Plasminogen Activator Inhibitor-1 Supports IL-8-Mediated Neutrophil Transendothelial Migration by Inhibition of the Constitutive Shedding of Endothelial IL-8/Heparan Sulfate/Syndecan-1 Complexes

PAI-1 inhibits neutrophil efferocytosis

“…Because apoptotic cell clearance is critical to the resolution of inflammation, our data suggest that PAI-1 may exacerbate inflammatory responses by blocking the clearance of apoptotic neutrophils, thereby allowing such neutrophils to become necrotic and to release their intracellular contents into the extracellular milieu. Our findings, together with previous studies demonstrating that PAI-1 enhances LPS induced neutrophil activation (22) and promotes the migration and infiltration of lymphocytes and neutrophils into inflammatory sites (19)(20)(21)27), demonstrate that PAI-1 has multiple proinflammatory roles that are independent of its participation in coagulation and microvascular thrombosis. We found that the enhanced neutrophil phagocytosis associated with PAI-1 deficiency can be abrogated by blocking LRP on macrophages with anti-LRP antibodies or the LRP-specific blocking peptide RAP, indicating that LRP participates in PAI-1 mediated modulation of efferocytosis.…”

“…Elevated serum and tissue levels of PAI-1 have been found in a number of inflammatory diseases, including myocardial infarction, sepsis, and acute lung injury, with increased circulating PAI-1 levels being associated with unfavorable outcomes (15)(16)(17)(18). Previous studies suggested that microvascular thrombosis associated with inhibition of fibrinolytic processes by PAI-1 and the role of PAI-1 as a chemotactic factor promoting the migration of lymphocytes and neutrophils into inflammatory sites contributed to its inflammatory effects (19)(20)(21). In addition, PAI-1 also appears to have intrinsic proinflammatory properties by potentiating Toll-like receptor 4 (TLR4) mediated activation of neutrophils (22).…”

Induction of a CXCL8 binding site on endothelial syndecan‐3 in rheumatoid synovium

“…The synthetic specificity of chemokine binding sites on HSPGs is further illustrated by syndecan-2. This is one of the HSPGs synthesized by cultured HUVECs (58,65) that harbor CXCL8 binding structures on their HS chains (16). Syndecan-2 is also a major HSPG expressed by monocyte-derived macrophages yet does not express binding motifs for CXCL8, and other chemokines, on its HS chains (66).…”

The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis

“…Inflammation in the CF lung is mediated in part by the presence of increased concentrations of GAGs which stabilise active CXCL8 and protect it from proteolytic degradation, therefore establishing a chemotactic gradient and promoting the influx of destructive neutrophils (Kuschert et al, 1999). The GAG most successful at binding CXCL8 is heparan sulphate when in association with the core protein syndecan-1 (Marshall et al, 2003). Potential therapeutics that directly target inflammatory processes and remove the need for prolonged use of corticosteroids are highly desirable (Konstan and Davis, 2002).…”