title: Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.
abstract: BACKGROUND
  Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS) and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury), intraperitoneal (IP) endotoxin administration (indirect lung injury) and, for comparison, intratracheal (IT) endotoxin administration (direct lung injury) with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation.
  
  
  METHODS
  Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10), BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration]), and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping), IP endotoxin (10 µg), or IT endotoxin (80 µg) with and without intratracheal (IT) IL-6 (25 ng or 200 ng) treatment.
  
  
  RESULTS
  Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin.
  
  
  CONCLUSIONS
  IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of ARDS.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Rhea
authors.initials: R
authors.lastname: Bhargava
authors.forename: William
authors.initials: W
authors.lastname: Janssen
authors.forename: Christopher
authors.initials: C
authors.lastname: Altmann
authors.forename: Ana
authors.initials: A
authors.lastname: Andrés-Hernando
authors.forename: Kayo
authors.initials: K
authors.lastname: Okamura
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
authors.forename: Nilesh
authors.initials: N
authors.lastname: Ahuja
authors.forename: Sarah
authors.initials: S
authors.lastname: Faubel
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications; D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001806:Blood Urea Nitrogen; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000276:immunology; D004731:Endotoxins / Q000633:toxicity; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000209:etiology* / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism
chemical_list: D016207:Cytokines; D004731:Endotoxins; D015850:Interleukin-6; C044101:endotoxin, Escherichia coli; D003404:Creatinine