Neutropenia, Inflammation, and the Kinetics of Transfused Neutrophils in Rabbits

Rosenshein, Marc S.; Price, Thomas H.; Dale, David C.

doi:10.1172/jci109496

Cited by 16 publications

(12 citation statements)

References 14 publications

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“…Rabbits were given vinblastine (0.75 mg/kg) i.v. through an ear vein as a bolus injection on day 1 (22,50). Blood smears were made for each vinblastine and control rabbit on day 3 using blood from an ear vein and were Giemsa stained to confirm the absence of PMNs.…”

Section: Methodsmentioning

confidence: 99%

Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin fromBacillus anthracis

et al. 2007

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Bacillus anthracis edema toxin (ET), composed of protective antigen and an adenylate cyclase edema factor (EF), elicits edema in host tissues, but the target cells and events leading from EF-mediated cyclic-AMP production to edema are unknown. We evaluated the direct effect of ET on several cell types in vitro and tested the possibility that mediators of vascular leakage, such as histamine, contribute to edema in rabbits given intradermal ET. ET increased the transendothelial electrical resistance of endothelial monolayers, a response that is mechanistically inconsistent with the in vivo vascular leakage induced by ET. Screening of several drugs by intradermal treatment prior to toxin injection demonstrated reduced ET-induced vascular leakage with a cyclo-oxygenase inhibitor (indomethacin), agents that interfere with histamine (pyrilamine or cromolyn), or a neurokinin antagonist (spantide). Systemic administration of indomethacin or celecoxib (cyclo-oxygenase inhibitors), pyrilamine, aprepitant (a neurokinin 1 receptor antagonist), or indomethacin with pyrilamine significantly reduced vascular leakage associated with ET. Although the effects of pyrilamine, cromolyn, or aprepitant on ET-induced vascular leakage suggest a possible role for mast cells (MC) and sensory neurons in ET-induced edema, ET did not elicit degranulation of human skin MC or substance P release from NT2N cells in vitro. Our results indicate that ET, acting indirectly or directly on a target yet to be identified, stimulates the production/release of multiple inflammatory mediators, specifically neurokinins, prostanoids, and histamine. These mediators, individually and through complex interactions, increase vascular permeability, and interventions directed at these mediators may benefit hosts infected with B. anthracis.Bacillus anthracis is a gram-positive, spore-forming bacillus that causes the disease known as anthrax. The vegetative form of B. anthracis results from spore inoculation of the host animal via cutaneous, gastrointestinal, or inhalational routes (57). Subsequently, spores germinate in a complex process that involves phagocytosis of spores by macrophages and transport of germinating spores within macrophages to regional lymphatics. The vegetative bacilli may then gain entry to the systemic circulation and spread to other sites in the host. This process is facilitated by virulence factors expressed by vegetative bacilli: (i) an antiphagocytic capsule and (ii) lethal toxin (LT) and edema toxin (ET). LT consists of protective antigen (PA) and lethal factor (LF), while ET consists of PA and edema factor (EF) (57).PA undergoes proteolytic cleavage to a 63-kDa monomer, with subsequent formation of a heptamer capable of binding up to three molecules of EF or LF (15). PA heptamers bind to two different widely expressed cell surface receptors, anthrax toxin receptor/tumor endothelial marker 8 and/or capillary morphogenesis protein 2, and undergo receptor-mediated endocytosis with trafficking to an acidic endosomal compartment (5,6,54). Aci...

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Section: Methodsmentioning

confidence: 99%

Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin fromBacillus anthracis

et al. 2007

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“…Neutrophil-depleted rabbits were prepared by intravenous injection of 0.75 mg/kg vinblastine (Sigma Chemical, St. Louis, Missouri) 3 days before the experiments (Rosenshein et al, 1979). The numbers of peripheral leukocytes before and after vinblastine treatment were 12.7 Ϯ 0.7 ϫ 10 6 /ml and 3.4 Ϯ 0.8 ϫ 10 6 /ml, respectively.…”

Section: Preparation Of Neutrophil-depleted Rabbitsmentioning

confidence: 99%

Involvement of CXC Chemokine Growth-Related Oncogene-α in Monosodium Urate Crystal-Induced Arthritis in Rabbits

Fujiwara

Ohkawara

Takagi

et al. 2002

Laboratory Investigation

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SUMMARY:Accumulation of neutrophils is a prominent feature of gouty arthritis in which CXC chemokines may play a role.Recently, we have shown that IL-8 (CXCL8) contributes to neutrophil influx in a rabbit model of gouty arthritis. Here, we demonstrate that growth-related oncogene-␣ (GRO␣) (CXCL1), a prototype of CXC chemokine, is also involved in this process. GRO␣ level in the joints peaked at 2 hours after intra-articular injection of monosodium urate crystals, at a time before the neutrophil influx reached the maximal level (9 hours). Once decreased, the level increased and reached the second peak at 9 hours. The kinetics was comparable to that of IL-8. Administration of anti-GRO␣ mAb attenuated the neutrophil influx at the same level as did the anti-IL-8 IgG, and combination of these antibodies enhanced the inhibition, resulting in a 33% reduction. Interaction of GRO␣ with TNF␣, IL-1␤, and IL-8 was next investigated by injecting antibodies or receptor antagonist with monosodium urate crystals. Administration of anti-TNF␣ mAb did not alter GRO␣ level at 2 hours, but inhibited the levels 9 hours after the injection. Treatment with either IL-1 receptor antagonist or anti-IL-8 IgG resulted in decreased levels of GRO␣ at 2 and 9 hours. Neutralization of GRO␣ with anti-GRO␣ mAb did not alter TNF␣, IL-1␤, and IL-8 levels at their peak (2 hours), but decreased the second peak of IL-1␤ (9 hours) and IL-8 (12 hours). These results provide evidence that GRO␣ as well as IL-8 are involved ad eundem in the neutrophil infiltration in this model. IL-1 and IL-8, but not TNF␣, are responsible in part for the initial phase of GRO␣, whereas these cytokines induce GRO␣ in a late phase. GRO␣ does not seem to initiate TNF␣, IL-1␤, and IL-8 in an early phase, but induces IL-1␤ and IL-8 in a late phase. (Lab Invest 2002, 82:1297-1304.

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“…On their way from the blood toward an affected tissue the cells must invade across the endothelium of postcapillary venules and the underlying basal lamina (1). This process involves adherence of neutrophils to the endothelial luminal surface, invasion and dissociation of endothelial cell junctions, and active participation of hydrolytic enzymes (2,3). The same is true for virtually every epithelium in the body that is traversed by human neutrophils before they accumulate at the site of inflammation (4).…”

Section: Introductionmentioning

confidence: 99%

Degradation of heparan sulfate in the subendothelial extracellular matrix by a readily released heparanase from human neutrophils. Possible role in invasion through basement membranes.

Matzner¹,

Bar-Ner²,

Yahalom³

et al. 1985

J. Clin. Invest.

200

146

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Freshly isolated human neutrophils were investigated for their ability to degrade heparan sulfate proteoglycans in the subendothelial extracellular matrix (ECM) produced by cultured corneal and vascular endothelial cells. The ECM was metabolically labeled with Na2(35S)04 and labeled degradation products were analyzed by gel filtration over Sepharose 6B. More than 90% of the released radioactivity consisted of heparan sulfate fragments 5-6 times smaller than intact heparan sulfate side chains released from the ECM by either papain or alkaline borohydride. These fragments were sensitive to deamination with nitrous acid and were not produced in the presence of either heparin or serine protease inhibitors. In contrast, degradation of soluble high molecular weight heparan sulfate proteoglycan, which was first released from the ECM, was inhibited by heparin but there was no effect of protease inhibitors. These results indicate that interaction of human neutrophils with the subendothelial ECM is associated with degradation of its heparan sulfate by means of a specific, newly identified, heparanase activity and that this degradation is facilitated to a large extent by serine proteases.The neutrophil heparanase was readily and preferentially released (15-25% of the cellular content in 60 min) by simply incubating the cells at 40C in the absence of added stimuli. Under these conditions, <5% of the cellular content of lactate dehydrogenase, lysozyme, and globin degrading proteases was released. Further purification of the neutrophil heparanase was achieved by its binding to heparin-Sepharose and elution at 1 M NaCI. It is suggested that heparanase activity is involved in the early events of extravasation and diapedesis of neutrophils in response to a threshold signal from an extravascular inflamed organ.

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Neutropenia, Inflammation, and the Kinetics of Transfused Neutrophils in Rabbits

Cited by 16 publications

References 14 publications

Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin fromBacillus anthracis

Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin fromBacillus anthracis

Involvement of CXC Chemokine Growth-Related Oncogene-α in Monosodium Urate Crystal-Induced Arthritis in Rabbits

Degradation of heparan sulfate in the subendothelial extracellular matrix by a readily released heparanase from human neutrophils. Possible role in invasion through basement membranes.

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