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Role for tumor necrosis factor as mediator of lung injury following lower torso ischemia
R Welbourn1, G Goldman, M O'Riordain
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Abstract:
Ischemia and reperfusion of the ischemic lower torso lead to a neutrophil- (PMN) dependent lung injury characterized by PMN sequestration and permeability edema. This mimics the injury seen after infusion of tumor necrosis factor alpha (TNF), a potent activator of PMN and endothelium. This study tests whether TNF is a mediator of the lung injury after lower torso ischemia. Anesthetized rats underwent 4 h of bilateral hindlimb tourniquet ischemia, followed by reperfusion for 10 min, 30 min, 1, 2, 3, and 4 h (n = 6 for each time point). Quantitative lung histology indicated progressive sequestration of PMN in the lungs, 25 +/- 3 (SE) PMN/10 high-power fields (HPF) 10 min after reperfusion vs. 20 +/- 2 PMN/10 HPF in sham animals (NS), increasing to 53 +/- 5 PMN/10 HPF after 4 h vs. 23 +/- 3 PMN/10 HPF in sham animals (P less than 0.01). There was lung permeability, shown by increasing protein accumulation in bronchoalveolar lavage (BAL) fluid, which 4 h after reperfusion was 599 +/- 91 vs. 214 +/- 35 micrograms/ml in sham animals (P less than 0.01). Similarly, there was edema, shown by the lung wet-to-dry weight ratio, which increased by 4 h to 4.70 +/- 0.12 vs. 4.02 +/- 0.17 in sham animals (P less than 0.01). There was generation of leukotriene B4 in BAL fluid (720 +/- 140 vs. 240 +/- 40 pg/ml, P less than 0.01), and in three of six rats tested at this time TNF was detected in plasma, with a mean value of 167 pg/ml. TNF was not detectable in any sham animal.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Lower torso ischemia-reperfusion causes lung injury mediated by neutrophils (PMN). Tumor necrosis factor alpha (TNF) appears to be a key mediator in this process, contributing to PMN sequestration and lung damage.
Area of Science:
- Physiology
- Immunology
- Pathology
Background:
- Ischemia-reperfusion (I/R) injury in the lower torso leads to lung damage.
- This injury involves neutrophil (PMN) sequestration and increased lung vascular permeability.
- Tumor necrosis factor alpha (TNF) is known to activate PMNs and endothelium, mimicking I/R injury.
Purpose of the Study:
- To investigate if TNF is a mediator of lung injury following lower torso ischemia-reperfusion.
- To quantify PMN sequestration, lung permeability, and edema in a rat model of lower torso I/R.
Main Methods:
- Rats underwent 4 hours of hindlimb tourniquet ischemia followed by varying reperfusion times (10 min to 4 h).
- Quantitative lung histology assessed PMN sequestration.
- Bronchoalveolar lavage (BAL) fluid analyzed for protein accumulation (permeability) and leukotriene B4.
- Lung wet-to-dry weight ratio measured for edema.
- Plasma TNF levels were measured.
Main Results:
- Progressive PMN sequestration in lungs was observed, significantly increasing after 4 h of reperfusion compared to sham animals.
- Lung permeability, indicated by protein accumulation in BAL fluid, significantly increased post-reperfusion.
- Lung edema, measured by wet-to-dry weight ratio, was significantly elevated at 4 h.
- Leukotriene B4 generation increased in BAL fluid.
- TNF was detected in the plasma of some rats after 4 h of reperfusion, but not in sham animals.
Conclusions:
- Lower torso ischemia-reperfusion induces significant lung injury.
- The findings suggest TNF plays a role in mediating this lung injury.
- Further research is warranted to elucidate the precise mechanisms of TNF involvement.