El-Awaisi, J. | Search bioRxiv

bioRxiv2025

Neutrophil and NET-driven pulmonary microvascular injury following myocardial injury: attenuation by S100A8/A9 inhibition

Myocardial infarction (MI) triggers not only local cardiac damage but also a systemic inflammatory response that extends to remote organs. The pulmonary microcirculation, by virtue of its dense capillary network and direct anatomical proximity to the heart, is particularly vulnerable. Neutrophils and their effector mechanisms, including neutrophil extracellular traps (NETs) and the alarmin S100A8/A9, have been implicated in adverse cardiovascular outcomes. However, their role in remote damage post-MI remains unclear. Using intravital in vivo imaging in murine MI models and analysis of human lung tissues, we show that MI induces rapid pulmonary neutrophil and platelet recruitment, formation of platelet-neutrophil aggregates within capillaries, and endothelial activation. These changes are accompanied by NET release, fibrin deposition, and microvascular obstruction, leading to impaired vascular perfusion and necrosis. These pulmonary disturbances closely parallel those in the infarcted myocardium and exceed responses observed in other organs such as the kidney and liver, highlighting the lung as a vulnerable target organ. Increased neutrophil recruitment was associated with marked upregulation of the neutrophil-derived, NET-associated alarmin S100A8/A9 in mouse and human lungs, where it co-localised with infiltrating neutrophils, NETs, and platelet aggregates. Additionally, we show that short-term pharmacological inhibition of S100A8/A9 with ABR-238901 significantly attenuated pulmonary neutrophil infiltration, reduced NETosis and fibrin deposition, and restored capillary perfusion while rebalancing the pulmonary immune landscape. Together, these findings identify the lung as a principal site of remote thrombo-inflammatory injury after MI and implicate S100A8/A9, a neutrophil-derived, NET-associated alarmin, as a mechanistic driver of pulmonary microvascular dysfunction. We propose that targeting this pathway could provide dual protection for both cardiac and pulmonary microcirculations in the acute phase of myocardial injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/675647v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@289725org.highwire.dtl.DTLVardef@db2011org.highwire.dtl.DTLVardef@16790dorg.highwire.dtl.DTLVardef@1655b17_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice

Sickle cell disease (SCD) leads to hemolytic anemia, vaso-occlusive crisis (VOC), hypoperfusion, and progressive organ damage. Hemin, released during hemolysis in SCD, induces platelet activation through CLEC-2, endothelial activation through TLR4, neutrophil adhesion and NETosis, all of which are regulated by spleen tyrosine kinase (Syk). In this study, we assessed neutrophil and platelet recruitment to the pulmonary, renal, splenic, and hepatic microvasculature in control and SCD mice following hemin injection and the effect of Syk inhibition on cell recruitment and organ perfusion. Compared to controls, SCD mice exhibited higher baseline neutrophil and platelet recruitment to the lungs without alterations in lung perfusion as measured by laser speckle contrast imaging. Injection of hemin increased cell recruitment to the pulmonary and renal vasculature with a concomitant reduction in organ perfusion. However, hemin injection did not change cell recruitment or organ perfusion in the spleen and liver, both of which were altered at baseline in SCD mice. Pretreatment of SCD mice with the Syk inhibitor BI-1002494 mitigated baseline and hemin-induced neutrophil and platelet adhesion in the pulmonary and renal microvasculature, with a corresponding normalization of perfusion. Syk regulates vascular integrity in the lung of SCD mice; whilst high concentrations of BI-1002494 increased bleeding, lowering drug concentrations preserved the inhibitory effect on platelet and neutrophil recruitment and lung perfusion and protected from bleeding complications. These data substantiate Syk as a mediator of vascular thrombo-inflammation and hypoperfusion in the lung and kidney of SCD and provide a rationale for pharmacological inhibition as a therapeutic strategy.

pathology↗