Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
Serum IL-6 is increased in patients with acute kidney injury (AKI) and is associated with prolonged mechanical ventilation and increased mortality. Inhibition of IL-6 in mice with AKI reduces lung injury associated with a reduction in the chemokine CXCL1 and lung neutrophils. Whether circulating IL-6 or locally produced lung IL-6 mediates lung injury after AKI is unknown. We hypothesized that circulating IL-6 mediates lung injury after AKI by increasing lung endothelial CXCL1 production and subsequent neutrophil infiltration. To test the role of circulating IL-6 in AKI-mediated lung injury, recombinant murine IL-6 was administered to IL-6-deficient mice. To test the role of CXCL1 in AKI-mediated lung injury, CXCL1 was inhibited by use of CXCR2-deficient mice and anti-CXCL1 antibodies in mice with ischemic AKI or bilateral nephrectomy. Injection of recombinant IL-6 to IL-6-deficient mice with AKI increased lung CXCL1 and lung neutrophils. Lung endothelial CXCL1 was increased after AKI. CXCR2-deficient and CXCL1 antibody-treated mice with ischemic AKI or bilateral nephrectomy had reduced lung neutrophil content. In summary, we demonstrate for the first time that circulating IL-6 is a mediator of lung inflammation and injury after AKI. Since serum IL-6 is increased in patients with either AKI or acute lung injury and predicts prolonged mechanical ventilation and increased mortality in both conditions, our data suggest that serum IL-6 is not simply a biomarker of poor outcomes but a pathogenic mediator of lung injury.
Department of Medicine, University of Colorado Denver, USA.
Nilesh
N
Ahuja
Ana
A
Andres-Hernando
Christopher
C
Altmann
Rhea
R
Bhargava
Jasna
J
Bacalja
Ryan G
RG
Webb
Zhibin
Z
He
Charles L
CL
Edelstein
Sarah
S
Faubel
D058186:Acute Kidney Injury / Q000097:blood / Q000150:complications* / Q000601:surgery; D055371:Acute Lung Injury / Q000097:blood / Q000209:etiology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D019559:Capillary Leak Syndrome / Q000097:blood / Q000209:etiology; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D007511:Ischemia / Q000097:blood / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000032:analysis; D011014:Pneumonia / Q000097:blood / Q000503:physiopathology; D023063:Receptors, Interleukin-8B / Q000172:deficiency
D000906:Antibodies; D015415:Biomarkers; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; D023063:Receptors, Interleukin-8B; D009195:Peroxidase