ABSTRACT: Introduction: The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology. Methods: We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay. Results: At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = −0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001). Conclusions: Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
Received 4 Feb 2014; first review completed 25 Feb 2014; accepted in final form 3 Apr 2014
Address reprint requests to Kathryn M. Gores, MD, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242. E-mail: firstname.lastname@example.org.
This work was supported by the National Center for Advancing Translational Science and the National Institutes of Health through 2 UL1 TR000442-06 and R01 HL 092056.
The authors have no financial disclosures and no conflicts of interest to report. All authors have approved the manuscript and its submission to this journal.
The content is solely the responsibility of the authors and does not necessarily represent official views of the NIH.
K.M.G. contributed to acquisition of data, analysis and interpretation of data, drafting the submitted article, and revising it critically for important intellectual content. A.S.D. and S.J.K. contributed to conception and design, acquisition of data, and approval of the final manuscript. L.P. contributed to data analysis and approval of the final manuscript. D.A.V. and M.M.M. contributed to subject recruitment and approval of the final manuscript. M.M. contributed to data analysis and revising the manuscript critically for intellectual content. K.C.D. contributed to study conception and design, acquisition of data, analysis and interpretation of data, drafting the submitted article, and revising it critically for important intellectual content.