Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia.

Abstract

We report that, in rats, the lethal consequences of high-dose endotoxin challenge are exacerbated by the intravascular administration of prostaglandin E1 but attenuated by the intravascular administration of endocytosable particles. This protection is mediated by opsonins. Nonopsonizable particles were unable to provide protection unless first pseudoopsonized with antibody directed against the CR3 (CD11b/CD18) phagocyte receptor. We show that endogenously opsonized particles can act in concert with prostaglandin El (putatively by elevation of neutrophil intracellular cAMP and the resultant downregulation of CR3) to completely rescue animals from the lethal late-stage sequelae of experimental endotoxemia. These data illustrate that the interaction of particles with cellular receptors can transform the overall systemic response to prostaglandin E1 from pro-to antiinflammatory. This suggests a role for multiple receptor engagement events in defining the systemic prostaglandin response and offers a rationale for developing new therapeutic modalities in the treatment of sepsis and other inflammatory diseases.

Immunocompromised Hosts: Immunopharmacology of Modern Antifungals

“…It has been known for some time that administration of liposomes to endotoxin-challenged mice protects them from endotoxin-induced death in a dose-dependent manner [88]. In serum, unilamellar liposomes adsorb fibrinogen and fibronectin, activate complement, and fix C3bi and are subsequently endocytosed by monocytes and neutrophils by engaging the integrin complement receptor 3 [88,89].…”

Prolonging the In Vivo Residence Time of Prostaglandin E1 with Biodegradable Nanoparticles

“…An alternative strategy consists of developing carriers for PGE 1 , such as lipid emulsion (7)(8)(9), liposomes (10,11) and synthetic polymers (12,13), to modulate its pharmacokinetics. In 1983, one of the authors established a treatment technique using a lipid emulsion (so called lipid microspheres) with an average diameter of 0.2μm, which was composed of soybean oil, a drug and lecithin as the emulsifier (7).…”

Pharmacotherapy of Acute Lung Injury and the Acute Respiratory Distress Syndrome

“…One explanation for lack of its efficacy was that PGE1 was not able to target neutrophils sufficiently at nontoxic doses. With the introduction of liposomal PGE1 in the mid-1990s, which provides a means of more selective delivery of PGE1 to neutrophils [95], PGE1 for therapy of ARDS was revisited. In a pilot study by Abraham et al [96] in 25 patients with ARDS, liposomal PGE1 caused statistically significant improvement in the oxygenation, lung compliance, and ventilator dependency.…”