Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets.

Abstract

OBJECTIVE:

To study angiotensin-converting enzyme 2 in a piglet model with acute respiratory distress syndrome and to evaluate the therapeutic potential of this substance in a preclinical setting, as this model allows the assessment of the same parameters required for monitoring the disease in human intensive care medicine. The acute respiratory distress syndrome is the most severe form of acute lung injury with a high mortality rate. As yet, there is no specific therapy for improving the clinical outcome. Recently, angiotensin-converting enzyme 2, which inactivates angiotensin II, has been shown to ameliorate acute lung injury in mice.

DESIGN:

Prospective, randomized, double-blinded animal study.

SETTING:

Animal research laboratory.

SUBJECTS:

Fifteen anesthetized and mechanically ventilated piglets.

INTERVENTIONS:

Acute respiratory distress syndrome was induced by lipopolysaccharide infusion. Thereafter, six animals were assigned randomly into angiotensin-converting enzyme 2 group, whereas another six animals served as control. Three animals received angiotensin-converting enzyme 2 without lipopolysaccharide pretreatment.

MEASUREMENTS AND MAIN RESULTS:

Systemic and pulmonary hemodynamics, blood gas exchange parameters, tumor necrosis factor-alpha, and angiotensin II levels were examined before acute respiratory distress syndrome induction and at various time points after administering angiotensin-converting enzyme 2 or saline. In addition, ventilation-perfusion distribution of the lung tissue was assessed by the multiple inert gas elimination technique. Animals treated with angiotensin-converting enzyme 2 maintained significantly higher PaO2 than the control group, and pulmonary hypertension was less pronounced. Furthermore, angiotensin II and tumor necrosis factor-alpha levels, both of which were substantially increased, returned to basal values. Multiple inert gas elimination technique revealed a more homogeneous pulmonary blood flow after treatment with angiotensin-converting enzyme 2. In intergroup comparisons, there were no differences in pulmonary blood flow to lung units with subnormal ventilation/perfusion ratios.

CONCLUSIONS:

Angiotensin-converting enzyme 2 attenuates arterial hypoxemia, pulmonary hypertension, and redistribution of pulmonary blood flow in a piglet model of acute respiratory distress syndrome, and may be a promising substance for clinical use.

• Authors: Benedikt Treml, Nikolaus Neu, Axel Kleinsasser, Christian Gritsch, Thomas Finsterwalder, Ralf Geiger, Manfred Schuster, Evelyne Janzek, Hans Loibner, Josef Penninger, Alexander Loeckinger
• Journal: Critical care medicine (Crit Care Med) Vol. 38 Issue 2 Pg. 596-601 (Feb 2010) ISSN: 1530-0293 [Electronic] United States
• PMID: 19851091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2

Topics

• Acute Lung Injury (drug therapy)
• Angiotensin-Converting Enzyme 2
• Animals
• Blood Gas Analysis
• Disease Models, Animal
• Female
• Heart Rate (drug effects)
• Hypertension, Pulmonary (drug therapy)
• Lipopolysaccharides (pharmacology)
• Male
• Peptidyl-Dipeptidase A (blood, therapeutic use)
• Pulmonary Circulation (drug effects)
• Recombinant Proteins (therapeutic use)
• Respiratory Distress Syndrome (drug therapy)
• Swine
• Tumor Necrosis Factor-alpha (blood)
• Ventilation-Perfusion Ratio (drug effects)