Abstract P3080: S100A8/9 Is A Key Regulator For Normal Heart Function During Pseudomonas Aeruginosa Infection

• Published in: Circulation research Vol. 131; no. Suppl_1
• Main Authors: Kumar, Naresh, Pestrak, Matthew J, Wu, Qian, Dellos-Nolan, Sheri, Shukla, Rajnikant, Mitchem, Cortney F., yu, Lianbo, Lafuse, William, Nagareddy, Prabhakara R, Ganesan, Latha P., Wozniak, Daniel, Rajaram, Murugesan V
• Format: Journal Article
• Language: English
• Published: 05.08.2022
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3080

Abstract only Rationale: P. aeruginosa ( P.a ) infection can cause severe pneumonia in ICU patients that leads to cardiac inflammation and cardiac dysfunction. Growing evidence indicates that a large number of neutrophils are recruited to the site of P.a. infection and releases S100A8/9 into the microenvironment. S100A8/9 has been shown to activate both the immune system (TLR4/RAGE) and has bactericidal properties. Often, hyperactivation of the inflammatory responses by S100A8/9 causes cardiac inflammation and dysfunction. Thus, we hypothesize that excessive production of S100A8/9 restrict bacterial growth and enhances the host immune response in order to control the infection and preserve heart function. Objective: To identify the mechanism of S100A8/9 mediated cardiac inflammation and cardiac dysfunction during P. aeruginosa infection. Methods and Results: To investigate the role of S100A8/9 in cardiac inflammation and cardiac dysfunction, we infected wild type (WT) and S100A8/9KO mice with P.a. intranasally. We monitored bodyweight at 24h intervals and measured weight loss, survival, and bacterial burden in the lungs and heart. We performed multicolor flow cytometry on BAL cells and heart cells for immune cell phenotyping and ELISA for cytokine levels. Also, we measured cardiac electric activity (EKG) and heart function (echocardiography). We found that bacterial burden in the lungs and heart was higher in S100A8/9KO mice than in WT, which correlated with increased mortality. We found severe cardiac electrical abnormalities (second-degree AV block) in S100A8/9KO mice and left ventricular dysfunction. However, there was no significant difference in the BALF immune cell phenotypes of both S100A8/9KO and WT infected mice. Finally, the S100A8/9 inhibitor enhanced the survival of P.a. infected mice. Conclusion: Our data demonstrate that neutrophil recruitment and release of S100A8/9 is critical to control bacterial growth in the lungs, however, uncontrolled neutrophil accumulation leads to excessive production of S100A8/9. Hyperactivation of the immune system by excessive S100A8/9 leads to systemic inflammation and bacterial dissemination of the heart. Furthermore, our studies revealed that blocking S100A8/9 receptor binding enhances the survival of mice during P.a. infection.