Monocyte-derived macrophage and alveolar macrophage fibronectin production and cathepsin D activity.

Alveolar macrophages are thought to play an important role in ongoing tissue breakdown and repair processes in the normal lung. The secretion and regulation of cathepsin D (important for the final breakdown of collagen) and fibronectin (involved in the healing process) in human peripheral blood monocytes (PBM) and pulmonary alveolar macrophages (PAM) were investigated. Cathepsin D enzyme activity was measured by quantitating the TCA-soluble fragments of [3H]hemoglobin. Freshly isolated PBM contained less cell-associated cathepsin D activity than did freshly isolated PAM (314 +/- 35 micrograms/10(6) cells vs 381 +/- 35 micrograms/10(6) cells, respectively). After 7-10 days in culture, cell-associated enzyme levels in both PBM and PAM were significantly increased (P less than 0.001 for PBM; P less than 0.0001 for PAM). In addition, freshly isolated PAM secreted more cathepsin D than did freshly isolated PBM (5.8 +/- 3.2 micrograms/10(6) cells vs 0.83 +/- 0.83 micrograms/10(6) cells, P less than 0.02). In the presence of LPS (10 micrograms/ml), cell-associated cathepsin D was inhibited in both PBM and PAM. With the addition of gamma-IFN (500 U/ml), both cell-associated and secreted enzyme were increased in freshly isolated and 10-day-cultured PBM and PAM. In parallel studies, fibronectin secretion (by ELISA assay) in both PBM and PAM increased over time in culture. LPS had no effect on PBM or PAM secretion of human fibronectin while gamma-IFN increased PBM and PAM fibronectin levels. Thus, both macrophage cathepsin D activity and fibronectin secretion are increased by gamma-interferon while macrophage cathepsin D activity, but not fibronectin secretion, is decreased by LPS. These studies demonstrate that human macrophage cathepsin D activity is actively modulated by inflammatory mediators and that macrophage mediators of tissue breakdown and repair are not modulated synchronously.

Rapamycin (sirolimus, rapamune).

Rapamycin is a novel immunosuppressive agent that is undergoing clinical trials for use in allograft rejection therapy. This paper reviews its in-vitro biological properties, the current state of knowledge concerning its mechanism of action, and its therapeutic applications.