Deficiency of Acute-Phase Serum Amyloid A Exacerbates Sepsis-Induced Mortality and Lung Injury in Mice.
Ailing JiAndrea C TrumbauerVictoria P NoffsingerLuke W MeredithBrittany DongQian WangLing GuoXiangan LiFrederick C De BeerNancy R WebbLisa R TannockMarlene E StarrChristopher M WatersPreetha ShridasPublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- wild type
- high fat diet induced
- acute kidney injury
- intensive care unit
- high density
- inflammatory response
- cardiovascular events
- mouse model
- cardiovascular disease
- immune response
- induced apoptosis
- single cell
- insulin resistance
- oxidative stress
- cell death
- liver failure
- toll like receptor
- lps induced
- adipose tissue
- signaling pathway
- peripheral blood
- anti inflammatory
- metabolic syndrome
- endothelial cells
- mass spectrometry
- long non coding rna
- combination therapy
- high glucose
- stress induced