Administration of exogenous tissue plasminogen activator reduces oedema in mice lacking the tissue plasminogen...

It has recently become apparent that tissue plasminogen activator (tPA) modulates inflammation in diseases such as rheumatoid arthritis (RA) and acute respiratory distress syndrome (ARDS). We have shown previously that tPA has anti-inflammatory activity in in vivo models of oedema or inflammation. The present study investigated the ability of exogenous recombinant tPA (rtPA) to reduce carrageenan-mediated oedema in mice lacking the tPA gene, testing the hypothesis that rtPA treatment may be beneficial in diseases such as RA and ARDS in which there is a paucity of endogenous tPA. Knockout mice deficient in the tPA gene and matching wild-type mice received an intraplantar injection (25 micro L) of carrageenan (1.5%, w/v) following either vehicle (sterile water for injection) or tPA (12 mg/kg). Footpad oedema was measured, an oedema index was calculated and tissue myeloperoxidase (MPO) activity was determined. Mean oedema indices were higher in untreated tPA (-/-) mice than untreated wild-type mice. Pretreatment with rtPA in either tPA (-/-) or wild-type mice reduced the mean measured peak footpad oedema index by 63 and 48%, respectively. Tissue MPO activity was not different between treatment groups. We conclude that exogenous rtPA has the ability to reduce acute oedema without altering neutrophil infiltration into the site of injury in both tPA (-/-) and wild-type mice and that endogenous tPA may participate in the inflammatory process, as evidenced by higher oedema indices in untreated tPA (-/-) mice. These data provide support for the potential clinical utility of exogenous rtPA in the treatment of inflammatory diseases, such as RA and ARDS, in which there is a paucity of tPA.