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Multiple organ damage caused by tumor necrosis factor and prevented by prior neutrophil depletion
A A Mallick1, A Ishizaka, K E Stephens
1Department of Medicine, Stanford University Medical Center, CA 94305-5236.
Abstract:
The effect of TNF on nonpulmonary multiple organ damage (MOD) was studied. Since polymorphonuclear leukocytes (PMN) are thought to play an important role in septic or TNF-induced MOD, we investigated both neutrophil sufficient (PMN+) and neutropenic (PMN-) guinea pigs. Sepsis was induced by Escherichia coli administration (2 x 10(9)/kg) or recombinant human TNF (1.4 x 10(6) U/kg) was infused into PMN+ and PMN- guinea pigs. During necropsy, the PMN+/TNF and PMN+/E coli animals exhibited marked damage in the adrenal glands, kidneys and liver as evidenced by hemorrhage, congestion, and PMN sequestration on histopathologic examination. There was also increased tissue albumin accumulation in the adrenal glands, kidneys, spleen, heart, and liver as demonstrated by 125I-labeled albumin determinations. In contrast, the PMN-/TNF group did not reveal histopathologic damage in any organ system and there was no abnormal organ accumulation of 125I-albumin. However, in PMN-/E coli animals, marked histopathologic damage in the adrenal glands and liver was evident. Furthermore, there were marked accumulations of 125I-albumin in the adrenals, heart, kidneys, liver, and spleen. Moreover, the PMN-/E coli guinea pigs had a much greater accumulation (p less than 0.01) of 125I-albumin in the kidneys than any other group including the PMN+/E coli group. Thus, nonpulmonary MOD in guinea pigs is caused by TNF administration and can be prevented by PMN depletion. However, while E coli administration also caused marked nonpulmonary MOD in neutrophil sufficient guinea pigs, equivalent or greater damage was produced in neutropenic animals. This suggests that while TNF-induced MOD may be primarily mediated by PMN, E coli-induced MOD seems to be mediated by more than PMN.
Insights
Tumor necrosis factor (TNF) causes nonpulmonary multiple organ damage (MOD), preventable by depleting polymorphonuclear leukocytes (PMN). Escherichia coli also causes MOD, but damage in neutropenic animals suggests mechanisms beyond PMN involvement.
Area of Science:
- Immunology
- Pathology
- Sepsis Research
Background:
- Polymorphonuclear leukocytes (PMN) are implicated in septic and TNF-induced multiple organ damage (MOD).
- Understanding the role of PMN in nonpulmonary MOD is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of TNF and Escherichia coli in causing nonpulmonary MOD.
- To determine the contribution of PMN to TNF- and E. coli-induced MOD in guinea pigs.
Main Methods:
- Comparison of organ damage and albumin accumulation in neutrophil-sufficient (PMN+) and neutropenic (PMN-) guinea pigs.
- Induction of sepsis using E. coli or administration of recombinant human TNF.
- Histopathological examination and 125I-labeled albumin determination for assessing tissue damage and vascular permeability.
Main Results:
- TNF administration caused significant organ damage (adrenals, kidneys, liver) and albumin accumulation in PMN+ guinea pigs, which was prevented in PMN- animals.
- E. coli administration induced MOD in PMN+ guinea pigs.
- In contrast, E. coli induced severe MOD and greater albumin accumulation in PMN- guinea pigs compared to PMN+ animals, particularly in the kidneys.
Conclusions:
- TNF-induced nonpulmonary MOD is primarily mediated by PMN and can be prevented by PMN depletion.
- E. coli-induced MOD involves mechanisms beyond PMN, as neutropenic animals exhibited significant damage, suggesting a complex interplay of factors.
- These findings differentiate the pathogenic mechanisms of TNF and E. coli in inducing nonpulmonary MOD.