Abstract Number: PB1286
Meeting: ISTH 2022 Congress
Background: The Acute Respiratory Distress Syndrome (ARDS) is a detrimental inflammatory disease state associated with high mortality. Especially, the infiltration of neutrophils into the pulmonary airspace is causative for the acute inflammation and lung injury. A role of platelet glycoprotein (GP)VI to host defense in a model of pneumonia-derived sepsis was suggested, but the underlying mechanisms remained elusive.
Aims: We aimed to mechanistically dissect the contribution of GPVI to thrombo-inflammation in the acute phase of experimental ARDS in mice.
Methods: GPVI was depleted in wild-type mice by injecting JAQ1 antibody. Acute alveolar inflammation was induced by intranasal instillation of lipopolysaccharide (LPS). A bronchoalveolar lavage (BAL) was performed after 4 hours and infiltrated cells, myeloperoxidase (MPO) activity, hemoglobin content and a set of cytokines were determined. MPO activity and Evans blue dye extravasation in the processed lung were analyzed. Furthermore, high resolution, multi-color confocal microscopy of cryosections and the ventilated lung (intravital confocal microscopy) was performed to assess cell-cell interactions during acute inflammation.
Results: Control mice developed a profound inflammatory response to LPS characterized by pulmonary and blood neutrophilia, hypothermia, and increased blood lactate levels. In contrast, GPVI depleted mice were clearly protected from pulmonary and systemic compromises as evidenced by reduced hypothermia and blood lactate levels, while inflammatory bleeding was not increased. This was accompanied by a markedly mitigated pulmonary neutrophilic infiltration and reduced platelet-neutrophil complex (PNC) formation in lung tissue as detectable in cryosections and by intravital microscopy. Remarkably, however, the extent of neutrophil extracellular trap (NET) formation was not different between control and GPVI-depleted animals. BAL analyses revealed diminished inflammatory cytokine levels and neutrophilic infiltrates in GPVI-depleted mice.
Conclusion(s): GPVI drives alveolar inflammation by promoting neutrophil recruitment and PNC formation, but not NETosis. GPVI inhibition might be a promising strategy to reduce the acute pulmonary inflammation causing ARDS.
To cite this abstract in AMA style:Burkard P, Schonhart C, Köhler D, Rosenberger P, Nieswandt B. GPVI drives pulmonary inflammation by mediating platelet-neutrophil complex formation in a murine model of ARDS [abstract]. https://abstracts.isth.org/abstract/gpvi-drives-pulmonary-inflammation-by-mediating-platelet-neutrophil-complex-formation-in-a-murine-model-of-ards/. Accessed February 28, 2024.
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