Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis.
(2013) In Journal of Thrombosis and Haemostasis 11(7). p.1385-1398- Abstract
- Background and objectives: Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase-9 might cleave surface expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis. Methods: Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine, myeloperoxidase levels, neutrophils in the lung as well as plasma levels of CD40L and MMP-9 were quantified. Results: CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease of platelet surface CD40L and increase of soluble... (More)
- Background and objectives: Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase-9 might cleave surface expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis. Methods: Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine, myeloperoxidase levels, neutrophils in the lung as well as plasma levels of CD40L and MMP-9 were quantified. Results: CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease of platelet surface CD40L and increase of soluble CD40L levels were significantly attenuated in MMP-9 gene-deficient mice. Moreover, pulmonary MPO activity and neutrophil infiltration in the alveolar space as well as edema formation and lung injury were markedly decreased in septic animals lacking MMP-9. In vitro studies revealed that inhibition of MMP-9 decreased platelet shedding of CD40L. Moreover, recombinant MMP-9 was capable of cleaving surface expressed CD40L on activated platelets. In human studies, plasma levels of MMP-9 were significantly increased in patients with septic shock compared to healthy controls although MMP-9 levels did not correlate with organ injury score. Conclusions: Our novel data propose a role of MMP-9 in regulating platelet-dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP-9 may be a useful strategy to limit acute lung injury in abdominal sepsis. This article is protected by copyright. All rights reserved. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3733363
- author
- Rahman, Milladur LU ; Zhang, Songen LU ; Chew, Michelle LU ; Syk, Ingvar LU ; Jeppsson, Bengt LU and Thorlacius, Henrik LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Thrombosis and Haemostasis
- volume
- 11
- issue
- 7
- pages
- 1385 - 1398
- publisher
- Wiley-Blackwell
- external identifiers
-
- wos:000321763500019
- pmid:23617547
- scopus:84880420104
- pmid:23617547
- ISSN
- 1538-7933
- DOI
- 10.1111/jth.12273
- language
- English
- LU publication?
- yes
- id
- 85d947c7-314e-4537-99f9-812f93e8ecfb (old id 3733363)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23617547?dopt=Abstract
- date added to LUP
- 2016-04-01 11:08:44
- date last changed
- 2022-04-20 17:22:42
@article{85d947c7-314e-4537-99f9-812f93e8ecfb, abstract = {{Background and objectives: Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase-9 might cleave surface expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis. Methods: Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine, myeloperoxidase levels, neutrophils in the lung as well as plasma levels of CD40L and MMP-9 were quantified. Results: CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease of platelet surface CD40L and increase of soluble CD40L levels were significantly attenuated in MMP-9 gene-deficient mice. Moreover, pulmonary MPO activity and neutrophil infiltration in the alveolar space as well as edema formation and lung injury were markedly decreased in septic animals lacking MMP-9. In vitro studies revealed that inhibition of MMP-9 decreased platelet shedding of CD40L. Moreover, recombinant MMP-9 was capable of cleaving surface expressed CD40L on activated platelets. In human studies, plasma levels of MMP-9 were significantly increased in patients with septic shock compared to healthy controls although MMP-9 levels did not correlate with organ injury score. Conclusions: Our novel data propose a role of MMP-9 in regulating platelet-dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP-9 may be a useful strategy to limit acute lung injury in abdominal sepsis. This article is protected by copyright. All rights reserved.}}, author = {{Rahman, Milladur and Zhang, Songen and Chew, Michelle and Syk, Ingvar and Jeppsson, Bengt and Thorlacius, Henrik}}, issn = {{1538-7933}}, language = {{eng}}, number = {{7}}, pages = {{1385--1398}}, publisher = {{Wiley-Blackwell}}, series = {{Journal of Thrombosis and Haemostasis}}, title = {{Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis.}}, url = {{http://dx.doi.org/10.1111/jth.12273}}, doi = {{10.1111/jth.12273}}, volume = {{11}}, year = {{2013}}, }