Effects of Activated Protein C on Ventilator-Induced Lung Injury in Rats

Abstract

Background: Mechanical ventilation with a high tidal volume (VT) increases lung and systemic plasminogen activator inhibitor (PAI)-1 levels and alveolar fibrin deposition. Activated protein C (APC) may decrease PAI activity in endothelial cell-conditioned medium and thus enhance fibrinolysis. Objectives: The aims of this study were to test the hypothesis that APC can neutralize PAI-1 activity and improve lung function in an animal model of ventilator-induced lung injury. Methods: Rats were ventilated with a high-volume zero positive end-expiratory pressure (PEEP; HVZP) protocol by a volume-cycled ventilator for 2 h at a VT of 30 ml/kg, a respiratory rate of 25 breaths/min, and an FiO₂ of 0.21. Fifteen minutes before ventilation, the rats received intravenous APC (250 µg/kg, HVZP+APC group) or normal saline (vehicle; HVZP group). Another group that received no ventilation served as the control group. Results: Levels of arterial blood gas tension were comparable between the two ventilation groups throughout the study period. Rats treated with the HVZP protocol exhibited significantly higher total protein and macrophage inflammatory protein-2 concentrations in bronchoalveolar lavage fluid (BALF) and higher lung PAI-1 mRNA expression and plasma active PAI-1 levels than did the control group. Administration of APC tended to reduce the BALF protein content and systemic PAI-1 activity but did not improve the lung histology in the HVZP+APC group. Plasma levels of D-dimers were comparable among the three study groups. Conclusions: These results suggest that APC administered at a higher dosage might improve lung function by reducing alveolar protein leakage and systemic coagulation.

Plasma‐derived human antithrombin attenuates ventilator‐induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats

“…We found no effect of AT on ventilator‐induced coagulopathy and inflammation in non‐infected rats. This might be surprising, as APC have been shown to be protective in healthy lungs subjected to ventilation [45,49]. In the present study, coagulation was only mildly activated by the ventilator, mechanical ventilation in combination with pneumonia, however, strongly increased TATc production.…”

The Effect of Tidal Volume on Systemic Inflammation in Acid-Induced Lung Injury

“…For example, primary or direct insults, such as gastric acid aspiration and/or pneumonia, appear to predispose the lung to secondary insults, such as MV, which may then culminate in overwhelming lung inflammation [7]. It is speculated that in this setting, the lung may represent a primary source of signaling mediators which could then translocate into the systemic circulation and elicit pathologic responses in downstream organs [8,9]. …”

New insights in ARDS pathogenesis

“…Increased levels of PAI-1 are present in bronchoalveolar fluid and plasma from patients with ARDS. PAI-1 suppresses tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) from converting plasminogen to plasmin, which ultimately leads to reduced fibrin degradation [86,[88][89][90][91][92][93].…”