Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy.
Acute kidney injury (AKI) is a serious problem in critically ill patients of intensive care units. It has been reported previously that AKI can induce acute lung injury (ALI), as well as cause injuries to other remote organs, including the lungs. Patients with AKI complicated by ALI show remarkably high mortality. ALI is characterized by neutrophil infiltration into the lung. Neutrophil elastase (NE) is a key enzyme for tissue injury caused by activated neutrophils, such as occurs in ALI. Therefore, this study investigated the role of NE in AKI-induced ALI using a specific NE inhibitor, sivelestat sodium hydrate (ONO-5046), in a mouse bilateral nephrectomy model. Bilateral nephrectomy showed not only a remarkable increase in blood urea nitrogen levels, but also demonstrated neutrophil infiltration into the lung, increased pulmonary inflammatory cytokine expression [interleukin-6, neutrophil chemokine keratinocyte-derived chemokine, and tumor necrosis factor-α], and protein leakage with early increases in both systemic and pulmonary NE activity. ONO-5046 treatment reduced NE activity and improved these pulmonary inflammatory responses. Additionally, ONO-5046-treated animals had longer survival times. These data demonstrate that increasing NE activity induces pulmonary inflammatory damage in a bilateral nephrectomy model. Blockade of NE activity will be a useful therapeutic strategy for ALI complications in AKI patients.
Ishii
Tomoko
T
Department of Nephrology, 107 Lab, University Hospital, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.
Doi
Kent
K
Okamoto
Koji
K
Imamura
Mitsuru
M
Dohi
Makoto
M
Yamamoto
Kazuhiko
K
Fujita
Toshiro
T
Noiri
Eisei
E
D055371:Acute Lung Injury / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D000818:Animals; D015153:Blotting, Western; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019272:Leukocyte Elastase / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy / Q000009:adverse effects*; D018375:Neutrophil Activation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D015850:Interleukin-6; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C074302:keratinocyte-derived chemokines; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine