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Neutrophil and nonneutrophil-mediated injury in intestinal ischemia-reperfusion
1Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Objective:
The role of polymorphonuclear neutrophils (PMN) was examined in local and remote organ injury after intestinal ischemia-reperfusion.
Summary Background Data:
PMN have been found to mediate the local injury in low flow intestinal ischemia-reperfusion. However, in complete intestinal ischemia-reperfusion, prevention of PMN adhesion by monoclonal antibodies to CD11b and CD18 reduces remote but not local intestinal injury. The role of PMN was further investigated in this setting.
Methods:
In a rat model of 1-hour complete intestinal ischemia and 4-hour reperfusion. PMN were manipulated in the following four ways: (1) inhibition of oxygen-free radicals using manganese superoxide dismutase and catalase (SOD/CAT), (2) antagonism of PMN elastase using secretory leukocyte protease inhibitor (SLPI), (3) neutropenia using PMN antisera, and (4) inhibition of activation and adhesion using interleukin-1 receptor antagonist (IL-1ra) and tumor necrosis factor binding protein (TNFbp). Lung injury was quantified by the pulmonary permeability index, which is the ratio of bronchoalveolar lavage to blood concentration of radiolabeled bovine serum albumin, and PMN sequestration by myeloperoxidase (MPO) activity. Liver injury was estimated by PMN counts using quantitative histologic examination and by serum glutamic pyruvic transaminase (SGPT). Local injury was quantified by MPO activity and histologic grading.
Results:
Neutropenia reduced the pulmonary permeability 80% from 11.0 +/- 0.5 x 10(-3) with saline treatment to 5.50 +/- 0.12 x 10(-3); IL-1ra, to 5.62 +/- 0.44 x 10(-3); and TNFbp, to 4.32 +/- 0.18 x 10(-3) (all p < 0.05). Pulmonary MPO rose from 0.03 +/- 0.01 U/g to 0.25 +/- 0.03 U/g (p < 0.05). This was reduced by neutropenia, 0.01 +/- 0.003 U/g, but not by inhibition of oxygen-free radicals or PMN elastase. IL-1ra inhibited PMN sequestration, reducing MPO to 0.12 +/- 0.01 (p < 0.05). Liver injury was 60% dependent on PMN. Ischemia-reperfusion increased SGPT from 20.3 +/- 0.7 IU/L in the sham-treated animals to 97.0 +/- 3.1 IU/L in the experimental animals. Neutropenia reduced this to 48.1 +/- 3.9 IU/L; IL-1ra, to 44.7 +/- 3.7 IU/L; SOD/CAT, to 64.0 +/- 3.38 IU/L; and SLPI, to 57.1 +/- 3.4 IU/L (p < 0.05 in all cases). Local injury was severe and unaffected by manipulation of the PMN.
Conclusions:
These data suggest that PMN and their products mediate most of the lung, part of the liver, and none of the local gut injury after intestinal ischemia-reperfusion.
Insights
Polymorphonuclear neutrophils (PMN) significantly contribute to lung and liver injury following intestinal ischemia-reperfusion. However, PMN do not appear to cause local gut injury in this model.
Area of Science:
- Gastroenterology
- Immunology
- Surgical Research
Background:
- Polymorphonuclear neutrophils (PMN) are implicated in local intestinal injury during low-flow ischemia-reperfusion.
- In complete intestinal ischemia-reperfusion, PMN adhesion blockade reduces remote organ injury but not local intestinal damage, necessitating further investigation into PMN's role.
Purpose of the Study:
- To investigate the specific role of polymorphonuclear neutrophils (PMN) in mediating local and remote organ injury following complete intestinal ischemia-reperfusion.
- To elucidate the mechanisms by which PMN contribute to injury in this experimental model.
Main Methods:
- A rat model of 1-hour complete intestinal ischemia followed by 4-hour reperfusion was utilized.
- PMN activity was manipulated through inhibition of oxygen-free radicals (SOD/CAT), antagonism of PMN elastase (SLPI), induction of neutropenia (PMN antisera), and blockade of activation/adhesion (IL-1ra, TNFbp).
- Lung injury was assessed via pulmonary permeability index and myeloperoxidase (MPO) activity; liver injury was evaluated by serum glutamic pyruvic transaminase (SGPT) and PMN counts; local gut injury was quantified by MPO activity and histologic grading.
Main Results:
- Neutropenia, IL-1ra, and TNFbp significantly reduced lung injury, indicated by decreased pulmonary permeability and MPO activity.
- PMN sequestration in the lungs was reduced by neutropenia and IL-1ra.
- Liver injury, measured by SGPT levels, was significantly reduced by neutropenia, IL-1ra, SOD/CAT, and SLPI, indicating a substantial PMN-dependent component.
- Local intestinal injury, assessed by MPO activity and histology, remained unaffected by any of the PMN-modulating interventions.
Conclusions:
- Polymorphonuclear neutrophils and their products are key mediators of lung injury following intestinal ischemia-reperfusion.
- PMN contribute significantly to liver injury in this model.
- Local intestinal injury after complete ischemia-reperfusion is not mediated by PMN.