Abstract 447: Deficiency Of Serum Amyloid A Exacerbates Sepsis-induced Acute Lung Injury In Mice

Abstract

Objectives: Serum Amyloid A (SAA) is a family of proteins whose plasma levels increase > 1000-fold in acute inflammatory states such as sepsis. We and others have demonstrated that SAA plays a causal role in mouse models of atherosclerosis. However, SAA may not be a valid therapeutic target if it is needed for host defense in inflammation. Here, we investigated the role of SAA in sepsis using mice deficient in all three acute-phase SAA isoforms (TKO). Approach and results: SAA deficiency significantly increased mortality rates in three experimental sepsis models. Survival rates in TKO and wild-type (WT) mice were: 25% and 55% after cecal ligation and puncture (CLP; p=0.02; n=10 each strain/gender); 0% and 45% after cecal slurry injection (p<0.0001; n=9 each strain); and 55% and 90 % after lipopolysaccharide injection (p<0.0001; n=10 each strain/gender). 24-hours after CLP, there were no apparent differences in liver, heart or kidney histology between genotypes. However, TKO mice had exacerbated lung pathology, including consolidation of lung tissues and atelectasis, compared to WT mice. RNAseq analysis of lungs excised 24-hours after CLP identified 664 genes differentially expressed (404 upregulated and 260 downregulated) in TKO compared to WT (p<0.05). Some of the genes that showed profound induction in the lungs of TKO compared to the WT were Proz, Dbp, Cxcl1, Cxcl2, Arg1 and Ackr1 . Gene ontology analysis revealed a significant enrichment of differentially expressed genes associated with chemokine production, chemokine and cytokine-mediated signaling, neutrophil chemotaxis and neutrophil migration in TKO lung tissues compared to WT tissues (p<0.01). Conclusions: SAA protects mice against sepsis-induced mortality, potentially by protecting the lung from tissue damage. Thus, the risk of infection should be considered when targeting SAA to ameliorate atherosclerosis.