Cited by 821Organ Transplantation Techniques and OutcomesLiver physiology and pathologyCardiac Ischemia and Reperfusion

The DOI matches its Crossref record; 42 of the 43 references it cites were found in a registry or an index; none of the 16 sources its claims cite is checked for support yet.

Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat.

Open access
Colletti, L M, Remick, D G, Burtch, G D, Kunkel, S L, Strieter, R M, Campbell, D A·1990·Journal of Clinical Investigation

Abstract

Cytokines are recognized as critical early mediators of organ injury. We attempted to determine whether or not severe hepatic ischemia/reperfusion injury results in tumor necrosis factor-alpha (TNF-alpha) release with subsequent local and systemic tissue injury. After 90 min of lobar hepatic ischemia, TNF was measurable during the reperfusion period in the plasma of all 14 experimental animals, with levels peaking between 9 and 352 pg/ml. Endotoxin was undetectable in the plasma of these animals. Pulmonary injury, as evidenced by a neutrophilic infiltrate, edema and intra-alveolar hemorrhage developed after hepatic reperfusion. The neutrophilic infiltrate was quantitated using a myeloperoxidase (MPO) assay; this demonstrated a significant increase in MPO after only 1 h of reperfusion. Anti-TNF antiserum pretreatment significantly reduced the pulmonary MPO after hepatic reperfusion. After a 12-h reperfusion period, there was histologic evidence of intra-alveolar hemorrhage and pulmonary edema. Morphometric assessment showed that pretreatment with anti-TNF antiserum was able to completely inhibit the development of pulmonary edema. Liver injury was quantitated by measuring serum glutamic pyruvic transaminase which showed peaks at 3 and 24 h. Anti-TNF antiserum pretreatment was able to significantly reduce both of these peak elevations. These data show that hepatic ischemia/reperfusion results in TNF production, and that this TNF is intimately associated with pulmonary and hepatic injury.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a rat model of 90-minute lobar hepatic ischemia/reperfusion, TNF became measurable in plasma in all 14 experimental animals and was associated with subsequent pulmonary and hepatic injury. Pretreatment with anti-TNF antiserum reduced pulmonary neutrophil sequestration, abolished pulmonary edema, and lowered serum SGPT elevations after reperfusion.

Key findings

  • After hepatic ischemia/reperfusion, TNF was measurable in plasma of all 14 experimental animals, with a mean peak level of 69.4±30.3 pg/ml and a range of 9–352 pg/ml; TNF was undetectable in sham-operated controls, and endotoxin was undetectable (<5 pg/ml).
  • Pulmonary neutrophil sequestration, measured by MPO, peaked after 1 h of reperfusion at 0.653±0.089 U versus 0.213±0.034 U in sham animals (P<0.005). Anti-TNF antiserum reduced MPO to 0.458±0.057 U compared with 0.701±0.040 U in control-serum animals (P<0.005), though it did not return values to sham baseline.
  • After 12 h of reperfusion, control-serum animals had 20±4 flooded alveoli/high-power field, whereas anti-TNF antiserum-treated animals had 0±0 (P<0.05 by Wilcoxon rank-sum test).
  • Serum SGPT peaked at 3 and 24 h after reperfusion; anti-TNF antiserum significantly reduced both peak elevations (P<0.05 at 3 h and P<0.005 at 24 h versus untreated and control-serum groups). Twenty-four-hour survival was 67% in untreated animals, 92% with anti-TNF antiserum, and 60% with control serum, but the differences were not statistically significant.

Methods

  • Adult male pathogen-free Sprague-Dawley rats (200–300 g) underwent 90 min of lobar hepatic ischemia using a Heifitz clip, with sham-operated controls treated identically except for vascular occlusion.
  • Plasma TNF activity was measured with a WEHI 164 subclone 13 bioassay; positive samples were confirmed by neutralization with polyclonal rabbit anti-murine TNF antiserum. Endotoxin was measured by a perchloric acid-modified chromogenic limulus assay.
  • Organ injury was assessed by pulmonary MPO assay, blinded histologic morphometry of edema-filled alveoli, and serum SGPT. Anti-TNF effects were tested by pretreating rats with polyclonal rabbit anti-murine TNF antiserum versus control rabbit serum. Statistical comparisons used Student Newman-Keuls or Wilcoxon rank-sum tests when data were not normally distributed.

Limitations

  • The paper states that 24-h survival differences were not statistically significant, most likely because of relatively small group sizes.
  • The paper states that further studies are needed to document the degree to which the observed pulmonary pathology is neutrophil dependent.
  • The paper states that the mechanism of TNF induction after hepatic ischemia/reperfusion is not completely clear; the text infers Kupffer cell production/leakage but does not directly establish the cellular source.
  • Evident from the text: anti-TNF antiserum did not prevent the transient hypotension after revascularization, so the protective effects observed were not attributable to hemodynamic stabilization.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci114656

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

Show all 41 claims

  • It may state two separate claims as one. 17
  • The quote only partly states this claim. 3
  • Probably not a substantial claim. 7
25 of 25
  • The paper relies on this without support.

    TNF is produced primarily by cells of the monocyte/macrophage lineage.

    “TNF is produced primarily by cells of the monocyte/macrophage lineage”
  • The paper relies on this without support.

    The liver Kupffer cell mass is the largest fixed macrophage population in the body.

    “the liver Kupffer cell mass is the largest fixed macrophage population in the body.”
  • The paper relies on this without support.

    The pulmonary circulation is the first vascular bed into which cytokines from injured liver are delivered.

    “the pulmonary circulation represents the first vascu- lar bed into which these cytokines are delivered”
  • The paper relies on this without support.

    The anti-TNF antiserum used in these experiments neutralizes TNF in vivo and does not have other relevant biological activities that could account for the observed protection.

    “pretreatment with neutralizing anti-TNF anti- serum blunted the neutrophilic infiltrate”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Hepatocyte-injury claim cites the Limulus-assay reference

    Minor

    The discussion cites reference 13 for prior findings about TNF, LPS, and hepatic necrosis, but reference 13 describes a method for the Limulus test rather than those findings.

  • Allograft-rejection citation points to a parasitic-infection paper

    Minor

    The text cites reference 24 for TNF in renal allograft rejection, but reference 24 is titled as a study of parasitic infections. The renal allograft rejection paper appears as reference 25.

2 of 2

Citations

Cites

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Show all 43 references

1 of the 43 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Glantz, S. A. 1987. Primer of Biostatistics. 2nd edition.
  2. Bevilacqua, M. P., J. S. Pober, G. R. Majeau, W. Fiers, R. S. Cotran, and M. A. Gimbrone. 1986. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endo- thelium. Proc. Natl. Acad. Sci. USA. 83:4533-4537.

Cited by

Sorted by citations

Items 601–700 of 821

Metadata

Authors
Colletti, L. M., Remick, D. G., Burtch, G. D., Kunkel, S. L., Strieter, R. M., & Campbell, D. A.
Affiliations
University of Michigan (US)
Venue
Journal of Clinical Investigation
Published
1990-06-01
Volume
85
Issue
6
Pages
1936-1943
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2099883737
Cited by
817
References
43
Citations by year
2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 16 · 2017: 12 · 2016: 6 · 2015: 15 · 2014: 12 · 2013: 20 · 2012: 24
FWCI
40.45
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01hl031237-32)
  • National Heart, Lung, and Blood Institute (HL-35276, HL31237, HL 31963, P01HL031963)
Topics
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
Keywords
TNF-α, hepatic ischemia-reperfusion injury, cytokines, pulmonary edema, intra-alveolar hemorrhage, neutrophil infiltration, myeloperoxidase, liver injury, systemic inflammatory response, endotoxin
MeSH terms
Alanine Transaminase, Animals, Hemodynamics, Ischemia, Liver, Liver Diseases, Lung, Peroxidase, Neutrophils, Time Factors, Tumor Necrosis Factor-alpha, Reperfusion Injury, Rats

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