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Platelet-Derived CD40L (CD154) Mediates Neutrophil Upregulation of Mac-1 and Recruitment in Septic Lung Injury.

Rahman, Milladur LU ; Zhang, Su LU ; Chew, Michelle LU ; Ersson, Anders LU ; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2009) In Annals of Surgery
Abstract
OBJECTIVE:: To define the role of CD40L in abdominal sepsis. BACKGROUND:: Platelets promote sepsis-induced pulmonary recruitment of neutrophils. However, the identity of the platelet-derived molecule regulating neutrophil infiltration is not known. The hypothesis of the present study was that platelet-derived CD40L might be responsible for platelet-mediated activation and accumulation of neutrophils in sepsis. METHODS:: Wild-type C57BL/6 mice and CD40L gene-deficient mice were exposed to cecal ligation and puncture (CLP). Lung edema, bronchoalveolar neutrophils, CD40L and macrophage inflammatory protein-2 (MIP-2) plasma levels, myeloperoxidase activity and Mac-1 expression were determined up to 24 hours after CLP induction. For platelet... (More)
OBJECTIVE:: To define the role of CD40L in abdominal sepsis. BACKGROUND:: Platelets promote sepsis-induced pulmonary recruitment of neutrophils. However, the identity of the platelet-derived molecule regulating neutrophil infiltration is not known. The hypothesis of the present study was that platelet-derived CD40L might be responsible for platelet-mediated activation and accumulation of neutrophils in sepsis. METHODS:: Wild-type C57BL/6 mice and CD40L gene-deficient mice were exposed to cecal ligation and puncture (CLP). Lung edema, bronchoalveolar neutrophils, CD40L and macrophage inflammatory protein-2 (MIP-2) plasma levels, myeloperoxidase activity and Mac-1 expression were determined up to 24 hours after CLP induction. For platelet depletion was an anti-GP1balpha antibody administered before CLP. RESULTS:: Plasma levels of soluble CD40L increased and surface expression of CD40L on platelets decreased in CLP mice. Platelet depletion reduced CLP-induced CD40L levels by 90%. CLP-provoked Mac-1 expression on neutrophils was abolished in CD40L-deficient mice. Interestingly, CLP-induced edema and myeloperoxidase activity in the lung as well as neutrophil infiltration in the broncoalveolar space were markedly reduced in mice lacking CD40L. In vitro experiments showed that CD40L was not capable of directly increasing Mac-1 levels on neutrophils. Instead, CLP-induced plasma levels of MIP-2 were significantly reduced in CD40L-deficient mice and inhibition of the MIP-2 receptor (CXCR2) decreased Mac-1 expression on neutrophils in septic animals. CONCLUSIONS:: CD40L derived from platelets is a potent activator of neutrophils and mediates sepsis-induced neutrophil recruitment and lung edema. The neutrophil activating mechanism of CD40L is indirect and mediated via MIP-2 formation and CXCR2 signaling. Targeting CD40L may be an effective approach to limit pulmonary damage in abdominal sepsis. (Less)
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Contribution to journal
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published
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in
Annals of Surgery
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:19806052
  • scopus:70449393352
ISSN
1528-1140
DOI
10.1097/SLA.0b013e3181bd95b7
language
English
LU publication?
yes
id
73c26db4-87f3-42f0-9e98-80b135fd34e2 (old id 1500627)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19806052?dopt=Abstract
date added to LUP
2009-11-04 10:47:22
date last changed
2017-10-29 04:28:58
@article{73c26db4-87f3-42f0-9e98-80b135fd34e2,
  abstract     = {OBJECTIVE:: To define the role of CD40L in abdominal sepsis. BACKGROUND:: Platelets promote sepsis-induced pulmonary recruitment of neutrophils. However, the identity of the platelet-derived molecule regulating neutrophil infiltration is not known. The hypothesis of the present study was that platelet-derived CD40L might be responsible for platelet-mediated activation and accumulation of neutrophils in sepsis. METHODS:: Wild-type C57BL/6 mice and CD40L gene-deficient mice were exposed to cecal ligation and puncture (CLP). Lung edema, bronchoalveolar neutrophils, CD40L and macrophage inflammatory protein-2 (MIP-2) plasma levels, myeloperoxidase activity and Mac-1 expression were determined up to 24 hours after CLP induction. For platelet depletion was an anti-GP1balpha antibody administered before CLP. RESULTS:: Plasma levels of soluble CD40L increased and surface expression of CD40L on platelets decreased in CLP mice. Platelet depletion reduced CLP-induced CD40L levels by 90%. CLP-provoked Mac-1 expression on neutrophils was abolished in CD40L-deficient mice. Interestingly, CLP-induced edema and myeloperoxidase activity in the lung as well as neutrophil infiltration in the broncoalveolar space were markedly reduced in mice lacking CD40L. In vitro experiments showed that CD40L was not capable of directly increasing Mac-1 levels on neutrophils. Instead, CLP-induced plasma levels of MIP-2 were significantly reduced in CD40L-deficient mice and inhibition of the MIP-2 receptor (CXCR2) decreased Mac-1 expression on neutrophils in septic animals. CONCLUSIONS:: CD40L derived from platelets is a potent activator of neutrophils and mediates sepsis-induced neutrophil recruitment and lung edema. The neutrophil activating mechanism of CD40L is indirect and mediated via MIP-2 formation and CXCR2 signaling. Targeting CD40L may be an effective approach to limit pulmonary damage in abdominal sepsis.},
  author       = {Rahman, Milladur and Zhang, Su and Chew, Michelle and Ersson, Anders and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1528-1140},
  language     = {eng},
  month        = {10},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Annals of Surgery},
  title        = {Platelet-Derived CD40L (CD154) Mediates Neutrophil Upregulation of Mac-1 and Recruitment in Septic Lung Injury.},
  url          = {http://dx.doi.org/10.1097/SLA.0b013e3181bd95b7},
  year         = {2009},
}