TY - JOUR
T1 - Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy
AU - Ishii, Tomoko
AU - Doi, Kent
AU - Okamoto, Koji
AU - Imamura, Mitsuru
AU - Dohi, Makoto
AU - Yamamoto, Kazuhiko
AU - Fujita, Toshiro
AU - Noiri, Eisei
N1 - Funding Information:
Supported by the BioBank Japan Project on the Implementation of Personalized Medicine # 3023168 , Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (E.N.), KAKEN-HI # 19590935 , MEXT, Japan (E.N.), the Special Coordination Funds for Promoting Science and Technologies # 1200015 , MEXT, Japan (E.N.), and KAKEN-HI # 21790795 , MEXT, Japan (K.D.).
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2010.090793
DO - 10.2353/ajpath.2010.090793
M3 - Article
C2 - 20709801
AN - SCOPUS:77957331068
VL - 177
SP - 1665
EP - 1673
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -