Abstract
Serum amyloid A (SAA) is a family of proteins, the plasma levels of which may increase >1000-fold in acute inflammatory states. We investigated the role of SAA in sepsis using mice deficient in all three acute-phase SAA isoforms (SAA-TKO). SAA deficiency significantly increased mortality rates in the three experimental sepsis mouse models: cecal ligation and puncture (CLP), cecal slurry (CS) injection, and lipopolysaccharide (LPS) treatments. SAA-TKO mice had exacerbated lung pathology compared to wild-type (WT) mice after CLP. A bulk RNA sequencing performed on lung tissues excised 24 h after CLP indicated significant enrichment in the expression of genes associated with chemokine production, chemokine and cytokine-mediated signaling, neutrophil chemotaxis, and neutrophil migration in SAA-TKO compared to WT mice. Consistently, myeloperoxidase activity and neutrophil counts were significantly increased in the lungs of septic SAA-TKO mice compared to WT mice. The in vitro treatment of HL-60, neutrophil-like cells, with SAA or SAA bound to a high-density lipoprotein (SAA-HDL), significantly decreased cellular transmigration through laminin-coated membranes compared to untreated cells. Thus, SAA potentially prevents neutrophil transmigration into injured lungs, thus reducing exacerbated tissue injury and mortality. In conclusion, we demonstrate for the first time that endogenous SAA plays a protective role in sepsis, including ameliorating lung injury.
Document Type
Article
Publication Date
12-2023
Digital Object Identifier (DOI)
https://doi.org/10.3390/ijms242417501
Funding Information
This work was supported by National Institutes of Health Grant HL147381 (to L.T. and P.S.), HL151419 (to C.M.W.), P30 GM127211/GM/NIGMS NIH HHS (to M.S. and P.S.), NIH R01 GM121796 (to X.L.), NIH 1R35 GM141478 (to X.L.); University of Kentucky Center for Clinical and Translational Science Pilot Award UL1TR001998 (to P.S.); United States Department of Veterans Affairs 1I01BX004639 (to X.L.).
Repository Citation
Ji, Ailing; Trumbauer, Andrea C.; Noffsinger, Victoria P.; Meredith, Luke W.; Dong, Brittany; Wang, Qian; Guo, Ling; Li, Xiangan; de Beer, Frederick C.; Webb, Nancy R.; Tannock, Lisa R.; Starr, Marlene E.; Waters, Christopher M.; and Shridas, Preetha, "Deficiency of Acute-Phase Serum Amyloid A Exacerbates Sepsis-Induced Mortality and Lung Injury in Mice" (2023). Saha Cardiovascular Research Center Faculty Publications. 76.
https://uknowledge.uky.edu/cvrc_facpub/76
Included in
Cardiology Commons, Catalysis and Reaction Engineering Commons, Circulatory and Respiratory Physiology Commons, Inorganic Chemistry Commons, Molecular Biology Commons, Organic Chemistry Commons, Other Computer Sciences Commons, Physical Chemistry Commons
Notes/Citation Information
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).