title: Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Gores
authors.forename: Angela S
authors.initials: AS
authors.lastname: Delsing
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Kraus
authors.forename: Linda
authors.initials: L
authors.lastname: Powers
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vaena
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Milhem
authors.forename: Martha
authors.initials: M
authors.lastname: Monick
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Doerschug
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood* / Q000502:physiology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000556:secondary; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007680:Kidney Neoplasms; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000556:secondary; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood / Q000139:chemically induced*; D011446:Prospective Studies; D012720:Severity of Illness Index; D014797:Vital Capacity / Q000187:drug effects / Q000502:physiology
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D015415:Biomarkers; D007376:Interleukin-2
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