Toll-Like Receptors and Agonist Responses in the Developing Fetal Sheep Lung

Hillman, Noah H.; Moss, Timothy; Nitsos, Ilias; Kramer, Boris W.; Bachurski, Cindy J.; Ikegami, Machiko; Jobe, Alan H.; Kallapur, Suhas G.

doi:10.1203/pdr.0b013e3181647b3a

Cited by 68 publications

(63 citation statements)

References 33 publications

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“…Bronchoalveolar lavage fluid (BAL) of the left lung was used to determine total protein content (23) and differential cell counts after cytospins. Tissue from the left lung was snap frozen for RNA isolation, and 10 g of total RNA was used for IL-1␤ and IL-6 RNAse protection assays (24,25). The right upper lobe was inflation fixed with 10% formalin (26), and this tissue was used for injury scores.…”

Section: Methodsmentioning

confidence: 99%

Ventilation-Mediated Injury After Preterm Delivery of Ureaplasma parvum Colonized Fetal Lambs

et al. 2010

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Ureaplasma species are the microorganisms most frequently isolated from women with preterm birth and are associated with an increased risk of bronchopulmonary dysplasia. Initiation of ventilation with high tidal volumes (V T ) causes lung injury and inflammation. We investigated whether antenatal colonization with Ureaplasma parvum serovar 3 (UP) would alter the inflammatory response to mechanical ventilation of preterm lambs. Merino ewes were given intraamniotic injections of UP at 55-d gestation, and the lambs were surgically delivered at 128 Ϯ 1 d gestation and assigned to three groups: 1) gentle ventilation (GV), 2) high V T ventilation, or 3) unventilated control. Lambs delivered from noncolonized ewes were assigned to parallel groups. GV lambs received surfactant before ventilation with a V T of 7 mL/kg, positive end expiratory pressure (PEEP) 5 cm H 2 O . High V T lambs received no PEEP and escalating V T to 15 mL/kg by 15 min. At 15 min, surfactant was given, V T was reduced to 7 mL/kg, and PEEP was increased to 5 cm H 2 O. Monocytes in bronchoalveolar lavage were increased by UP, but colonization did not affect lung function. High V T ventilation increased Egr-1 signaling, proinflammatory cytokine expression, and injury scores compared with GV. Antenatal colonization with UP did not change lung function or modulate the lung injury and inflammation caused by high V T ventilation. (Pediatr Res 67: 630-635, 2010)

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Section: Methodsmentioning

confidence: 99%

Ventilation-Mediated Injury After Preterm Delivery of Ureaplasma parvum Colonized Fetal Lambs

et al. 2010

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“…Protein (23), and cell counts and differentials using cytospins were measured from the BALF. Total RNA was isolated from lung and liver, and 10 g of total RNA was used for IL-1␤, IL-6, IL-8, and TLR-4 quantitation using RNAse protection assays (24,25). LPS was measured in plasma collected after 3 h of ventilation using a Limulus amebocyte lysate assay (Bio Whittaker, Walkersville, MD) (16).…”

Section: Methodsmentioning

confidence: 99%

Lung and Systemic Inflammation in Preterm Lambs on Continuous Positive Airway Pressure or Conventional Ventilation

et al. 2009

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Intratracheal lipopolysaccharide (LPS) causes acute inflammation and injurious mechanical ventilation results in pulmonary and systemic inflammation. We aimed to determine in preterm lungs if continuous positive airway pressure (CPAP) protects against pulmonary and systemic inflammation, compared with conventional mechanical ventilation (CMV) after intratracheal LPS. Preterm fetuses were exposed to maternal betamethasone and Epostane 36 h before delivery at 133 d gestational age (term ϭ 150 d). Lambs were intubated and randomized to receive gentle CMV (tidal volume 8 mL/kg) or CPAP with 8 cm H 2 O pressure. Surfactant (10 mg/kg) mixed with 1 mg LPS or saline was instilled into the trachea at 15 min. Blood gas status, ventilation variables, and arterial pressures were recorded for 3 h. Static pressure-volume curves and lung and systemic inflammation were assessed postmortem. CPAP lambs had elevated Paco 2 and minute ventilation compared with the CMV lambs. Cytokine mRNA was increased in the lungs and liver of CPAP and CMV lambs relative to unventilated controls. Intratracheal LPS amplified the cytokine mRNA responses of IL-1␤, IL-6, and IL-8 in the lung and liver. Blood neutrophils decreased similarly after LPS in CPAP and CMV groups. Cytokine markers of lung injury or the systemic response to intratracheal LPS were not decreased by CPAP relative to CMV, in preterm lambs. . Similarly, ventilation with lung volumes that approach or exceed total lung capacity will stretch the lungs and cause injury (3,4). The preterm fetal lung is particularly vulnerable to lung injury during the transition from a fluid-filled lung to airway breathing because surfactant deficiency increases the pressures required to open the lung, the lung aerates nonuniformly, and the delicate tissues of the preterm lung are easily stretched (5,6). The use of continuous positive airway pressure (CPAP) is being advocated for transitioning the preterm fetal lung to air breathing as a way to decrease lung injury (7,8). Although CPAP can cause lung injury in sepsis models (9), CPAP can decrease indicators of lung injury in preterm lambs (10) compared with conventional mechanical ventilation (CMV) and its use has been associated with decreased bronchopulmonary dysplasia (11).Prior exposure of the adult lung to pro-inflammatory mediators such as endotoxin amplifies lung injury caused by ventilation from low lung volumes or elevated lung volumes (9,12,13), and the mediators can enter the systemic circulation and cause systemic inflammatory responses (14,15). Termventilated lambs do not leak endotoxin from the airspaces into the systemic circulation unless the lungs are over-stretched (16). In contrast, preterm lungs leak endotoxin or IL-1 with conventional ventilation (16,17). Chorioamnionitis is associated with many preterm deliveries before 32 wk gestational age, and inflammatory mediators are present in the fetal lung (18,19). We hypothesized that spontaneous breathing with CPAP would protect the preterm lung and minimize a systemic inflamma...

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“…70 The lung inflammation could be induced by LPS from periodontal organisms, 71 but a synthetic agonist for Toll-like receptor (TLR)-2 did not cause a consistent fetal lung inflammation. 72 Intraamniotic injections of endotoxin at 60 to 80 days of gestational age (40 to 55% of gestation) resulted in fetal lung inflammation at 125 days (term 150 days). 73 The experimental sheep work therefore suggests that the immature fetus can mount inflammation after exposure to some proinflammatory stimuli, with subsequent structural changes suggestive of lung maturation.…”

Section: Lungsmentioning

confidence: 99%

Chorioamnionitis: a multiorgan disease of the fetus?

et al. 2010

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The bacterial infection of chorion and amnion is a common finding in premature delivery and is referred to as chorioamnionitis. As the mother rarely shows symptoms of a systemic inflammation, the course of chorioamnionitis is frequently asymptomatic and chronic. In contrast, the fetal inflammatory response syndrome represents a separate phenomenon, including umbilical inflammation and increased serum levels of proinflammatory cytokines in the fetus. Ascending maternal infections frequently lead to systemic fetal inflammatory reaction. Clinical studies have shown that antenatal exposure to inflammation puts the extremely immature neonates at a high risk for worsening pulmonary, neurological and other organ development. Interestingly, the presence of chorioamnionitis is associated with a lower rate of neonatal mortality in extremely immature newborns. In the following review, the pathogeneses of inflammation-associated perinatal morbidity are outlined. The concept of fetal multiorganic disease during intrauterine infection is introduced and discussed.

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Toll-Like Receptors and Agonist Responses in the Developing Fetal Sheep Lung

Cited by 68 publications

References 33 publications

Ventilation-Mediated Injury After Preterm Delivery of Ureaplasma parvum Colonized Fetal Lambs

Ventilation-Mediated Injury After Preterm Delivery of Ureaplasma parvum Colonized Fetal Lambs

Lung and Systemic Inflammation in Preterm Lambs on Continuous Positive Airway Pressure or Conventional Ventilation

Chorioamnionitis: a multiorgan disease of the fetus?

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