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

Abstract

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 ...

A Single Instillation of Amorphous Silica Nanoparticles Induced Inflammatory Responses and Tissue Damage until Day 28 after Exposure

“…According to prior reports, SAA3 mRNA increased 13-15 fold in the ventilated lung when challenged with ovalbumin. 34) In the present study, the body weight of mice treated with SiNPs was apparently decreased compared with that of the control group on day 1 after instillation. In this point, we also guess that the decreases in weight gain may have resulted from the severe acute inflammatory response induced by instillation of SiNPs.…”

Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy

“…Saa3, an isoform of SaA, is an acute-phase reactant induced in both liver and extrahepatic sites in response to proinflammatory stimuli, and its increased expression in the lung has been observed in animal models of LPS-induced lung injury (32,37). A direct pathophysiological role in facilitation of ALI under conditions of ischemic AKI remains to be determined but, as demonstrated by its greater than 40-fold increase in early lung gene expression, Saa3 is an attractive candidate gene to be investigated as a potential mediator of AKI-induced ALI in future studies.…”

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

“…51 Proinflammatory cytokine mRNA in the fetal liver was inconsistently and minimally increased; plasma IL-6 and IL-8 levels were minimally increased. 33,49,52 Also, cytokine mRNA levels in the placenta and gut did not increase appreciably. 49 Therefore, a diffuse systemic fetal inflammatory response did not explain the local lung inflammation.…”