Abstract
Introduction: Recent studies suggest that platelets are key regulators of ARDS, however the exact mechanisms remain elusive. C-type lectin-like receptor 2 (CLEC-2) is highly expressed on platelets and has been shown to regulate vascular integrity at sites of acute inflammation. Its ligand, Podoplanin, is expressed highly on alveolar type I epithelial cells and on inflammatory macrophages. Therefore, we investigated the role of CLEC-2 in a murine model of ARDS.
Methods: CLEC-2 deficiency was established in two mouse strains using either tamoxifen-inducible or platelet-specific deletion via a Cre-lox system. Combining these with IT instillations of LPS (40µg), we analysed lung function by infra-red oximetry and the inflammatory response within the lungs compared to CLEC-2 sufficient littermate controls.
Results: In tamoxifen-induced CLEC-2 deficient mice arterial O2 saturation during IT-LPS was significantly reduced, with levels at 72h and 96h reduced to 78.2% and 78.3%, respectively, compared to 83.6% and 82.6% in control animals (p=0.0202). A 2.7 fold increase in BAL neutrophils (p<0.05) and protein (p<0.001) was observed 48h post IT-LPS. Moreover, significant increases in the neutrophil chemokines CXCL1 (14.8 fold; p=0.0001), CXCL2 (3.0 fold; p=0.0004) and CCL3 (2.4 fold; p=0.008) were detected in deficient animals. These differences were phenocopied in the platelet-specific deficient strain.
Conclusion: Taken together our data suggest that CLEC-2 expression on activated platelets is beneficial during murine lung injury, reducing alveolar inflammatory damage. These observations highlight platelet CLEC-2 as a protein whose dysregulation may contribute to ARDS.
- Copyright ©the authors 2016
