Key Point

Angiopoietin-2 may serve as a relevant biomarker of acute lung injury in patients with sepsis-associated ARDS.

BOSTON—Angiopoietin-2 (Ang-2) may play a critical role in disrupting normal pulmonary endothelial function, a recent study has suggested.¹ Investigators at Beth Israel Deaconess Medical Center and Harvard School of Public Health, both in Boston, found that excess Ang-2 signaling could promote pulmonary vascular leak in patients with sepsis-associated ARDS.

Investigators first measured circulating Ang-2 levels in 22 patients with sepsis over a two-month period. Findings revealed that after starting with the highest circulating Ang-2 levels, patients with severe sepsis developed even higher peak Ang-2 levels during the course of hospitalization. Patients with mild sepsis and 29 control patients without sepsis had Ang-2 serum levels that generally remained at 10 ng/mL or lower.

Results from one patient’s serum showed the presence of a serum activity during severe sepsis that induced endothelial barrier disruption. In addition, clinical resolution correlated with falling Ang-2 levels and decreased barrier-disrupting activity. This activity was reversed with Ang-1, suggesting that "Ang-2 in the serum of human patients is at least partially responsible for altering endothelial architecture in sepsis," noted lead author Samir M. Parikh, MD, and colleagues. Investigators then established that Ang-2 alone could promote pathologic structural changes in endothelial monolayers and found that Ang-2 stimulation for eight hours increased permeability by approximately 20% compared with the control.

Lastly, investigators examined lung sections from adult mice treated either with placebo or with Ang-2 (10 µg) and found increased cellularity, congestion, and early extravasation into air spaces three hours after systemic administration of Ang-2; these changes were more pronounced at 48 hours following a total Ang-2 dose of 20 µg. Control mice, however, exhibited alveolar septa that formed a fine, thin network. These findings "establish an in vivo causative role for Ang-2 in pulmonary vascular leak and further substantiate the in vitro permeability effects observed earlier with Ang-2 stimulation," the investigators stated.

They added, "These results collectively argue that elevated circulating Ang-2 occurs in severe sepsis and that excess Ang-2 can produce pulmonary hyperpermeability in vivo." The investigators suggested that if Ang-2 is confirmed as a relevant biomarker of acute lung injury, Ang-2 values could be followed in at-risk patients to "identify someone who would particularly benefit from therapy directed against leak itself in an effort to halt the evolution of ARDS at its earliest exudative phase."

However, they pointed out that their results do not definitively show that only endothelial changes cause Ang-2 distortion. One possible explanation for this effect is that excess Ang-2 not only "distorts microvascular architecture ... but also potentially interferes with larger vessels by exerting effects on tone that change hydrostatic pressure to favor extravasation."

Dr. Parikh and colleagues also cautioned that the correlation between serum Ang-2 and poor gas exchange in patients with severe sepsis may not be causative, and several alternate explanations of the correlation need to be addressed in future studies to "further define the role of the endothelium—as opposed to the epithelium—in defending the alveolar permeability barrier."

—John Merriman

Reference
1. Parikh SM, Mammoto T, Schultz A, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 2006;3:e46.

Return to table of contents