lung and cardiovascular responses and fetal-placental growth and lung surfactant levels in a sheep mode...
At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxygenation and rapidly improves circulatory recovery in asphyxiated newborns. We hypothesised that lung aeration, in the absence of an increase in arterial oxygenation, can increase heart rate (HR) in asphyxiated near-term lambs.
Lambs were delivered and...
Background:
Preterm infants can be inadvertently exposed to high tidal volumes (VT) during resuscitation in the delivery room due to limitations of available equipment. High VT ventilation of preterm lambs produces cerebral white matter (WM) pathology similar to that observed in preterm infants who develop cerebral palsy. We hypothesized that huma...
Background
A cornerstone of neonatal resuscitation teaching suggests that a rapid vagal-mediated bradycardia is one of the first signs of perinatal compromise. As this understanding is based primarily on fetal studies, we investigated whether the heart rate and blood pressure response to total asphyxia is influenced by whether the animal is in uter...
Background
The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, h...
Introduction
Preterm newborns often require mechanical respiratory support that can result in ventilation-induced lung injury (VILI), despite exogenous surfactant treatment. Human amnion epithelial cells (hAECs) reduce lung inflammation and resultant abnormal lung development in preterm animals; co-administration with surfactant is a potential ther...
Intrauterine inflammation is a major contributor to preterm birth and has adverse effects on preterm neonatal cardiovascular physiology. Cardiomyocyte maturation occurs in late gestation in species such as humans and sheep. We tested the hypothesis that intrauterine inflammation has deleterious effects on cardiac function in preterm sheep which mig...
Atherosclerosis is a chronic condition that may begin prior to birth, particularly in the presence of factors that act through inflammatory pathways. Inflammation may alter epigenetic marks, and changes in methylation are observed in atherosclerotic lesions. We hypothesised that intrauterine inflammation (chorioamnionitis, which complicates 1-4% of...
In neonatal resuscitation, the use of a sustained inflation (SI) may facilitate lung aeration. Previous studies comparing different resuscitation devices have shown that one model of self-inflating bag (SIB) could not deliver an SI. We aimed to compare the delivery of an SI using four SIBs with that of a T-piece.
In intubated preterm lambs, we comp...
Key points
Erythropoietin (EPO) has been suggested as a potential treatment for bronchopulmonary dysplasia (BPD) in preterm infants.
Ventilation‐induced lung injury (VILI) is a major cause of BPD in preterm neonates. We investigated whether early high‐dose EPO ( i.v. 5000 IU kg ⁻¹ ) administration can reduce lung inflammation and injury resultant f...
Diaphragmatic contractility is reduced in preterm lambs after lipopolysaccharide (LPS) exposure in utero. The mechanism of impaired fetal diaphragm contractility after LPS exposure is unknown. We hypothesise that in utero exposure to LPS induces a deficiency of mitochondrial complex activity and oxidative damage in the fetal diaphragm. To test this...
With a view to developing a cell therapy for chronic lung disease, human amnion epithelial cells (hAECs) have been shown to prevent acute lung injury. Whether they can repair established lung disease is unknown. We aimed to assess whether hAECs can repair existing lung damage induced
in mice by bleomycin and whether the timing of cell administratio...
Key points
Intrauterine inflammation impairs fetal pulmonary vascular development and increases cerebral metabolism in fetal sheep. Whether these structural and metabolic changes have functional consequences for fetal cardiopulmonary and cerebral haemodynamics is presently unknown.
We demonstrated that intra‐amniotic administration of lipopolysacch...
Preterm birth is associated with inflammation of the fetal membranes (chorioamnionitis). We aimed to establish how chorioamnionitis affects contractile function and phenotype of the preterm diaphragm. Pregnant ewes received intra-amniotic injections of saline or 10 mg lipopolysaccharide (LPS) 2d or 7d prior to delivery at 121d gestation (term = 150...
Preterm birth occurs in 11% of live births globally and accounts for 35% of all newborn deaths. Preterm newborns have immature immune systems, with reduced innate and adaptive immunity; their immune systems may be further compromised by various factors associated with preterm birth. The immune systems of preterm infants have a smaller pool of monoc...
Background aims:
Human amnion epithelial cells (hAECs) prevent pulmonary inflammation and injury in fetal sheep exposed to intrauterine lipopolysaccharide. We hypothesized that hAECs would similarly mitigate hyperoxia-induced neonatal lung injury.
Methods:
Newborn mouse pups were randomized to either normoxia (inspired O2 content (FiO2) = 0.21,...
Background:
Intrauterine inflammation adversely affects cardiopulmonary, systemic, and cerebral hemodynamics in preterm neonates, but its impact on responses to endotracheal tube (ETT) suction, known to affect hemodynamics, is unknown. We hypothesized that intrauterine inflammation would alter the cardiopulmonary and cerebral hemodynamic response...
Intrauterine infection, such as occurs in chorioamnionitis, is a principal cause of preterm birth and is a strong risk factor for neurological morbidity and cerebral palsy. This study aims to examine whether human amnion epithelial cells (hAECs) can be used as a potential therapeutic agent to reduce brain injury induced by intra-amniotic administra...
Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucoc...
Key points
Intrauterine inflammation is associated with preterm birth and poor long‐term cardiopulmonary and neurological outcomes. The effect of intrauterine inflammation on the cardiopulmonary and cerebral haemodynamic transition after preterm birth is poorly understood.
We demonstrated that intrauterine inflammation increased pulmonary vascular...
In this study, we determined the gene and/or protein expression of hypothalamic–pituitary–adrenal (HPA) axis regulatory molecules following synthetic glucocorticoid exposures. Pregnant sheep received intramuscular saline or betamethasone (BET) injections at 104 (BET-1), 104 and 111(BET-2) or 104, 111 and 118 (BET-3) days of gestation (dG). Samples...
Preterm birth is a major cause of perinatal mortality and long-term morbidity. Chorioamnionitis is a common cause of preterm birth. Clinical chorioamnionitis, characterised by maternal fever, leukocytosis, tachycardia, uterine tenderness, and preterm rupture of membranes, is less common than subclinical/histologic chorioamnionitis, which is asympto...
Life-threatening anomalies can occur during the development of the embryo as a result of genetic and/or environmental factors. Some of these are now amenable to surgical intervention, and novel corrective procedures have increasing success rates. The fetus is highly dependent upon the placenta and its physico-chemical environment for growth and dev...
It is common practice in Australian agriculture to remove the tails of lambs to prevent infection and to castrate males to prevent behavioural problems and unwanted reproduction. We have studied the pain and stress responses to these interventions by measuring changes in the hypothalamic-pituitary-adrenal (HPA) axis and β-endorphin levels. Further,...
Background:
Preterm infants often receive mechanical ventilation and oxygen at birth. Exposure to large tidal volumes (V(T)s) at birth causes lung inflammation, and oxygen may amplify the injury. We hypothesized that normal V(T) ventilation at birth causes lung injury that is exacerbated by 95% oxygen.
Methods:
The head and chest of anesthetized...
Background and Aims In neonatal resuscitation, the use of a sustained inflation (SI) after birth may facilitate lung recruitment. We aimed to assess the ability of several SIB to deliver a SI.
Method In a newborn preterm lamb, we compared 4 different SIB devices fitted with a PEEP valve against a T-piece, using a flow of 8 Lpm. Four operators aimed...