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PMID: 11086028 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis.

The Journal of clinical investigation ·Vol. 106 ·No. 10 ·2000-11-00 ·Pages 1271-80

Guo RF, Huber-Lang M, Wang X, Sarma V, Padgaonkar VA, Craig RA, Riedemann NC, McClintock SD, Hlaing T, Shi MM, Ward PA

Abstract

Multiorgan apoptosis occurs during sepsis. Following cecal ligation and puncture (CLP) in rats, thymocytes underwent apoptosis in a time-dependent manner. C5a blockade dramatically reduced thymocyte apoptosis as measured by thymic weight, binding of annexin V to thymocytes, and laddering of thymocyte DNA. When C5a was generated in vivo by infusion of purified cobra venom factor (CVF), thymocyte apoptosis was significantly increased. Similar results were found when CVF was injected in vivo during the early stages of CLP. In animals 12 hours after induction of CLP, there was an increase in the activities of caspase-3, -6, and -9, but not caspase-1 and -8. Cytosolic cytochrome c levels increased by twofold, whereas mitochondrial levels showed a 50% decrease. Western blot analysis revealed that the content of Bcl-X(L) (but not of Bcl-2, BAX, Bad, and Bim) significantly decreased in thymocytes after CLP. C5a blockade in the sepsis model almost completely inhibited caspase-3, -6, and -9 activation, significantly preserved cytochrome c in the mitochondrial fraction, and restored Bcl-X(L) expression. These data suggest that systemic activation of complement induces C5a-dependent apoptosis of thymocytes and that the blockade of C5a during sepsis rescues thymocytes from apoptosis.

MeSH Terms
Animals Apoptosis Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 Carrier Proteins/biosynthesis Caspase 3 Caspase 6 Caspase 9 Caspases/metabolism Complement C5a/immunology,metabolism Cytochrome c Group/metabolism Enzyme Activation Male Membrane Proteins Mitochondria/metabolism NF-kappa B/metabolism Organ Size Proto-Oncogene Proteins/biosynthesis Proto-Oncogene Proteins c-bcl-2/biosynthesis Rabbits Rats Rats, Long-Evans Sepsis/metabolism Thymus Gland/cytology,metabolism bcl-2-Associated X Protein bcl-Associated Death Protein bcl-X Protein
Chemicals
Apoptosis Regulatory Proteins Bad protein, rat Bax protein, rat Bcl-2-Like Protein 11 Bcl2l1 protein, rat Bcl2l11 protein, rat Carrier Proteins Cytochrome c Group Membrane Proteins NF-kappa B Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 bcl-2-Associated X Protein bcl-Associated Death Protein bcl-X Protein Complement C5a Casp3 protein, rat Casp6 protein, rat Casp9 protein, rat Caspase 3 Caspase 6 Caspase 9 Caspases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Guo R F
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Huber-Lang M
Wang X
Sarma V
Padgaonkar V A
Craig R A
Riedemann N C
McClintock S D
Hlaing T
Shi M M
Ward P A
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI10793
Published
2000-11-00
Pages
1271-80
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC381438
Subset
IM
Grants
NHLBI NIH HHS · P01 HL031963 · United States
NHLBI NIH HHS · HL-31963 · United States
External Links
PubMed source DOI: 10.1172/JCI10793 PMC Full Text View journal details
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