title: Antecedent acute kidney injury worsens subsequent endotoxin-induced lung inflammation in a two-hit mouse model.
abstract: Acute kidney injury (AKI) contributes greatly to morbidity and mortality in critically ill adults and children. Patients with AKI who subsequently develop lung injury are known to suffer worse outcomes compared with patients with lung injury alone. Isolated experimental kidney ischemia alters distal lung water balance and capillary permeability, but the effects of such an aberration on subsequent lung injury are unknown. We present a clinically relevant two-hit murine model wherein a proximal AKI through bilateral renal ischemia (30 min) is followed by a subsequent acute lung injury (ALI) via intratracheal LPS endotoxin (50 μg at 24 h after surgery). Mice demonstrated AKI by elevation of serum creatinine and renal histopathological damage. Mice with ALI and preexisting AKI had increased lung neutrophilia in bronchoalveolar lavage fluid and by myeloperoxidase activity over Sham-ALI mice. Additionally, lung histopathological damage was greater in ALI mice with preexisting AKI than Sham-ALI mice. There was uniform elevation of monocyte chemoattractant protein-1 in kidney, serum, and lung tissue in animals with both AKI and ALI over those with either injury alone. The additive lung inflammation after ALI with antecedent AKI was abrogated in MCP-1-deficient mice. Taken together, our two-hit model demonstrates that kidney injury may prime the lung for a heightened inflammatory response to subsequent injury and MCP-1 may be involved in this model of kidney-lung cross talk. The model holds clinical relevance for patients at risk of lung injury after ischemic injury to the kidney.
authors.affiliation: Divisions of Critical Care, Cincinnati Children’s Hospital and Medical Center, Ohio, USA. Rajit.basu@cchmc.org
authors.forename: Rajit K
authors.initials: RK
authors.lastname: Basu
authors.forename: Emily
authors.initials: E
authors.lastname: Donaworth
authors.forename: Derek S
authors.initials: DS
authors.lastname: Wheeler
authors.forename: Prasad
authors.initials: P
authors.lastname: Devarajan
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000453:epidemiology* / Q000503:physiopathology*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology; D015897:Comorbidity; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004731:Endotoxins / Q000009:adverse effects*; D007511:Ischemia / Q000453:epidemiology / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000453:epidemiology* / Q000503:physiopathology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D004731:Endotoxins; D003404:Creatinine