Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

Morohoshi, Yuichi; Matsuoka, Katsuyoshi; Chinen, Hiroshi; Kamada, Nobuhiko; Sato, Toshiro; Hisamatsu, Tadakazu; Okamoto, Susumu; Inoue, Nagamu; Takaishi, Hiromasa; Ogata, Haruhiko; Iwao, Yasushi; Hibi, Toshifumi

doi:10.1007/s00535-005-1768-8

Cited by 66 publications

(48 citation statements)

References 24 publications

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“…5046 have also been demonstrated on neutrophil-mediated other organ injury models such as hippocampal neuronal damage after transient forebrain ischemia, 40 neurological damage after spinal cord injury, 41 collageninduced arthritis, 42 and acute colitis. 20 Although one randomized controlled trial including 492 patients demonstrated no improvement of ALI by ONO-5046, 18 several small trials showed beneficial effects of ONO-5046 on ALI in critically ill patients. 17,19 No clinical trial evaluating ONO-5046 on ALI complicated with AKI has been reported in the relevant literature.…”

Section: Discussionmentioning

confidence: 99%

“…In the previous study on a mouse model of acute colitis, treatment of ONO-5046 at the dose of 50 mg/kg twice a day improved histological damages and suppressed the NE activities. 20 The same amount of saline was injected to the BNxϩsaline and the sham group. Animals were killed 6 hours or 24 hours after the surgery and blood and lung specimens were harvested for analyses, except for survival analysis.…”

Section: Animals and Surgical Protocolmentioning

confidence: 99%

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Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Ishii

Doi

Okamoto

et al. 2010

The American Journal of Pathology

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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-␣], 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. Acute lung injury (ALI) is a life-threatening condition that is frequently complicated with acute kidney injury (AKI), which is a serious condition in intensive care units. The ALI mortality is higher than 50% and increases with the development of other organ failure including AKI.1 One report described a mortality rate higher than 80% for patients with AKI complicated with ALI.2 Current prevention and treatment strategies for AKI cannot sufficiently improve the mortality of these severely ill patients. Although many basic and clinical researchers are investigating novel therapies for AKI, 3 targeting of other organ damages caused by AKI is also necessary for improving AKI outcomes.Recently, it has been suggested that AKI influences other remote organs including the lungs.4 -6 Experimental evidence indicates that AKI-induced ALI occurs not only by volume overload, but also through deleterious kidneylung interactions. Mechanisms of AKI-induced ALI include dysregulation of inflammatory reaction, innate immune response, oxidative stress, apoptosis, and soluble mediator metabolism.7 Rodent models of bilateral nephrectomy (BNx) and renal ischemia reperfusion have been used to investigate the role of AKI in the pathogenesis of ALI. 8 -11 Ischemic AKI engenders increased pulmonary vascular permeability by down-regulating pulmonary epithelial sodium channel, Na,K-ATPase, and aquaporin-5. 10 Ischemic AKI induced leukocyte accumulation and activation of inflammatory transcription factors such as nuclear factor-B and p38 mitogen-activated protein kinase in the lung, which was attenuated by an anti-infla...

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Section: Discussionmentioning

confidence: 99%

Section: Animals and Surgical Protocolmentioning

confidence: 99%

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Ishii

Doi

Okamoto

et al. 2010

The American Journal of Pathology

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“…For instance, inhibition of tryptase and chymase was shown to inhibit leukocyte peritoneum infiltration [98]. Nafamostat mesilate (or FUT-175) a broad-spectrum serine protease inhibitor and neutrophil elastase specific inhibitor has been used and efficiently reduced parameters of inflammation in a model of IBD [28,99,100]. Altogether, these findings underline that defects in serine antiprotease functions and/or expression can have serious clinical consequences in the context of IBD.…”

Section: Other Inhibitorsmentioning

confidence: 96%

Proteases/Antiproteases in Inflammatory Bowel Diseases

Motta¹,

Martin²,

Vergnolle³

2011

Proteases and Their Receptors in Inflammation

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Protein turnover is orchestrated by a large array of proteases, and the gastrointestinal tract is the organ the most exposed to proteases, whether they originate from the pancreas for digestive purpose, from resident cells, from infiltrated inflammatory cells, or from microorganisms present in the intestinal lumen. To maintain tissue homeostasis, the gastrointestinal tract has developed mechanisms that tightly regulate the proteolytic balance in the tissues. Those mechanisms range from physical barriers (mucus layer, tight control of intestinal epithelial cell paraand transcellular passages) to molecular control of proteolytic activity through endogenous protease inhibitors. In the setting of inflammation, gastrointestinal tissues are overflowed with massive proteolytic activity that contributes to the generation of inflammatory symptoms. The present chapter analyses the disruption of the protease-antiprotease balance in the context of inflammatory bowel disease. It proposes to review the type of proteases that are present in the gastrointestinal tract, their known effects on the generation and/or maintenance of inflammatory symptoms, and their mechanisms of action. Further, the role of endogenous protease inhibitors is discussed, as well as the potential use of protease inhibition, as new possible therapeutic approach to treat chronic inflammatory disorders of the gut.

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“…However, some of the granules also undergo exocytosis, resulting in the release of the proteases outside the cell, with consequent degradation of extracellular matrix components and damage to epithelial cells (31). The importance of this aspect of the inflammatory response is highlighted by the observation that inhibition of neutrophil elastase results in significant amelioration of dextran sulfate sodium (DSS)-induced colitis in mice (77). Interestingly, some neutrophil proteases also have anti-inflammatory effects.…”

Section: Phagocyte Inflammatory Mediatorsmentioning

confidence: 99%

Intestinal innate immunity and the pathogenesis of Salmonella enteritis

Srikanth

Cherayil

2007

Immunol Res

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Acute gastroenteritis caused by Salmonella typhimurium infection is a clinical problem with significant public health impact. The availability of several experimental models of this condition has allowed detailed investigation of the cellular and molecular interactions involved in its pathogenesis. Such studies have shed light on the roles played by bacterial virulence factors and host innate immune mechanisms in the development of intestinal inflammation.

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Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

Abstract: ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.

Cited by 66 publications

References 24 publications

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Neutrophil Elastase Contributes to Acute Lung Injury Induced by Bilateral Nephrectomy

Proteases/Antiproteases in Inflammatory Bowel Diseases

Intestinal innate immunity and the pathogenesis of Salmonella enteritis

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