title: Acute lung injury and acute kidney injury are established by four hours in experimental sepsis and are improved with pre, but not post, sepsis administration of TNF-α antibodies.
abstract: BACKGROUND
  Acute kidney injury (AKI) and acute lung injury (ALI) are serious complications of sepsis. AKI is often viewed as a late complication of sepsis. Notably, the onset of AKI relative to ALI is unclear as routine measures of kidney function (BUN and creatinine) are insensitive and increase late. In this study, we hypothesized that AKI and ALI would occur simultaneously due to a shared pathophysiology (i.e., TNF-α mediated systemic inflammatory response syndrome [SIRS]), but that sensitive markers of kidney function would be required to identify AKI.
  
  
  METHODS
  Sepsis was induced in adult male C57B/6 mice with 5 different one time doses of intraperitoneal (IP) endotoxin (LPS) (0.00001, 0.0001, 0.001, 0.01, or 0.25 mg) or cecal ligation and puncture (CLP). SIRS was assessed by serum proinflammatory cytokines (TNF-α, IL-1β, CXCL1, IL-6), ALI was assessed by lung inflammation (lung myeloperoxidase [MPO] activity), and AKI was assessed by serum creatinine, BUN, and glomerular filtration rate (GFR) (by FITC-labeled inulin clearance) at 4 hours. 20 µgs of TNF-α antibody (Ab) or vehicle were injected IP 2 hours before or 2 hours after IP LPS.
  
  
  RESULTS
  Serum cytokines increased with all 5 doses of LPS; AKI and ALI were detected within 4 hours of IP LPS or CLP, using sensitive markers of GFR and lung inflammation, respectively. Notably, creatinine did not increase with any dose; BUN increased with 0.01 and 0.25 mg. Remarkably, GFR was reduced 50% in the 0.001 mg LPS dose, demonstrating that dramatic loss of kidney function can occur in sepsis without a change in BUN or creatinine. Prophylactic TNF-α Ab reduced serum cytokines, lung MPO activity, and BUN; however, post-sepsis administration had no effect.
  
  
  CONCLUSIONS
  ALI and AKI occur together early in the course of sepsis and TNF-α plays a role in the early pathogenesis of both.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Rhea
authors.initials: R
authors.lastname: Bhargava
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Altmann
authors.forename: Ana
authors.initials: A
authors.lastname: Andres-Hernando
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Webb
authors.forename: Kayo
authors.initials: K
authors.lastname: Okamura
authors.forename: Yimu
authors.initials: Y
authors.lastname: Yang
authors.forename: Sandor
authors.initials: S
authors.lastname: Falk
authors.forename: Eric P
authors.initials: EP
authors.lastname: Schmidt
authors.forename: Sarah
authors.initials: S
authors.lastname: Faubel
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D055371:Acute Lung Injury / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity; D005919:Glomerular Filtration Rate / Q000187:drug effects; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000172:deficiency / Q000494:pharmacology / Q000652:urine; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000652:urine; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000150:complications*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D004731:Endotoxins; D015850:Interleukin-6; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D016753:Interleukin-10; D003404:Creatinine; D009195:Peroxidase