Plasmin Inhibitors Prevent Leukocyte Accumulation and Remodeling Events in the Postischemic Microvasculature

Abstract

Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well as inhibitors of the serine protease plasmin including tranexamic acid and ε-aminocaproic acid were found to significantly diminish I/R-elicited intravascular firm adherence and (subsequent) transmigration of neutrophils. Remodeling of collagen IV within the postischemic perivenular basement membrane was almost completely abrogated in animals treated with plasmin inhibitors or aprotinin. In separate experiments, incubation with plasmin did not directly activate neutrophils. Extravascular, but not intravascular administration of plasmin caused a dose-dependent increase in numbers of firmly adherent and transmigrated neutrophils. Blockade of mast cell activation as well as inhibition of leukotriene synthesis or antagonism of the platelet-activating-factor receptor significantly reduced plasmin-dependent neutrophil responses. In conclusion, our data suggest that extravasated plasmin(ogen) mediates neutrophil recruitment in vivo via activation of perivascular mast cells and secondary generation of lipid mediators. Aprotinin as well as the plasmin inhibitors tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall.

Plasmin Induces In Vivo Monocyte Recruitment through Protease-Activated Receptor-1–, MEK/ERK-, and CCR2-Mediated Signaling

“…To achieve this, finely coordinated mechanisms exist by which intravascular leukocytes become able to penetrate the vascular wall and migrate to the sites of injury or infection (8). The administration of Pla to the cremaster muscle of mice, at the same dose used in the present work (2 mg), induced firm adhesion and subsequent transmigration of leukocytes (42). In an attempt to understand better how Pla injection induced leukocyte migration, we used an in vivo model by injecting human Pla into the pleural cavity of mice and detected significant leukocyte recruitment.…”

Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation

“…41 Factors associated with mast cell activation were also reduced in H/R-incited sickle mice following CP55,940 treatment. GM-CSF and white blood cell counts are elevated in SCA patients 26 and in sickle mice, and are both further increased by H/R incitement.…”

Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue

“…In this regard, the role of proteases in particular for leukocyte migration remains an issue of controversial debate. [11][12][13][14][15][16][17][18] Over one third of all known proteolytic enzymes are serine proteases, which are characterized by the ability to hydrolyze the peptide bond of their substrates via a nucleophilic serine residue in the active site. Among these enzymes, plasmin is one of the most prominent members regarding its elementary function in the fibrinolytic system.…”