Intratracheal Endotoxin Causes Systemic Inflammation  in Ventilated Preterm Lambs

Kramer, Boris W.; Ikegami, Machiko; Jobe, Alan H.

doi:10.1164/ajrccm.165.4.2011118

Cited by 49 publications

(46 citation statements)

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“…We previously reported increased lung mRNA expression of these cytokines by 2h in ventilated preterm lambs compared with unventilated fetal controls (11). In addition, we demonstrated that exposure to ventilation and IT endotoxin causes a modest increase in lung IL-1␤ and IL-6 mRNAs in preterm and near term lambs (23-and 13-fold respectively) (14). We now show a much more robust expression of SAA3 mRNA in the lungs of these animals (366 fold increase).…”

Section: Serum Amyloid A3 Induction In Preterm Lambssupporting

confidence: 57%

“…Mechanical ventilation contributes to neonatal morbidity and mortality (9,10) by causing lung inflammation with the induction of the proinflammatory cytokine cascade (11)(12)(13). Intratracheal endotoxin induces both lung inflammation and a systemic inflammatory response in preterm and term ventilated lambs (14). Whether there is induction of a lung acute phase reactant response in these models is not known.…”

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Pulmonary and Systemic Induction of SAA3 After Ventilation and Endotoxin in Preterm Lambs

et al. 2005

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Serum amyloid A (SAA), an acute phase reactant (APR) protein, is induced in liver during systemic inflammation. Serum amyloid A3 (SAA3), an isoform of SAA, is induced in both liver and extra hepatic sites in response to proinflammatory stimuli such as cytokines. Previously, we showed a modest increase in plasma cytokine levels in a preterm lamb model of lung injury. The study objective was to determine the relative contributions of lung and liver to the acute phase response during postnatal lung injury. Preterm (130d) and near term (141d) newborn lambs (term ϭ 150d) were randomized to either no ventilation (controls), ventilation ϩ intratracheal (IT) endotoxin (endo) or ventilation ϩ IT saline. A group of near term lambs were exposed to ventilation ϩ IV endotoxin. In the lungs, ventilation alone increased SAA3 mRNA 3-and 13-fold while ventilation ϩ IT endotoxin increased SAA3 mRNA 64 and 366-fold above controls in preterm and near term lambs, respectively. In the liver, SAA3 mRNA was induced by ventilation alone (three-fold) and ventilation ϩ IT endotoxin (45-fold) above controls in both preterm and near term animals. Ventilation ϩ IV endotoxin caused the highest increase in SAA3 mRNA (212- The acute phase of the systemic inflammatory response is characterized by the hepatic synthesis and increased plasma concentrations of acute phase reactants (APR) such as heat shock proteins, C reactive protein (CRP), and the serum amyloids (1-3). The serum amyloid A family of proteins is one of the major APR whose plasma levels can increase up to 1000-fold in response to inflammation (4). Several isoforms of the SAA protein are conserved across species. The liver is the main source of SAA1 and SAA2 isoforms whereas SAA3 isoform expression is increased in liver as well as extra hepatic tissues (4 -7). We identified SAA3 as an endotoxin inducible gene in the fetal lung using subtraction hybridization of endotoxin versus saline exposed lung mRNA (8). No information is available regarding the biology of SAA3 in preterm newborn animals exposed to postnatal lung injury induced by mechanical ventilation, oxygen or endotoxin.Mechanical ventilation and pulmonary infections frequently cause lung injury in preterm infants. Mechanical ventilation contributes to neonatal morbidity and mortality (9,10) by causing lung inflammation with the induction of the proinflammatory cytokine cascade (11-13). Intratracheal endotoxin induces both lung inflammation and a systemic inflammatory response in preterm and term ventilated lambs (14). Whether there is induction of a lung acute phase reactant response in these models is not known. Furthermore, the occurrence of a systemic acute phase reactant response on lung exposure to pro-inflammatory stimuli is not well characterized. We hypothesized that SAA3 mRNA expression would increase in the preterm newborn lung postnatally exposed to proinflammatory stimuli. We, therefore, examined the effect of mechanical ventilation with or without endotoxin exposure on SAA3 mRNA induction in preterm and near term ...

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Section: Serum Amyloid A3 Induction In Preterm Lambssupporting

confidence: 57%

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confidence: 99%

Pulmonary and Systemic Induction of SAA3 After Ventilation and Endotoxin in Preterm Lambs

et al. 2005

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“…However, inflammation must be controlled to avoid systemic inflammation, which may be lethal. 54,70 Many factors affect the modulation of the inflammatory response, such as antenatal steroid therapy, resuscitation, surfactant therapy, mechanical ventilation, oxygen toxicity and pulmonary and/or systemic infection. 7 Along with the immaturity of the preterm immune system, 71 antenatal and postnatal factors may also condition and modulate the pulmonary inflammation.…”

Section: Glucocorticoids and Chorioamnionitismentioning

confidence: 99%

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

Kramer¹

2008

J Perinatol

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“…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).…”

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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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Intratracheal Endotoxin Causes Systemic Inflammation in Ventilated Preterm Lambs

Cited by 49 publications

References 39 publications

Pulmonary and Systemic Induction of SAA3 After Ventilation and Endotoxin in Preterm Lambs

Pulmonary and Systemic Induction of SAA3 After Ventilation and Endotoxin in Preterm Lambs

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

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

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