Complement dependency of cardiomyocyte release of mediators during sepsis

We have recently shown that antibodyâ induced blockade of C5a, C5a receptors, or ILâ 17A greatly reduced the harmful outcomes of sepsis. In the current study, normal cardiomyocytes from young (300 g) male Spragueâ Dawley rats responded in vitro to C5a (ED50=55 nM) with release of ILâ 6 and TNFα, peaking between 2 to 8 h. Neutralizing antibodies to mouse C5a or ILâ 17A (ED50=40 μg for each, based on improved survival) reduced spontaneous in vitro release of cardiosuppressive cytokines and chemokines in cardiomyocytes obtained from mice with polymicrobial sepsis. A nonâ neutralizing C5a antibody had no such effects. Cardiomyocytes from septic mice (C57Bl/6) showed increased mRNA for TNFR1, ILâ 6 (gp80), and C5aR at 6 h after sepsis. Cardiomyocytes from septic C5aRâ /â or C5L2â /â mice did not show spontaneous in vitro release of cytokines and chemokines. These data suggest that cardiomyocytes from septic mice release suppressive cytokines in a C5aâ , C5aRâ , and ILâ 17Aâ dependent manner, followed by mediator reactivity with receptors on cardiomyocytes, resulting in defective contractility and relaxation. These data may be relevant to a strategy for the treatment of heart dysfunction developing during sepsis.â Atefi, G., Zetoune, F. S., Herron, T. J., Jalife, J., Bosmann, M., Chen, A., Alâ Aref, R., Sarma, J. V., Ward, P. A. Complement dependency of cardiomyocyte release of mediators during sepsis. FASEB J. 25, 2500â 2508 (2011). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153592/1/fsb2025007040.pd