Neutrophil apoptosis inhibits endothelial cell proliferation during delayed infection by overexpression of PIM kinase

Abstract

Through the clinical analysis of wound edge samples of patients with chronic infectious wounds, we found that there were a good deal of acute and chronic inflammatory cells infiltrating around the wound edge of chronic wounds, most of which were neutrophils. Prior investigations have demonstrated the apoptosis of neutrophils is significantly delayed in the state of infection, and a good deal of neutrophils with delayed apoptosis gather around the wound. Whether it will affect the wound healing has not been fully clarified. In this study, we used PIM kinase inhibitor to promote the apoptosis of neutrophils and thus promote the wound healing by making infected wounds in rats. After LPS stimulation of the rat's back wound, the neutrophils at the edge of the wound infiltrated a lot, the expression profile of CD31 decreased significantly, and the expression of PIM kinase and inflammatory factors at the edge of the wound increased significantly; After the use of PIM kinase inhibitor, the expression of CD31 at the wound margin increased significantly, and the expression of PIM kinase and inflammatory factors at the wound margin decreased significantly. LPS stimulation of neutrophil delayed apoptosis can inhibit the proliferation of HMEC1; The use of PIM447 can promote the apoptosis of neutrophils and thus the proliferation of HMEC1. The mechanism study found that LPS can promote the expression of Bcl2 and downregulate the transcriptional profile of BAX and Caspase3 via the Bcl2/Caspase3 signaling pathway, thereby facilitating the expression of PIM kinase. Our data shows that: LPS can delay neutrophil apoptosis in infectious wounds caused by Gram-negative bacteria, resulting in a large amount of neutrophil infiltration at the wound margin, which inhibits the proliferation of endothelial cells. The mechanism by which LPS inhibits neutrophil apoptosis may involve promoting the expression of neutrophil PIM kinase and regulating the Bcl2/Caspase3 pathway.