Drotrecogin Alfa (activated) Prevents Smoke-Induced Increases in Pulmonary Microvascular Permeability and Proinflammatory Cytokine IL-1β in Rats

Abstract

In an established rat model of smoke inhalation injury, we conducted a dose-response study to examine the protective effects of Xigris [drotrecogin alfa (activated) (DrotAA)], a recombinant form of human activated protein C (APC). DrotAA is a serine protease (approximately 55 kD molecular weight) with the same amino acid sequence and the glycosylation site as human plasma-derived APC. A total of 120 F344/NH rats (half each gender, approximately 175 g body weight) were randomly divided into five groups and exposed nose-only to air or diesel fuel smoke for 20 min. These rats were then i.v. administered with DrotAA in 0, 5, 10, and 20 mg/kg body weight, respectively, immediately following smoke exposure. Treatment with DrotAA significantly attenuated smoke inhalation injury in a dose-dependent manner at 2 hours after insult, as indicated by preserving microvascular permeability and proinflammatory cytokine IL-1beta (but not TNF-alpha and neuropeptide substance P) in bronchoalveolar lavage fluid (BALF). Moreover, the rats treated with 20 mg/ kg of DrotAA had an improvement of the expiration phase of pulmonary dynamic compliance. At all dosages, however, DrotAA also significantly increased all phases of pulmonary resistance compared with either the controls or to smoke inhalation alone. Generally, these data suggest that DrotAA may exert an anti-inflammatory effect by inhibiting cytokine-mediated inflammatory amplification. However, additional studies following a clinical course are needed to confirm the maximum efficiency and possible side effects of this recombined human activated protein C.

Recombinant human-activated protein C inhibits cardiomyocyte apoptosis in a rat model of myocardial ischemia–reperfusion

“…Mizutani et al [22] reported that intravenous administration of 100 mg/kg activated protein C significantly inhibited ischemia-reperfusioninduced increases in renal levels of TNF-a in rats. On the other hand, Wong et al [21] did not observe decrease in bronchoalveolar lavage fluid TNF-a levels with activated protein C doses of 5, 10 and 20 mg/kg. In the present study, 2 mg/kg/h activated protein C was infused intravenously, as the regimen with 2 mg/kg activated protein C intravenous bolus injection was reported to be protective in ischemic brain cells.…”

“…Activated protein C has been shown to inhibit the generation of TNF-a in several studies [20]. Few studies, however, failed to demonstrate a decrease in TNF-a level after administration of activated protein C [21]. This may be partly due to the wide dose range of activated protein C used in different trials.…”

Activated protein C therapy in a rat heat stroke model*

“…In rats, an intravenous dose of 100 g/kg, 2 mg/kg, or 20 mg/kg of APC, respectively, was found to prevent endotoxin-induced hypotension (52), ischemic stroke (53), or smoke-induced increases in pulmonary microvascular permeability and proinflammatory cytokine IL-1␤ (54). In the present results, a bolus injection of APC (0.5, 5, or 20 mg/kg, intravenously) significantly improved survival during heat stroke in rats.…”

Inhaled Activated Protein C Protects Mice from Ventilator-Induced Lung Injury.

“…Higher doses increased airway resistance and tissue elastance, possibly by inducing bronchoconstriction. Increases in airway resistance with APC have also been described with intravenous injection in rats [38], although data in humans are lacking. At the doses chosen the aforementioned phenomena were not observed and no effects on other important outcomes such as lung histology or mechanics could be documented by APC administration in lungs ventilated with protective Vts [see Figure S2 in Additional file 1].…”