On the basis of our studies to date using the experimental model of sepsis induced by cecal ligation/puncture (CLP) in rats, serious impairment of innate immunity develops. This results in what appears to be a C5a-dependent defect in assembly of NADPH oxidase and defective phagocytic function of neutrophils. These defects can be reproduced by in vitro exposure of neutrophils to concentrations of C5a found in sepsis. In the first aim, we will evaluate how in vitro exposure of neutrophils to C5a results in detective signaling pathways: phorbol 12-myristate 13-acetate (PMA)-induced activation of phosphokinase C (PKC) which results in assembly of NADPH oxidase; and cell activation by engagement of FcyRs resulting in phagocytic responses. In the second aim, we will evaluate the same signaling pathways in blood neutrophils from CLP animals and determine if treatment with anti-C5a prevents defective signaling. In the third aim, we will determine if treatment of normal rats and mice and CLP rats and mice with anti-C5a compromises innate immunity, as assessed by bacterial clearance (Pseudomonas sp. and Klebsiella sp.) from lungs and evaluate the effects on survival. In the fourth aim, we will employ microarray analysis in CLP rats to define, as a function of time, alterations in global gene expression in organs that are predisposed to injury during sepsis (liver, lungs, kidneys, thymus) and determine if treatment with anti-C5a prevents this pattern of gene expression. It is possible that microarrary analysis will be predictive of organ susceptibility to damage during sepsis. Collectively, these studies should provide important evidence related to the mechanisms by which complement activation during sepsis impairs innate immunity.
| 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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