Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis.

Department of Clinical Sciences, Malmo, Section of Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden.
Agents and Actions (Impact Factor: 1.59). 02/2012; 61(6):571-9. DOI: 10.1007/s00011-012-0446-6
Source: PubMed

ABSTRACT Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.
Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.
The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.
We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.

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    ABSTRACT: Matrix metalloproteinases (MMPs) and their inhibitors essentially contribute to a variety of pathophysiologies by modulating cell migration, tissue degradation and inflammation. Platelet-associated MMP activity appears to play a major role in these processes. First, platelets can concentrate leukocyte-derived MMP activity to sites of vascular injury by leukocyte recruitment. Second, platelets stimulate MMP production in e.g. leukocytes, endothelial cells, or tumour cells by direct receptor interaction or/and by paracrine pathways. Third, platelets synthesise and secrete a variety of MMPs including MMP-1, MMP-2, MMP-3, and MMP-14 (MT1-MMP), and potentially MMP-9 as well as the tissue inhibitors of metalloproteinase (TIMPs). This review focuses on platelet-derived and platelet-induced MMPs and their inhibitors.
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May 21, 2014