α2-Antiplasmin and plasminogen activator inhibitors in healing human skin wounds

Abstract

Mechanical injury of tissues is followed by the formation of a provisional fibrin matrix, which is later replaced by granulation tissue. The fibrinolytic proteinase, plasmin, is thought to contribute to the displacement of the primary matrix. Plasmin is generated from the ubiquitous proenzyme plasminogen by plasminogen activators. The system of plasminogen activation is controlled at several levels: plasminogen activator inhibitors (PAI-1 and PAI-2) counteract the activity of plasminogen activators and alpha 2-antiplasmin inhibits the activity of plasmin. In order to elucidate the mechanisms that regulate the plasminogen activator system in healing human skin wounds, we performed the immunohistological study reported here. The plasmin inhibitor alpha 2-antiplasmin and PAI-2 were found in the primary fibrin-rich matrix and in the granulation tissue. alpha 2-Antiplasmin was diffusely distributed in the tissue and its distribution correlated with the presence and localization of plasmin(ogen) except that, in contrast to plasmin(ogen), the alpha 2-antiplasmin was apparently not cell-associated. The stainings for PAI-2 increased with time and paralleled the development of the cellular infiltrate. PAI-2 was found in association with cells, which were identified by double immunofluorescence stainings as monocytes/macrophages and fibroblasts. In line with the immunohistological data, polymerase chain reaction after reverse transcription revealed mRNA for PAI-2 in healing human skin wounds. Taken together, our findings indicate that in healing human skin wounds, PAI-2 is the primary regulator of plasminogen activators, whereas alpha 2-antiplasmin may serve to control plasmin activity.

Therapy with a Purified Plasminogen Concentrate in an Infant with Ligneous Conjunctivitis and Homozygous Plasminogen Deficiency

“…43 In addition to the Glu460Stop plasminogen mutation, two other homozygous mutations (Arg216→His and Trp597Stop) have recently been identified in two unrelated Turkish girls with ligneous conjunctivitis and severe type I plasminogen deficiency. 17 These molecular genetic findings confirm assumptions by others 4,23,29 that ligneous conjunctivitis is inherited, probably in an autosomal recessive manner.…”

“…Immunofluorescence staining for plasmin and plasminogen deposits in the granulation tissue was performed with use of previously described murine antihuman antibodies to plasmin and plasminogen 22 and fluorescein isothiocyanate-labeled antimouse IgG antibodies. 23 …”

Induction of the Plasminogen Activator System Accompanies Peripheral Nerve Regeneration after Sciatic Nerve Crush

“…The increase of PA-dependent activity and PA mRNA at the crush site within 1 d of crush could be attributed to reactive and infiltrating neutrophils, macrophages, fibroblasts, and Schwann cells into the area of injury. All of these cell types express components of the PA system (Eaton et al, 1984;Heiple and Ossowski, 1986;Wilson and Francis, 1987;Grau and Moroz, 1989;Varani et al, 1992;Kung and Lau, 1993;Schafer et al, 1994;Rao et al, 1995;Kindzelskii et al, 1996;Shetty et al, 1996;Xiao et al, 1998). Additionally, we demonstrated with immunostaining that macrophages and neutrophils were present at the crush site within 1 d after crush injury (Fig.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In healing wounds, the plasma-derived ECM is cleared through extracellular proteolysis by fibrinolytic enzymes (59) and through endocytosis by CCR2 + macrophages (60). In the healing infarct, clearance of the fibrin-based provisional matrix by the plasminogen/plasmin system is an important part of the reparative response.…”