Protective Effect of Neutrophil Elastase Inhibitor (FR136706) in Lethal Acute Liver Failure Induced by D-Galactosamine and Lipopolysaccharide in Rats

Uchida, Yoichiro; Kaibori, Masaki; Hijikawa, Takeshi; Ishizaki, Morihiko; Ozaki, Takashi; Tanaka, Hironori; Matsui, Kosuke; Tokuhara, Katsuji; Kwon, A‐Hon; Kamiyama, Yasuo; Okumura, Tadayoshi

doi:10.1016/j.jss.2007.04.001

Cited by 14 publications

(9 citation statements)

References 49 publications

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“…The effect of elastase inhibitors has been investigated in several situations with lung hyper inflammation, and some reports described beneficial results in patients with ALI/ ARDS or in rodent models of ALI further supporting the pathogenic role of released elastase (see for example [230][231][232] and references herein).…”

Section: Secondary Necrosis Of Monocytes/macrophages Eosinophils Andmentioning

confidence: 84%

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

2008

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In metazoans apoptosis is a major physiological process of cell elimination during development and in tissue homeostasis and can be involved in pathological situations. In vitro, apoptosis proceeds through an execution phase during which cell dismantling is initiated, with or without fragmentation into apoptotic bodies, but with maintenance of a near-to-intact cytoplasmic membrane, followed by a transition to a necrotic cell elimination traditionally called "secondary necrosis". Secondary necrosis involves activation of self-hydrolytic enzymes, and swelling of the cell or of the apoptotic bodies, generalized and irreparable damage to the cytoplasmic membrane, and culminates with cell disruption. In vivo, under normal conditions, the elimination of apoptosing cells or apoptotic bodies is by removal through engulfment by scavengers prompted by the exposure of engulfment signals during the execution phase of apoptosis; if this removal fails progression to secondary necrosis ensues as in the in vitro situation. In vivo secondary necrosis occurs when massive apoptosis overwhelms the available scavenging capacity, or when the scavenger mechanism is directly impaired, and may result in leakage of the cell contents with induction of tissue injury and inflammatory and autoimmune responses. Several disorders where secondary necrosis has been implicated as a pathogenic mechanism will be reviewed.

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Section: Secondary Necrosis Of Monocytes/macrophages Eosinophils Andmentioning

confidence: 84%

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

2008

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“…In unstimulated cells, NF-jB is a heterodimer consisting of two subunits, p65 and p50. In its latent from, NF-jB is located in the cytoplasm and is bound to its inhibitor, IjB [37]. Once activated, phosphorylated NF-jB is dissociated from IjB and translocated into the nucleus, where it activates the transcription of TNF-a [38].…”

Section: Discussionmentioning

confidence: 99%

Protective effect of melittin on inflammation and apoptosis in acute liver failure

et al. 2011

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Acute hepatic failure remains an extremely poor prognosis and still results in high mortality. Therefore, better treatment is urgently needed. Melittin, a major component of bee venom, is known to inhibit inflammatory reactions induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α in various cell types. However, there is no evidence of the anti-inflammatory and anti-apoptotic effect of melittin on liver cells. In the present study, we investigated the effects of melittin on D: -galactosamine (GalN)/lipopolysaccharide (LPS)-induced acute hepatic failure. Acute liver injury was induced with GalN/LPS to determine in vivo efficacy of melittin. Mice were randomly divided into four groups: sterile saline treated group (NC), melittin only treated group (NM), GalN/LPS-treated group (GalN/LPS), and GalN/LPS treated with melittin group (M+GalN/LPS). Mice were given intraperitoneal GalN/LPS with or without melittin treatment. Liver injury was assessed biochemically and histologically. Inflammatory cytokines in the serum, apoptosis of hepatocytes, and cleavage of caspase-3 in the liver were determined. The expression of TNF-α and interleukin (IL)-1β were increased in the GalN/LPS group. However, treatment of melittin attenuated the increase of inflammatory cytokines. The M+GalN/LPS group showed significantly fewer apoptotic cells compared to the GalN/LPS group. Melittin significantly inhibited the expression of caspase and bax protein levels as well as cytochrome c release in vivo. In addition, melittin prevented the activation of the transcription factor nuclear factor-kappa B (NF-κB) induced by GalN/LPS. These results clearly indicate that melittin provided protection against GalN/LPS-induced acute hepatic failure through the inhibition of inflammatory cytokines and apoptosis.

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“…11). The pivotal role of chemokines for leukocyte extravasation and leukocyte cytotoxicity in the liver is convincingly demonstrated by the attenuation of hepatic leukocyte recruitment and leukocyte-mediated injury after neutralizing or inhibiting CXC chemokines in models of hepatic I/R (118,370,477), endotoxemia (687, 957), agonistic Fas antibody-induced liver injury (190), and acute Gal/LPSinduced liver failure (830). At the same time, there is evidence that the importance of chemokines may markedly vary between different experimental models used, pharmaceutical approaches applied, and pathophysiological situations present.…”

Section: Leukocyte Transendothelial Migration and Parenchymal Cellmentioning

confidence: 99%

“…For example, analysis of conditioned medium from ␣-naphthylisothiocyanate-treated leukocytes indicates the presence of both cathepsin G and elastase activities, which causes hepatocellular damage in vitro (294). The clear involvement of leukocytic proteases in cell killing has been shown among others 1) by the protective effect of a neutrophil elastase inhibitor or antileukoproteinase in lethal acute liver failure and in endotoxin-induced liver injury after partial hepatectomy (170,437,830), 2) by the attenuation of liver I/R injury through an urinary trypsin inhibitor (484,924), and 3) by the reduction of liver fibrin deposition, plasma PAI-1 concentration, and parenchymal injury after LPS/ranitidine exposure (147).…”

Section: Leukocyte Transendothelial Migration and Parenchymal Cellmentioning

confidence: 99%

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

Vollmar

Menger²

2009

Physiological Reviews

425

368

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The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.

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Protective Effect of Neutrophil Elastase Inhibitor (FR136706) in Lethal Acute Liver Failure Induced by D-Galactosamine and Lipopolysaccharide in Rats

Cited by 14 publications

References 49 publications

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

Protective effect of melittin on inflammation and apoptosis in acute liver failure

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

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