Lower nephron toxicity of a highly purified cytotoxin from Pseudomonas aeruginosa in rats

Weiner, R.N.; Reinacher, M.

doi:10.1016/0014-4800(82)90040-5

Cited by 9 publications

(1 citation statement)

References 43 publications

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“…The marked PGI2 generation induced by cytotoxin is indicative of toxin attack on the endothelial cells in the present study. This is in accordance with experiments with rats, in which deposition of cytotoxin in the endothelial cells of nearly all organs, including the lung, could be demonstrated immunohistologically (60). Correspondingly, a significant release of angiotensin-converting enzyme, an endothelial cell marker, into the lung lymph fluid could be demonstrated during Pseudomonas bacteremia in sheep (18).…”

Section: Discussionsupporting

confidence: 90%

Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs

Seeger¹,

Walmrath²,

Neuhof³

et al. 1986

Infect Immun

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The effects of Pseudomonas aeruginosa cytotoxin on the pulmonary microvasculature were studied in blood-free, perfused, isolated rabbit lungs. Cytotoxin was administered to the recirculating Krebs Henseleit albumin (1%) buffer during two consecutive 30-min-perfusion phases (phases 1 and 2) at a concentration of 13 ,ug/ml, followed by a third perfusion phase (phase 3) without toxin. After perfusion phases 2 and 3, the capillary filtration coefficient (Kf,c) and vascular compliance were determined gravimetrically from two-step microvascular pressure increments under zero-flow conditions. Cytotoxin caused a continuous release of K+ and lactate dehydrogenase, which started within the first 5 min and amounted to about 50% of the total lung cellular K+ and 5 to 7% of the total lactate dehydrogenase by the end of the experiment. The toxin caused the continuous generation of prostaglandin 12, which was detectable in the perfusates of all perfusion phases at maximum values five times above the control values and which was measured in the bronchoalveolar lavage fluid at the end of the experiment. Thromboxane generation in toxin-treated lungs did not significantly exceed that of control lungs or of lungs with mechanically induced edema. Cytotoxin caused a gradual increase in pulmonary vascular resistance, to maximum values 2.5 times above the control, starting within 1 min; the increase was partially reversible after washout of the toxin. After a lag period of 20 to 30 min, the lungs gained weight, amounting to a mean gain of 9.1 g at the end of the experiments. After perfusion phases 2 and 3, an almost fourfold increase in Kf1,, which was not reversible after washout of the toxin, was measured, whereas the values of vascular compliance were not altered. We conclude that pseudomonal cytotoxin may be an important factor in the pathogenesis of prolonged microvascular injury, encountered in states of P. aeruginosa sepsis or acute lung failure with secondarily acquired P. aeruginosa pneumonia.

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Section: Discussionsupporting

confidence: 90%

Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs

Seeger¹,

Walmrath²,

Neuhof³

et al. 1986

Infect Immun

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Pseudomonas aeruginosa cytotoxin stimulates prostacyclin production in cultured pulmonary artery endothelial cells: Membrane attack and calcium influx

Suttorp

Seeger

Uhl

et al. 1985

Journal Cellular Physiology

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The effects of highly purified Pseudomonas aeruginosa cytotoxin were investigated on cultured pulmonary artery endothelial cells. This toxin dose-dependently (7.5-60 micrograms/ml) and time-dependently (20-75 minutes) stimulated the release of radiolabeled arachidonic acid and metabolites and the synthesis of prostacyclin in the absence of overt cell damage (no enhanced lactate dehydrogenase [LDH] release). Preincubation of the toxin with neutralizing antibodies abolished the effect. The toxin response on endothelial cells required extracellular calcium but not magnesium and was accompanied by a calcium influx. Interference with intracellular calcium function by TMB 8 or with (calcium)-calmodulin function by trifluoperazine and W7 dose-dependently reduced the cytotoxin mediated synthesis of prostacyclin. Calcium channel blockers (nimodipine, diltiazem, verapamil, D 888), however, were ineffective in this system. Following addition of cytotoxin to endothelial cells, an increased passive permeability for small marker molecules (potassium, 45calcium, 3H-sucrose), but for large ones (3H-inulin, 3H-dextran, LDH) was noted, suggesting that cytotoxin creates discrete hydrophilic transmembrane lesions of about 0.5-1.5 nm in diameter. These data are compatible with the notion that Pseudomonas aeruginosa cytotoxin triggers the arachidonic acid pathway in cultured pulmonary artery endothelial cells by calcium influx and suggest that this calcium influx may proceed through toxin created transmembrane lesions.

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A cytotoxin of pseudomonas aeruginosa acts directly on the cortical thick ascending limb of henle's loop of rabbit kidney

et al. 1982

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The present study examines directly the effect of a cytotoxin of Pseudomonas aeruginosa on the in vitro perfused rabbit cortical thick ascending limb of the loop of Henle (cTAL). 25 cTAL segments were perfused at high rate. The open circuit transepithelial electrical PD (PDte) and the specific electrical transepithelial resistance (Rt) were recorded continuously. From PDte/Rt the equivalent short circuit current (Isc) was calculated. The Isc was 214 +/- 30 mu A.cm-2 under control conditions, and decreased significantly to 74 +/- 34 mu A.cm-2 60 s after the addition of toxin (2 mg.1(-1)) to the lumen perfusate. Microscopic observation and photographs taken at that time clearly indicated swelling of the cTAL cells. Thereafter inhibition of active transport proceeded further, Rt fell progressively, and cells started to desquamate from the basement membrane. This effect of the toxin was dose dependent, and was half maximal at approximately 1.2 mg.1(-1). From the bath side the effect was less marked and higher doses of toxin had to be used (half maximal effect at 5 mg.1(-1)). We conclude that this toxin of Pseudomonas aeruginosa exerts its toxic effect on the cTAL segment by increasing primarily the permeability of the lumen membrane.

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Lower nephron toxicity of a highly purified cytotoxin from Pseudomonas aeruginosa in rats

Cited by 9 publications

References 43 publications

Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs

Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs

Pseudomonas aeruginosa cytotoxin stimulates prostacyclin production in cultured pulmonary artery endothelial cells: Membrane attack and calcium influx

A cytotoxin of pseudomonas aeruginosa acts directly on the cortical thick ascending limb of henle's loop of rabbit kidney

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