Abstract
There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific or hematopoietic-specific podoplanin deficient, mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS.
Highlights
Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome of acute respiratory failure in the critically ill
We demonstrate that following IT-LPS, platelets are present in bronchoalveolar lavage (BAL) in aggregates with neutrophils, which allows for C-type lectin-like 2 (CLEC-2) interaction with podoplanin expressed on BAL inflammatory alveolar macrophages
The data presented in this study 1) confirm that platelets are present in the alveolar space during inflammation, primarily in aggregates with neutrophils; 2) show that CLEC-2 expressed on platelets protects against excessive lung inflammation in a mouse model of ARDS; 3) are suggestive of a nonessential, or redundant, role for the CLEC-2 ligand, podoplanin, on AECI and lymphatic endothelial cells (LECs) during lung development and function during inflammation; and 4) implicate podoplanin expression on hematopoietic-derived cells in protecting against exaggerated lung inflammation in a mouse model of ARDS
Summary
Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome of acute respiratory failure in the critically ill. It is the final common pathway of response to a variety of direct pulmonary insults such as bacterial/viral pneumonia and gastric aspiration, or indirect insults such as abdominal sepsis or battlefield trauma [10, 35, 45]. There are no current readily available tests that can clearly identify those who are at high risk of ARDS, and no therapeutic interventions proven to prevent its occurrence. Other mechanistic insights into the pathophysiology of ARDS are needed to identify new pathways for therapeutic manipulation
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