In this completely revised Competiting Renewal Application, we will continue to pursue evidence that, during experimental sepsis after cecal ligation and puncture (CLP) in rodents, regulation of the inflammatory system is lost, resulting in a variety of harmful outcomes (organ dysfunction, loss of innate immune functions of phagocytic cells and activation of the clotting/fibrinolytic system). These outcomes are linked to uncontrolled activation of the complement system, generation of C5a and its interaction with its receptors (C5aR and C5L2). The balance in receptor engagement determines adverse and lethal outcomes.
In Aim 1. we propose to use C5a receptor KO mice to determine how survival after CLP is affected and how systemic levels of inflammatory mediators are affected.
In Aim 2 we will pursue our recent studies which indicate that in sepsis heart and cardiomyocyte (CM) dysfunction can be linked to interaction of C5a with C5aR on CMs, the signaling mechanisms involved, and the extent to which CMs can produce harmful mediators during sepsis.
In Aim 3 we will pursue evidence that C5a can cause bleb formation and shedding of C5aR-enriched microparticles (MPs) in vitro and in vivo during sepsis and whether MP appearance after CLP is C5a dependent, the signaling mechanisms involved, and whether MPs represent a useful biomarker of sepsis. Finally, in Aim 4 we will pursue evidence that IL-17 production is driven by IL-23 and functions as """"""""master switch"""""""" during sepsis to promote systemic production of harmful inflammatory mediators. The unifying theme in these studies is sepsis-induced production of C5a which, interacting with its receptors, results in highly destructive outcomes. ? ? ?
| Fattahi, Fatemeh; Russell, Mark W; Malan, Elizabeth A et al. (2018) Harmful Roles of TLR3 and TLR9 in Cardiac Dysfunction Developing during Polymicrobial Sepsis. Biomed Res Int 2018:4302726 |
| Fattahi, Fatemeh; Frydrych, Lynn M; Bian, Guowu et al. (2018) Role of complement C5a and histones in septic cardiomyopathy. Mol Immunol 102:32-41 |
| Fattahi, Fatemeh; Ward, Peter A (2017) Complement and sepsis-induced heart dysfunction. Mol Immunol 84:57-64 |
| Fattahi, Fatemeh; Kalbitz, Miriam; Malan, Elizabeth A et al. (2017) Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. FASEB J 31:4129-4139 |
| Fattahi, Fatemeh; Grailer, Jamison J; Lu, Hope et al. (2017) Selective Biological Responses of Phagocytes and Lungs to Purified Histones. J Innate Immun 9:300-317 |
| Kalbitz, Miriam; Fattahi, Fatemeh; Grailer, Jamison J et al. (2016) Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis. FASEB J 30:3997-4006 |
| Haggadone, Mikel D; Grailer, Jamison J; Fattahi, Fatemeh et al. (2016) Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes. Mediators Inflamm 2016:1340156 |
| Delano, Matthew J; Ward, Peter A (2016) Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 126:23-31 |
| Kalbitz, Miriam; Fattahi, Fatemeh; Herron, Todd J et al. (2016) Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro. J Immunol 197:2353-61 |
| Fattahi, Fatemeh; Ward, Peter A (2016) Anti-inflammatory interventions-what has worked, not worked, and what may work in the future. Transl Res 167:1-6 |
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